1) The human genome is the genome of Homo sapiens, which is stored on 23 chromosome

pairs. 22 of these are autosomal chromosome pairs, while the remaining pair is sexdetermining. The haploid human genome occupies a total of just over 3 billion DNA base
pairs. The Human Genome Project (HGP) produced a reference sequence of the euchromatic
human genome, which is used worldwide in biomedical sciences.
The haploid human genome contains ca. 23,000 protein-coding genes, far fewer than had been
expected before its sequencing.[1][2] In fact, only about 1.5% of the genome codes for proteins,
while the rest consists of non-coding RNA genes, regulatory sequences, introns, and
(controversially named) "junk" DNA.[3] he Human Genome Organisation (HUGO) is an
organization involved in the Human Genome Project, a project about mapping the human
genome. HUGO was established in 1989 as an international organization, primarily to foster
collaboration between genome scientists around the world. The HUGO Gene Nomenclature
Committee (HGNC), sometimes referred to as "HUGO", is one of HUGO's most active
committees and aims to assign a unique gene name and symbol to each human gene.Human
genes are distributed unevenly across the chromosomes. Each chromosome contains various
gene-rich and gene-poor regions, which seem to be correlated with chromosome bands and
GC-content. The significance of these nonrandom patterns of gene density is not well
understood.[citation needed] In addition to protein coding genes, the human genome contains
thousands of RNA genes, including tRNA, ribosomal RNA, microRNA, and other non-coding
RNA genes.[citation
Regulatory sequences
The human genome has many different regulatory sequences which are crucial to controlling
gene expression. These are typically short sequences that appear near or within genes. A
systematic understanding of these regulatory sequences and how they together act as a gene
regulatory network is only beginning to emerge from computational, high-throughput
expression and comparative genomics studies. Some types of non-coding DNA are genetic
"switches" that do not encode proteins, but do regulate when and where genes are expressed.[5]
Other DNA
Protein-coding sequences (specifically, coding exons) comprise less than 1.5% of the human
genome.[3] Aside from genes and known regulatory sequences, the human genome contains
vast regions of DNA the function of which, if any, remains unknown. These regions in fact
comprise the vast majority, by some estimates 97%, of the human genome size. Much of this
is composed of:
Polymorphism[1] in biology occurs when two or more clearly different phenotypes exist in the
same population of a species in other words, the occurrence of more than one form or
morph. In order to be classified as such, morphs must occupy the same habitat at the same
time and belong to a panmictic population (one with random mating).[2]

Polymorphism is common in nature; it is related to biodiversity, genetic variation and

adaptation; it usually functions to retain variety of form in a population living in a varied
environment.[3]:126 The most common example is sexual dimorphism, which occurs in many
organisms. Other examples are mimetic forms of butterflies (see mimicry), and human
haemoglobin and blood types.
2) Gene expression is the process by which information from a gene is used in the synthesis
of a functional gene product. These products are often proteins, but in non-protein coding
genes such as rRNA genes or tRNA genes, the product is a functional RNA. The process of
gene expression is used by all known life - eukaryotes (including multicellular organisms),
prokaryotes (bacteria and archaea) and viruses - to generate the macromolecular machinery
for life. Several steps in the gene expression process may be modulated, including the
transcription, RNA splicing, translation, and post-translational modification of a protein. Gene
regulation gives the cell control over structure and function, and is the basis for cellular
differentiation, morphogenesis and the versatility and adaptability of any organism. Gene
regulation may also serve as a substrate for evolutionary change, since control of the timing,
location, and amount of gene expression can have a profound effect on the functions (actions)
of the gene in a cell or in a multicellular organism.
In genetics, gene expression is the most fundamental level at which genotype gives rise to the
phenotype. The genetic code is "interpreted" by gene expression, and the properties of the
expression products give rise to the organism's phenotype.
genetic code is the set of rules by which information encoded in genetic material (DNA or
mRNA sequences) is translated into proteins (amino acid sequences) by living cells. The code
defines a mapping between tri-nucleotide sequences, called codons, and amino acids. With
some exceptions,[1] a triplet codon in a nucleic acid sequence specifies a single amino acid.
Because the vast majority of genes are encoded with exactly the same code (see the RNA
codon table), this particular code is often referred to as the canonical or standard genetic code,
or simply the genetic code, though in fact there are many variant codes. For example, protein
synthesis in human mitochondria relies on a genetic code that differs from the standard
genetic code.
Amino acid synthesis
Amino acids are the monomers that are polymerized to produce proteins. Amino acid
synthesis is the set of biochemical processes (metabolic pathways) that build the amino acids
from carbon sources like glucose.
Many organisms have the ability to synthesize only a subset of the amino acids they need.
Adult humans, for example, need to obtain 10 of the 20 amino acids from their food.

Transcription
In transcription an mRNA chain is generated, with one strand of the DNA double helix
in the genome as template. This strand is called the template strand. Transcription can
be divided into 3 stages: Initiation, Elongation and Termination, each regulated by a
large number of proteins such as transcription factors and coactivators that ensure the
correct gene is transcribed.
The DNA strand is read in the 3' to 5' direction and the mRNA is transcribed in the 5' to 3'
direction by the RNA polymerase.
Transcription occurs in the cell nucleus, where the DNA is held. The DNA structure of the cell
is made up of two helixes made up of sugar and phosphate held together by the bases. The
sugar and the phosphate are joined together by covalent bond. The DNA is "unzipped" by the
enzyme helicase, leaving the single nucleotide chain open to be copied. RNA polymerase
reads the DNA strand from 3 prime (3') end to the 5 prime (5') end, while it synthesizes a
single strand of messenger RNA in the 5' to 3' direction. The general RNA structure is very
similar to the DNA structure, but in RNA the nucleotide uracil takes the place that thymine
occupies in DNA. The single strand of mRNA leaves the nucleus through nuclear pores, and
migrates into the cytoplasm.
The first product of transcription differs in prokaryotic cells from that of eukaryotic cells, as
in prokaryotic cells the product is mRNA, which needs no post-transcriptional modification,
while in eukaryotic cells, the first product is called primary transcript, that needs posttranscriptional modification (capping with 7 methyl guanosine, tailing with a poly A tail) to
give hnRNA (heterophil nuclear RNA). hnRNA then undergoes splicing of introns (non
coding parts of the gene) via spliceosomes to produce the final mRNA.
Translation
The synthesis of proteins is known as translation. Translation occurs in the cytoplasm,
where the ribosomes are located. Ribosomes are made of a small and large subunit that
surround the mRNA. In translation, messenger RNA (mRNA) is decoded to produce a
specific polypeptide according to the rules specified by the trinucleotide genetic code.
This uses an mRNA sequence as a template to guide the synthesis of a chain of amino
acids that form a protein. Translation proceeds in four phases: activation, initiation,
elongation, and termination (all describing the growth of the amino acid chain, or
polypeptide that is the product of translation).
In activation, the correct amino acid (AA) is joined to the correct transfer RNA (tRNA).
While this is not technically a step in translation, it is required for translation to proceed. The
AA is joined by its carboxyl group to the 3' OH of the tRNA by an ester bond. When the
tRNA has an amino acid linked to it, it is termed "charged". Initiation involves the small
subunit of the ribosome binding to 5' end of mRNA with the help of initiation factors (IF),
other proteins that assist the process. Elongation occurs when the next aminoacyl-tRNA
(charged tRNA) in line binds to the ribosome along with GTP and an elongation factor.
Termination of the polypeptide happens when the A site of the ribosome faces a stop codon

(UAA, UAG, or UGA). When this happens, no tRNA can recognize it, but releasing factor
can recognize nonsense codons and causes the release of the polypeptide chain. The capacity
of disabling or inhibiting translation in protein biosynthesis is used by antibiotics such as:
anisomycin, cycloheximide, chloramphenicol, tetracycline, streptomycin, erythromycin,
puromycin etc.
Translation is the process of converting the mRNA codon sequences into an amino acid
polypeptide chain.
1.Amino acid activation
2.Initiation - A ribosome attaches to the mRNA and starts to code at the FMet codon (usually
AUG, sometimes GUG or UUG).
3.Elongation - tRNA brings the corresponding amino acid (which has an anticodon that
identifies the amino acid as the corresponding molecule to a codon) to each codon as the
ribosome moves down the mRNA strand.
4.Termination - Reading of the final mRNA codon (aka the STOP codon), which ends the
synthesis of the peptide chain and releases it.
Regulation of gene expression
The patchy colours of a tortoiseshell cat are the result of different levels of expression of
pigmentation genes in different areas of the skin.
Regulation of gene expression refers to the control of the amount and timing of appearance of
the functional product of a gene. Control of expression is vital to allow a cell to produce the
gene products it needs when it needs them; in turn this gives cells the flexibility to adapt to a
variable environment, external signals, damage to the cell, etc. Some simple examples of
where gene expression is important are:

Control of Insulin expression so it gives a signal for blood glucose regulation

X chromosome inactivation in female mammals to prevent an "overdose" of the genes

it contains.

Cyclin expression levels control progression through the eukaryotic cell cycle

Any step of gene expression may be modulated, from the DNA-RNA transcription step to
post-translational modification of a protein. The stability of the final gene product, whether it
is RNA or protein, also contributes to the expression level of the gene - an unstable product
results in a low expression level. In general gene expression is regulated through changes[17] in
the number and type of interactions between molecules[18] that collectively influence
transcription of DNA[19] and translation of RNA.[20]

Numerous terms are used to describe types of genes depending on how they are regulated,
these include:

A constitutive gene is a gene that is transcribed continually compared to a facultative

gene which is only transcribed when needed.

A housekeeping gene is typically a constitutive gene that is transcribed at a relatively

constant level. The housekeeping gene's products are typically needed for maintenance
of the cell. It is generally assumed that their expression is unaffected by experimental
conditions. Examples include actin, GAPDH and ubiquitin.

A facultative gene is a gene which is only transcribed when needed compared to a

constitutive gene.

An inducible gene is a gene whose expression is either responsive to environmental

change or dependent on the position in the cell

3) A chromosome is an organized structure of DNA and protein that is found in cells. It is a

single piece of coiled DNA containing many genes, regulatory elements and other nucleotide
sequences. Chromosomes also contain DNA-bound proteins, which serve to package the
DNA and control its functions. The word chromosome comes from the Greek
(chroma, colour) and (soma, body) due to their property of being very strongly stained
by particular dyes.
Chromosomes vary widely between different organisms. The DNA molecule may be circular
or linear, and can be composed of 10,000 to 1,000,000,000[1] nucleotides in a long chain.
Typically eukaryotic cells (cells with nuclei) have large linear chromosomes and prokaryotic
cells (cells without defined nuclei) have smaller circular chromosomes, although there are
many exceptions to this rule. Furthermore, cells may contain more than one type of
chromosome; for example, mitochondria in most eukaryotes and chloroplasts in plants have
their own small chromosomes.
In eukaryotes, nuclear chromosomes are packaged by proteins into a condensed structure
called chromatin. This allows the very long DNA molecules to fit into the cell nucleus. The
structure of chromosomes and chromatin varies through the cell cycle. Chromosomes are the
essential unit for cellular division and must be replicated, divided, and passed successfully to
their daughter cells so as to ensure the genetic diversity and survival of their progeny.
Chromosomes may exist as either duplicated or unduplicatedunduplicated chromosomes
are single linear strands, whereas duplicated chromosomes (copied during synthesis phase)
contain two copies joined by a
In practice "chromosome" is a rather loosely defined term. In prokaryotes and viruses, the
term genophore is more appropriate when no chromatin is present. However, a large body of
work uses the term chromosome regardless of chromatin content. In prokaryotes DNA is
usually arranged as a circle, which is tightly coiled in on itself, sometimes accompanied by
one or more smaller, circular DNA molecules called plasmids. These small circular genomes
are also found in mitochondria and chloroplasts, reflecting their bacterial origins. The

simplest genophores are found in viruses: these DNA or RNA molecules are short linear or
circular genophores that often lack structural proteins.
Mitochondrial DNA (mtDNA) is the DNA located in organelles called mitochondria,
structures within eukaryotic cells that convert the chemical energy from food into a form that
cells can use, ATP. Most other DNA present in eukaryotic organisms is found in the cell
nucleus.
mtDNA is replicated by the DNA polymerase gamma complex which is composed of a 140
kDa catalytic DNA polymerase encoded by the POLG gene and a 55 kDa accessory subunit
encoded by the POLG2 gene. During embryogenesis, replication of mtDNA is strictly downregulated from the fertilized oocyte through the preimplantation embryo.[2] At the blastocyst
stage, the onset of mtDNA replication is specific to the cells of the trophectoderm.[2] In
contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the
signals to differentiate to specific cell types.[2]
Structure
In humans (and probably in metazoans in general), 100-10,000 separate copies of
mtDNA are usually present per cell (egg and sperm cells are exceptions). In mammals,
each double-stranded circular mtDNA molecule consists of 15,000-17,000 base pairs. The
two strands of mtDNA are differentiated by their nucleotide content with the guanine
rich strand referred to as the heavy strand, and the cytosine rich strand referred to as
the light strand. The heavy strand encodes 28 genes, and the light strand encodes 9 genes
for a total of 37 genes. Of the 37 genes, 13 are for proteins (polypeptides), 22 are for
transfer RNA (tRNA) and two are for the small and large subunits of ribosomal RNA
(rRNA).
4) KARYOTYPE:
The number size and shape of the chromosomes of a somatic cell arranged in a standard
manner.

position of centromere - arm length ratio

secondary constrictions (nucleolar organisers)

The normal human karyotype has 46 chromosomes

23 derived from each parent

sex is determined by X and y chromosomes

Males are XY

Females are XX

The sex of an offspring is determined by the sex chromosome carried in the

sperm

Chromosomes are described with the following categories:

Metacentric:

centromere is median or near median

chromosome has two well defined arms with a length ratio varying from 1:1 to 2.5:1

Acrocentric:

centromere is close to one end of the chromosome

one arm is substantially smaller than the other and the arm ratio ranges from 3:1 to
10:1

Telocentric:

centromere is a strictly terminal entity and the chromosome is one armed

Chromosomes are always arranged with the short arm on top

Short arm is labeled P (French for petit)

Long arm is labeled Q

Standard nomenclature been developed for human chromosomes:

Paris nomenclature 1978

Total number of chromosomes

Sex chromosome constitution

Description of abnormality i.e. 46,XX normal female 46,Y male

Human chromosomes are divided into 7 groups & sex chromosomes

A 1-3 Large metacentric 1,2 or submetacentric

B 4,5 Large submetacentric, all similar

C 6-12, X Medium sized, submetacentric - difficult

D 13-15 medium-sized acrocentric plus satellites

E 16-18 short metacentric 16 or submetacentric 17,18

F 19-20 Short metacentrics

Human Karyotype 46 Chromosomes

There are 23 pairs of chromosomes in the nuclei of most human cells. Chromosome pairs 1
22 are called autosomes, and the remaining pair are the sex chromosomes. There are two
types of sex chromosome, X and Y. Females typically have two Xs, males an X and a Y.
Ploidy is a term that refers to the number of chromosome sets. Where there are two sets of
chromosomes, as is the case with humans, the term used to describe such cells is diploid.
Cells with three sets would be called triploid, four sets tetraploid, and so on.
Abnormal Karyotypes in Humans
Health and development can be affected by issues with chromosome number and structure.
Chromosomal abnormalities are distinct from those genetic disorders caused by mutations.
For example, the signs of Down syndrome are a result of extra chromosome 21 genes, not a
mutation.
Aneuploidy is the term used to describe an abnormality in chromosome number. In humans,
types of aneuploidy include:
Read on

Klinefelter Syndrome Basic Genetics

Turner Syndrome Basic Genetics

Human Chromosomes and the Genes They Carry

Monosomy. This refers to one chromosome being present, and one missing. For
example, females with Turner syndrome may have one X chromosome instead of two.

Disomy. This refers to the presence of two chromosomes, and is typical in humans.

Trisomy. This refers to the presence of three chromosomes. For example, people with
Down syndrome have a partial or extra chromosome 21.

Tetrasomy. This refers to the presence of four chromosomes. For example, females
with XXXX syndrome have four X chromosomes instead of two.

Nullisomy. This is where both chromosomes of a pair are missing.

Human zygotes can sometimes receive extra sets of chromosomes. This means the cells are no
longer diploid, and the result is usually miscarriage. One cause of this is polyspermy, where
an egg is fertilized by more than one sperm.

Heteromorphism: Something different in form. Chromosome heteromorphisms are normal

variations in the
appearance of chromosomes.
heteromorphism
1. the quality of differing in form from the standard or norm.
2. the condition of existing in different forms at different stages of development, as certain
insects.
5) Monogenic diseases result from modifications in a single gene occurring in all cells of the
body. Though relatively rare, they affect millions of people worldwide. Scientists currently
estimate that over 10,000 of human diseases are known to be monogenic. Pure genetic
diseases are caused by a single error in a single gene in the human DNA. The nature of
disease depends on the functions performed by the modified gene. The single-gene or
monogenic diseases can be classified into three main categories:

Dominant

Recessive

X-linked

All human beings have two sets or copies of each gene called allele; one copy on each side
of the chromosome pair. Recessive diseases are monogenic disorders that occur due to
damages in both copies or allele. Dominant diseases are monogenic disorders that involve
damage to only one gene copy. X linked diseases are monogenic disorders that are linked to
defective genes on the X chromosome which is the sex chromosome. The X linked alleles can
also be dominant or recessive. These alleles are expressed equally in men and women, more
so in men as they carry only one copy of X chromosome (XY) whereas women carry two
(XX).
Monogenic diseases are responsible for a heavy loss of life. The global prevalence of all
single gene diseases at birth is approximately 10/1000. In Canada, it has been estimated that
taken together, monogenic diseases may account for upto 40% of the work of hospital based
paediatric practice (Scriver, 1995).
Thalassaemia
Sickle cell anemia
Haemophilia
Cystic Fibrosis
Tay sachs disease
Fragile X syndrome
Huntington's disease

How Do Mutations Occur?

Everyone acquires some changes to their DNA during the course of their lives. These
changes occur in a number of ways. Sometimes there are simple copying errors that are
introduced when DNA replicates itself. (Every time a cell divides, all of its DNA is duplicated
so that the each of the two resulting cells have a full set of DNA.) Other changes are
introduced as a result of DNA damage through environmental agents including sunlight,
cigarette smoke, and radiation. Our cells have built in mechanisms that catch and repair most
of the changes that occur during DNA replication or from environmental damage. As we age,
however, our DNA repair does not work as effectively and we accumulate changes in our
DNA.
Some of these changes occur in cells of the body such as in skin cells as a result of sun
exposure but are not passed on to children. But other errors can occur in the DNA of cells
that produce the eggs and sperm. These are called germline mutations and can be passed from
parent to child. If a child inherits a germline mutation from their parents, every cell in their
body will have this error in their DNA. Germline mutations are what cause diseases to run in
families, and are responsible for the kind of hereditary diseases covered by Genetic Health. A
gene is essentially a sentence made up of the bases A, T, G, and C that describes how to make
a protein. Any changes to those instructions can alter the gene's meaning and change the
protein that is made, or how or when a cell makes that protein. There are many different ways
to alter a gene, just as there are many different ways to introduce typos into a sentence. In the
following examples of some types of mutations, we use the sentence "The fat cat ate the wee
rat" as a sample gene:

6) Chromosomal aberrations
Chromosomal aberrations are disruptions in the normal chromosomal content of a cell, and
are a major cause of genetic conditions in humans, such as Down syndrome. Some
chromosome abnormalities do not cause disease in carriers, such as translocations, or
chromosomal inversions, although they may lead to a higher chance of birthing a child with a
chromosome disorder. Abnormal numbers of chromosomes or chromosome sets, aneuploidy,
may be lethal or give rise to genetic disorders. Genetic counseling is offered for families that
may carry a chromosome rearrangement.
The gain or loss of DNA from chromosomes can lead to a variety of genetic disorders. Human
examples include:

Cri du chat, which is caused by the deletion of part of the short arm of chromosome 5.
"Cri du chat" means "cry of the cat" in French, and the condition was so-named
because affected babies make high-pitched cries that sound like those of a cat.
Affected individuals have wide-set eyes, a small head and jaw, moderate to severe
mental health issues, and are very short.

Down syndrome, usually is caused by an extra copy of chromosome 21 (trisomy 21).

Characteristics include decreased muscle tone, stockier build, asymmetrical skull,
slanting eyes and mild to moderate developmental disability.[46]

Edwards syndrome, which is the second-most-common trisomy; Down syndrome is

the most common. It is a trisomy of chromosome 18. Symptoms include motor
retardation, developmental disability and numerous congenital anomalies causing
serious health problems. Ninety percent die in infancy; however, those that live past
their first birthday usually are quite healthy thereafter. They have a characteristic
clenched hands and overlapping fingers.

Idic15, abbreviation for Isodicentric 15 on chromosome 15; also called the following
names due to various researches, but they all mean the same; IDIC(15), Inverted
duplication 15, extra Marker, Inv dup 15, partial tetrasomy 15

Jacobsen syndrome, also called the terminal 11q deletion disorder.[47] This is a very
rare disorder. Those affected have normal intelligence or mild developmental
disability, with poor expressive language skills. Most have a bleeding disorder called
Paris-Trousseau syndrome.

Klinefelter's syndrome (XXY). Men with Klinefelter syndrome are usually sterile, and
tend to have longer arms and legs and to be taller than their peers. Boys with the
syndrome are often shy and quiet, and have a higher incidence of speech delay and
dyslexia. During puberty, without testosterone treatment, some of them may develop
gynecomastia.

Patau Syndrome, also called D-Syndrome or trisomy-13. Symptoms are somewhat

similar to those of trisomy-18, but they do not have the characteristic hand shape.

Small supernumerary marker chromosome. This means there is an extra, abnormal

chromosome. Features depend on the origin of the extra genetic material. Cat-eye
syndrome and isodicentric chromosome 15 syndrome (or Idic15) are both caused by a
supernumerary marker chromosome, as is Pallister-Killian syndrome.

Triple-X syndrome (XXX). XXX girls tend to be tall and thin. They have a higher
incidence of dyslexia.

Turner syndrome (X instead of XX or XY). In Turner syndrome, female sexual

characteristics are present but underdeveloped. People with Turner syndrome often
have a short stature, low hairline, abnormal eye features and bone development and a
"caved-in" appearance to the chest.

XYY syndrome. XYY boys are usually taller than their siblings. Like XXY boys and
XXX girls, they are somewhat more likely to have learning difficulties.

Wolf-Hirschhorn syndrome, which is caused by partial deletion of the short arm of

chromosome 4. It is characterized by severe growth retardation and severe to profound
mental health issues.

Chromosomal mutations produce changes in whole chromosomes (more than one gene) or in
the number of chromosomes present.

Deletion loss of part of a chromosome

Duplication extra copies of a part of a chromosome

Inversion reverse the direction of a part of a chromosome

Translocation part of a chromosome breaks off and attaches to another chromosome

Most mutations are neutral have little or no effect. Chromosomal aberrations are the
changes in the structure of chromosomes. It has a great role in evolution. A detailed graphical
display of all human chromosomes and the diseases annotated at the correct spot may be
found at the Oak Ridge National Laboratory.[48
7) The cell cycle, or cell-division cycle, is the series of events that takes place in a cell
leading to its division and duplication (replication). In cells without a nucleus (prokaryotic),
the cell cycle occurs via a process termed binary fission. In cells with a nucleus (eukaryotes),
the cell cycle can be divided in two brief periods: interphaseduring which the cell grows,
accumulating nutrients needed for mitosis and duplicating its DNAand the mitosis (M)
phase, during which the cell splits itself into two distinct cells, often called "daughter cells".
The cell-division cycle is a vital process by which a single-celled fertilized egg develops into
a mature organism, as well as the process by which hair, skin, blood cells, and some internal
organs are renewed.
Apoptosis (pronounced /ptoss/ or /pptoss/)[1][2] is the process of programmed
cell death (PCD) that may occur in multicellular organisms. Biochemical events lead to
characteristic cell changes (morphology) and death. These changes include blebbing, loss of
cell membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin
condensation, and chromosomal DNA fragmentation. (See also Apoptosis DNA
fragmentation.) Apoptosis differs from necrosis, in which the cellular debris can damage the
organism.
In contrast to necrosis, which is a form of traumatic cell death that results from acute cellular
injury, apoptosis, in general, confers advantages during an organism's life cycle. For example,
the differentiation of fingers and toes in a developing human embryo occurs because cells
between the fingers apoptose; the result is that the digits are separate. Between 50 and 70
billion cells die each day due to apoptosis in the average human adult.[medical citation needed] For an
average child between the ages of 8 and 14, approximately 20 billion to 30 billion cells die a
day.[medical citation needed]
Research in and around apoptosis has increased substantially since the early 1990s. In
addition to its importance as a biological phenomenon, defective apoptotic processes have
been implicated in an extensive variety of diseases. Excessive apoptosis causes atrophy, such

as in ischemic damage, whereas an insufficient amount results in uncontrolled cell prolifeA

growth factor is a naturally occurring substance capable of stimulating cellular growth,[1]
proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth
factors are important for regulating a variety of cellular processes.
Growth factors typically act as signaling molecules between cells. Examples are cytokines
and hormones that bind to specific receptors on the surface of their target cells.

They often promote cell differentiation and maturation, which varies between growth
factors. For example, bone morphogenic proteins stimulate bone cell differentiation,
while fibroblast growth factors and vascular endothelial growth factors stimulate
blood vessel differentiation (angiogenesis).ration, such as cancer. Growth factor is
sometimes used interchangeably among scientists with the term cytokine. Historically,
cytokines were associated with hematopoietic (blood forming) cells and immune
system cells (e.g., lymphocytes and tissue cells from spleen, thymus, and lymph
nodes). For the circulatory system and bone marrow in which cells can occur in a
liquid suspension and not bound up in solid tissue, it makes sense for them to
communicate by soluble, circulating protein molecules. However, as different lines of
research converged, it became clear that some of the same signaling proteins the
hematopoietic and immune systems used were also being used by all sorts of other
cells and tissues, during development and in the mature organism. Adrenomedullin
(AM)

Autocrine motility factor

Bone morphogenetic proteins (BMPs)

Epidermal growth factor (EGF)

Erythropoietin (EPO)

Fibroblast growth factor (FGF)

Granulocyte-colony stimulating factor (G-CSF)

Granulocyte-macrophage colony stimulating factor (GM-CSF)

Growth differentiation factor-9 (GDF9)

In biology, signal transduction is a mechanism that converts a mechanical/chemical

stimulus to a cell into a specific cellular response.[1] Signal transduction starts with a
signal to a receptor, and ends with a change in cell function.

Transmembrane receptors span the cell membrane, with part of the receptor outside
and part inside the cell. The chemical signal binds to the outer portion of the receptor,
changing its shape and conveying another signal inside the cell. Some chemical

messengers, such as testosterone, can pass through the cell membrane, and bind
directly to receptors in the cytoplasm or nucleus.

Sometimes there is a cascade of signals within the cell. With each step of the cascade,
the signal can be amplified, so a small signal can result in a large response.[1]
Eventually, the signal creates a change in the cell, either in the expression of the DNA
in the nucleus or in the activity of enzymes in the cytoplasm.

These processes can take milliseconds (for ion flux), minutes (for protein- and lipidmediated kinase cascades), hours, or days (for gene expression).

In molecular biology and genetics, a transcription factor (sometimes called a

sequence-specific DNA-binding factor) is a protein that binds to specific DNA
sequences, thereby controlling the movement (or transcription) of genetic information
from DNA to mRNA.[1][2] Transcription factors perform this function alone or with
other proteins in a complex, by promoting (as an activator), or blocking (as a
repressor) the recruitment of RNA polymerase (the enzyme that performs the
transcription of genetic information from DNA to RNA) to specific genes.[3][4][5]

A defining feature of transcription factors is that they contain one or more DNAbinding domains (DBDs), which attach to specific sequences of DNA adjacent to the
genes that they regulate.[6][7] Additional proteins such as coactivators, chromatin
remodelers, histone acetylases, deacetylases, kinases, and methylases, while also
playing crucial roles in gene regulation, lack DNA-binding domains, and, therefore,
are not classified as transcription factors.[8]

8) Proto-oncogene
A proto-oncogene is a normal gene that can become an oncogene due to mutations or
increased expression. The resultant protein may be termed an oncoprotein.[6] Proto-oncogenes
code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are
often involved in signal transduction and execution of mitogenic signals, usually through their
protein products. Upon activation, a proto-oncogene (or its product) becomes a tumorinducing agent, an oncogene.[7] Examples of proto-oncogenes include RAS, WNT, MYC,
ERK, and TRK.
Activation
The proto-oncogene can become an oncogene by a relatively small modification of its original
function. There are three basic activation types:

A mutation within a proto-oncogene can cause a change in the protein structure,

causing
o an increase in protein (enzyme) activity

o a loss of regulation

An increase in protein concentration, caused by

o an increase of protein expression (through misregulation)
o an increase of protein (mRNA) stability, prolonging its existence and thus its
activity in the cell
o a gene duplication (one type of chromosome abnormality), resulting in an
increased amount of protein in the cell

A chromosomal translocation (another type of chromosome abnormality), causing

o an increased gene expression in the wrong cell type or at wrong times
o the expression of a constitutively active hybrid protein. This type of aberration
in a dividing stem cell in the bone marrow leads to adult leukemia

The expression of oncogenes can be regulated by microRNAs (miRNAs), small RNAs 21-25
nucleotides in length that control gene expression by downregulating them.[8] Mutations in
such microRNAs (known as oncomirs) can lead to activation of oncogenes.[9] Antisense
messenger RNAs could theoretically be used to block the effects of oncogenes.
Category
Growth factors, or mitogens
Receptor tyrosine kinases
Cytoplasmic tyrosine kinases
Cytoplasmic Serine/threonine
kinases and their regulatory
subunits
Regulatory GTPases
Transcription factors

Examples
c-Sis
epidermal growth factor receptor (EGFR), platelet-derived
growth factor receptor (PDGFR), and vascular endothelial
growth factor receptor (VEGFR), HER2/neu
Src-family, Syk-ZAP-70 family, and BTK family of tyrosine
kinases, the Abl gene in CML - Philadelphia chromosome
Raf kinase, and cyclin-dependent kinases (through
overexpression).
Ras protein
myc gene

9) A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on
the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the
cell can progress to cancer, usually in combination with other genetic changes.

Functions
Tumor-suppressor genes, or more precisely, the proteins for which they code, either have a
dampening or repressive effect on the regulation of the cell cycle or promote apoptosis, and
sometimes do both. The functions of tumor-suppressor proteins fall into several categories
including the following:[4]
1. Repression of genes that are essential for the continuing of the cell cycle. If these
genes are not expressed, the cell cycle does not continue, effectively inhibiting cell
division.
2. Coupling the cell cycle to DNA damage. As long as there is damaged DNA in the cell,
it should not divide. If the damage can be repaired, the cell cycle can continue.
3. If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell
death) to remove the threat it poses for the greater good of the organism.
4. Some proteins involved in cell adhesion prevent tumor cells from dispersing, block
loss of contact inhibition, and inhibit metastasis. These proteins are known as
metastasis suppressors.[5][6]
5. DNA repair proteins are usually classified as tumor suppressors as well, as mutations
in such their genes increase the risk of cancer, for example mutations in HNPCC,
MEN1 and BRCA. Furthermore, increased mutation rate from decreased DNA repair
leads to increased inactivation of other tumor suppressors and activation of oncogenes.
[7]

Examples
The first tumor-suppressor protein discovered was the Retinoblastoma protein (pRb) in human
retinoblastoma; however, recent evidence has also implicated pRb as a tumor-survival factor.
Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53
gene. Homozygous loss of p53 is found in 70% of colon cancers, 3050% of breast cancers,
and 50% of lung cancers. Mutated p53 is also involved in the pathophysiology of leukemias,
lymphomas, sarcomas, and neurogenic tumors. Abnormalities of the p53 gene can be inherited
in Li-Fraumeni syndrome (LFS), which increases the risk of developing various types of
cancers.
PTEN acts by opposing the action of PI3K, which is essential for anti-apoptotic, protumorogenic Akt activation.
Other examples of tumor suppressors include APC, CD95, ST5, ST7, and ST14.
10) Inheritance of Autosomoal Dominant Genetic Diseases
A genetic trait is often said to be dominant or recessive. A dominant trait is more likely to
cause disease, because only one of the two copies of each gene needs to be damaged. In
dominant genetic diseases, the "bad" gene overcomes the "good" gene and disease occurs,

whereas in recessive diseases the good gene is an adequate backup and recessive diseases do
not occur unless both copies are damaged. But it is not always so black and white. One gene
does not always win or lose, and there is a whole spectrum of levels of dominance, depending
on how much damage a bad gene does and how adequately the second good gene can
compensate for the failing bad gene. Generally speaking, a dominant disease affects a gene for
a structural protein, causing malformed proteins that cause disease even though the other half
of the produced proteins are correct. For comparison, recessive genes often affect genes
producing hormones or enzymes, because the backup good gene can often still produce
adequate quantities of the hormone, and only if both are wrong is there a disease.
Inheritance patterns for autosomal dominance: This refers to diseases where the error is in
one of the autosome chromosomes, and the bad gene dominates. Some features of autosomal
dominant genetic diseases are:

No carriers: Everyone who has the genetic error gets the disease, because the bad
gene is dominant. There is no such thing as a carrier for a dominant disease. A few
dominant genetic diseases like Huntington's disease only cause symptoms later in life,
so that people cannot know that they have the disease in early life, but this is not the
same as being a carrier: these people actually have the disease.

Usually inherited: For a person to have the disease, one of the parents must have had
the disease. A child with the disease cannot be born to parents without the disease,
except very rarely due to random genetic mutations.

Parent-to-child transmission: Usually 50%. For one parent with disease, there is
usually a 50% chance of passing the disease onto children. Male and female children
are equally at risk.

Both affected parents to child transmission: Usually 75% chance. If both parents
have the disease, they each have one bad gene and one good gene. The child has a
75% chance of disease (50% chance of dominant disease, 25% chance of doubledominance) and 25% chance of being disease-free (and also not being a carrier as
there are no carriers for dominant diseases).

Double-dominant parent to child transmission: usually 100%. If one parent has

double-dominant disease (see discussion of double dominance below), even if the
other parent is not affected, the chance is 100% chance of having children with the
disease. Males and female children have the same chance.

Undiseased parents to child transmission: People without the disease cannot give
the disease to children, because they do not have a bad gene. There are no carriers for
dominant genetic diseases so it is unlikely to be affected without knowing it (though
some dominant genetic diseases like Huntington's disease only cause symptoms later
in life). If neither parent has the genetic disease, the risk for a child is almost nil.
Extremely rarely, a random genetic mutation may give rise to the disease, which is

presumably how the diseases occurred in the first place through the history of the
human race.

Other children: If a couple has a child with this dominant disease, what are the odds
for another child. Usually a child getting the disease means that one of the parents
have the disease.

Vertical inheritance: Every generation is affected, called a "vertical" pattern, as seen

on a family tree. By comparison, recessive diseases tend to have a horizontal pattern
with alternating generations affected.

Gender bias: Male or females get the disease equally, because an autosomal error is
unrelated to the sex chromosomes.

Autosomal dominant inheritance

Affected individuals have one copy of the altered gene. An alteration in only one gene is
sufficient to cause the disorder.
(Often these genes produce structural proteins or proteins where co-operation between
molecules is important.)
Examples:
o Neurofibromatosis
o Marfan syndrome
o Tuberous sclerosis
o Familial Breast and Ovarian cancer susceptibility (BRCA1 and BRCA2)
o Familial Hypercholesterolaemia
Key Features:
o Males and females equally affected
o The disorder is not typically transmitted by unaffected family members
o Vertical pattern of inheritance with affected individuals in multiple
generations.

Offspring risk: There is a 50% risk that each offspring of an affected individual
receives the altered gene from their affected parent and is affected with the disorder.

Additional factors in autosomal dominant inheritance

There are a number of factors that can make Autosomal Dominant conditions less
straightforward. These include:
o Late-onset. Some autosomal dominant disorders may have late or variable age
of onset of symptoms (e.g. Huntington disease). Hence, the status of his parent
may not yet be known when a young adult is making reproductive decisions.
o Variable expressivity. The severity of the disorder may vary between
different affected members of the same family. Autosomal dominant disorders
may also demonstrate pleiotropy, that is cause a variety of manifestations in
different organs and systems (e.g. Tuberous sclerosis, which affects skin, CNS
and kidneys). Hence different family members affected with the same disorder
may exhibit different manifestations.
o Variable penetrance. Some of the individuals who inherit the altered gene do
not develop the disorder this is called non-penetrance. This may lead to false
reassurance regarding offspring risk.
o New mutations. In affected individuals for whom there is no history of the
disorder, the disorder may have arisen due to a new mutation in one of the
gametes that went on to form that individual. In some disorders, the proportion
of cases resulting from new mutations is substantial, e.g. Achondroplasia
(80%), Neurofibromatosis (50%), Marfan disease (25%).
o Anticipation. In some disorders inherited in an autosomal dominant manner,
the alteration in the gene is due to a gene expansion. This expansion may be
unstable, expand further on transmission and can cause more severe symptoms
in offspring than in parents. Examples include:

Myotonic dystrophy

Fragile X syndrome

11) Autosomal recessive inheritance

Affected individuals have two copies of the altered gene; those who carry one copy are
usually unaffected carriers.
(Autosomal recessive disorders include many inborn errors of metabolism, due to altered
genes in pathways where a single functioning gene is sufficient for the pathway to function.)
Examples:
o Cystic Fibrosis
o Tay-Sachs disease
o Spinal Muscular Atrophy
Key Features:
o Males and females equally affected

o The disorder is usually transmitted by two unaffected carrier parents; hence

typically there is often no family history.
o Horizontal pattern of inheritance. Typically the disease only manifests
within a single group of brothers and sisters (or in consanguineous families,
cousins).
Offspring risk:
o There is a 25% risk that each offspring of two carrier parents receives the
altered gene from each of their carrier parents and is thus affected with the
disorder. If the offspring proves to be unaffected, there is a 2/3 likelihood that
they will be a carrier.
o The offspring of an affected individual and a non-carrier will be all be
unaffected, if one can be certain that the partner is a non-carrier. However,
carrier testing may not always be able to determine for certain that a person is a
non-carrier. The risk increases if there is a high carrier frequency of the
disorder within the population or the affected individual chooses a
consanguineous partner.
Additional factors in autosomal recessive inheritance
o Onset, expressivity and penetrance. Most autosomal recessive disorders are
early onset, fully penetrant and show little clinical variability between family
members (they breed true). However, variations can occur between families
in the severity of a disorder (e.g. Cystic Fibrosis). The causes of this
variability are not fully understood.
o New mutations. New mutations are rare in autosomal recessive disorders.
o Consanguinity. In a consanguineous partnership (e.g. a cousin marriage), there
is a higher likelihood of both individuals carrying the same altered gene,
inherited from a common ancestor (e.g. a shared grandparent).
o Ethnicity. The carrier frequency of particular autosomal recessive disorders
varies significantly between different ethnic groups. This has implications for
population screening programmes and for carrier testing partners of known
carriers.
o Heterogeneity. Some autosomal recessive disorders may arise due to
alterations in a number of different genes (e.g. sensorineural hearing loss,
retinitis pigmentosa). The offspring of two affected individuals would all be
unaffected if the parents conditions are due to recessive mutations in different
genes.

Some examples of autosomal recessive diseases are Cystic Fibrosis, Phenylketonuria,

Sickle Cell Anemia, Tay Sachs, Albinism, and galactosemia. See autosomal recessive
diseases for a full list.

Recessive diseases often occur in genes that produce an enzyme. In a carrier, who has
only one bad copy, there is often no disease, because the second gene can pull up the
slack, and maintain health. In some recessive diseases, a carrier gets a mild form of the
disease.

Autosomal recessive diseases are relatively rare, because to get the disease a person
must inherit a bad gene from each parent, not just one. So both parents must have a
bad gene. However, parents can be carriers without the disease, since they typically
only have one bad gene themselves.

12) The inheritance of a trait (phenotype) that is determined by a gene located on one of the
sex chromosomes. Genetic studies of many species have been facilitated by focusing on such
traits because of their characteristic patterns of familial transmission and the ability to localize
their genes to a specific chromosome. As the ability to map a gene to any of an organisms
chromosomes has improved markedly, reliance on the specific pattern of inheritance has
waned.
The expectations of sex-linked inheritance in any species depend on how the chromosomes
determine sex. For example, in humans, males are heterogametic, having one X chromosome
and one Y chromosome, whereas females are homogametic, having two X chromosomes. In
human males, the entire X chromosome is active (not all genes are active in every cell),
whereas one of a female's X chromosomes is largely inactive. Random inactivation of one X
chromosome occurs during the early stages of female embryogenesis, and every cell that
descends from a particular embryonic cell has the same X chromosome inactivated. The result
is dosage compensation for X-linked genes between the sexes. A specific gene on the long
arm of the X chromosome, called XIST at band q13, is a strong candidate for the gene that
controls X inactivation. This pattern of sex determination occurs in most vertebrates, but in
birds and many insects and fish the male is the homogametic sex. See also Sex determination.
In general terms, traits determined by genes on sex chromosomes are not different from traits
determined by autosomal genes. Sex-linked traits are distinguishable by their mode of
transmission through successive generations of a family. In humans it is preferable to speak in
terms of X-linked or Y-linked inheritance.
Red-green color blindness was the first human trait proven to be due to a gene on a specific
chromosome. The characteristics of this pattern of inheritance are readily evident. Males are
more noticeably or severely affected than females; in the case of red-green color blindness,
women who have one copy of the mutant gene (that is, are heterozygous or carriers) are not at
all affected. Among offspring of carrier mothers, on average one-half of their sons are
affected, whereas one-half of their daughters are carriers. Affected fathers cannot pass their
mutant X chromosome to their sons, but do pass it to all of their daughters, who thereby are
carriers. A number of other well-known human conditions behave in this manner, including
the two forms of hemophilia, Duchenne muscular dystrophy, and glucose-6-phosphate
dehydrogenase deficiency that predisposes to hemolytic anemia. See also Anemia; Color
vision; Hemophilia; Muscular dystrophy.
Refined cytogenetic and molecular techniques have supplemented family studies as a method
for characterizing sex-linked inheritance and for mapping genes to sex chromosomes in many

species. Over 400 human traits and diseases seem to be encoded by genes on the X
chromosome, and over 200 genes have been mapped. Among mammals, genes on the X
chromosome are highly conserved. Thus, identifying a sex-linked trait in mice is strong
evidence that a similar trait, and underlying gene, exists on the human X chromosome.
13) Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria,
the organelles that are the "powerhouses" found in most eukaryotic cells. Mitochondria
convert the energy of food molecules into the ATP that powers most cell functions.
Mitochondrial diseases are often caused by mutations to mitochondrial DNA that affect
mitochondria function. Mitochondrial diseases take on unique characteristics both because of
the way the diseases are often inherited and because mitochondria are so critical to cell
function. The subclass of these diseases that have neuromuscular disease symptoms are often
called a mitochondrial myopathy.
Diabetes mellitus and deafness (DAD)

o this combination at an early age can be due to mitochondrial disease

o Diabetes mellitus and deafness can also be found together for other reasons

Leber's hereditary optic neuropathy (LHON)

o visual loss beginning in young adulthood
o eye disorder characterized by progressive loss of central vision due to
degeneration of the optic nerves and retina
o Wolff-Parkinson-White syndrome
o multiple sclerosis-type disease
o affects 1 in 50,000 people in Finland

Leigh syndrome, subacute sclerosing encephalopathy

o after normal development the disease usually begins late in the first year of
life, although onset may occur in adulthood
o a rapid decline in function occurs and is marked by seizures, altered states of
consciousness, dementia, ventilatory failure

Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)

o progressive symptoms as described in the acronym

o dementia

Symptoms include poor growth, loss of muscle coordination, muscle weakness, visual
problems, hearing problems, learning disabilities, mental retardation, heart disease,
liver disease, kidney disease, gastrointestinal disorders, respiratory disorders,
neurological problems, and dementia.

Mitochondrial disorders may be caused by mutations, acquired or inherited, in

mitochondrial DNA (mtDNA) or in nuclear genes that code for mitochondrial
components. They may also be the result of acquired mitochondrial dysfunction due to
adverse effects of drugs, infections, or other environmental causes (see MeSH).

Mitochondrial DNA inheritance behaves differently from autosomal and sex-linked

inheritance. Nuclear DNA has two copies per cell (except for sperm and egg cells),
and one copy is inherited from the father and the other from the mother. Mitochondrial
DNA, however, is strictly inherited from the mother and each mitochondrial organelle
typically contains multiple mtDNA copies (see Heteroplasmy). During cell division
the mitochondrial DNA copies segregate randomly between the two new
mitochondria, and then those new mitochondria make more copies. If only a few of
the mtDNA copies inherited from the mother are defective, mitochondrial division
may cause most of the defective copies to end up in just one of the new mitochondria
(for more detailed inheritance patterns, see Human mitochondrial genetics).
Mitochondrial disease may become clinically apparent once the number of affected
mitochondria reaches a certain level; this phenomenon is called "threshold
expression".

Mitochondrial DNA mutations occur frequently, due to the lack of the error checking
capability that nuclear DNA has (see Mutation rate). This means that mitochondrial
DNA disorders may occur spontaneously and relatively often. Defects in enzymes that
control mitochondrial DNA replication (all of which are encoded for by genes in the
nuclear DNA) may also cause mitochondrial DNA mutations.

14) Cytogenetics is a branch of genetics that is concerned with the study of the structure and
function of the cell, especially the chromosomes.[1] It includes routine analysis of G-Banded
chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such
as fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH).
Techniques
Routine analysis
Routine chromosome analysis refers to analysis of metaphase chromosomes which have been
banded using trypsin followed by Giemsa, Leishmanns, or a mixture of the two. This creates
unique banding patterns on the chromosomes. The molecular mechanism and reason for these
patterns is unknown, although it likely related to replication timing and chromatin packing.

Several chromosome-banding techniques are used in cytogenetics laboratories. Quinacrine

banding (Q-banding) was the first staining method used to produce specific banding patterns.
This method requires a fluorescence microscope and is no longer as widely used as Giemsa
banding (G-banding). Reverse banding (R-banding) requires heat treatment and reverses the
usual white and black pattern that is seen in G-bands and Q-bands. This method is particularly
helpful for staining the distal ends of chromosomes. Other staining techniques include Cbanding and nucleolar organizing region stains (NOR stains). These latter methods
specifically stain certain portions of the chromosome. C-banding stains the constitutive
heterochromatin, which usually lies near the centromere, and NOR staining highlights the
satellites and stalks of acrocentric chromosomes.
Slide preparation
Cells from bone marrow, blood, amniotic fluid, cord blood, tumor, and tissues (including skin,
umbilical cord, liver, and many other organs) can be cultured using standard cell culture
techniques in order to increase their number. A mitotic inhibitor (colchicine, colcemid) is then
added to the culture. This stops cell division at mitosis which allows an increased yield of
mitotic cells for analysis. The cells are then centrifuged and media and mitotic inhibitor is
removed, and replaced with a hypotonic solution. This causes the cells to swell so that the
chromosomes will spread when added to a slide. After the cells have been allowed to sit in
hypotonic, Carnoy's fixative (3:1 methanol to glacial acetic acid) is added. This kills the cells,
lyses the red blood cells, and hardens the nuclei of the remaining white blood cells. The cells
are generally fixed repeatedly to remove any debris or remaining red blood cells. The cell
suspension is then dropped onto specimen slides. After aging the slides in an oven or waiting
a few days they are ready for banding and analysis.
Analysis
Analysis of banded chromosomes is done at a microscope by a clinical laboratory specialist in
cytogenetics (CLSp(CG)). Generally 20 cells are analyzed which is enough to rule out
mosaicism to an acceptable level. The results are summarized and given to a board-certified
medical geneticist and a pathologist for review, and to write an interpretation taking into
account the patients previous history and other clinical findings. The results are then given out
reported in an International System for Human Cytogenetic Nomenclature 2005 (ISCN2005).
What are some of the DNA technologies used in forensic investigations?
Restriction Fragment Length Polymorphism (RFLP)
RFLP is a technique for analyzing the variable lengths of DNA fragments that result from
digesting a DNA sample with a special kind of enzyme. This enzyme, a restriction
endonuclease, cuts DNA at a specific sequence pattern know as a restriction endonuclease
recognition site. The presence or absence of certain recognition sites in a DNA sample
generates variable lengths of DNA fragments, which are separated using gel electrophoresis.
They are then hybridized with DNA probes that bind to a complementary DNA sequence in
the sample.

PCR Analysis
Polymerase chain reaction (PCR) is used to make millions of exact copies of DNA from a
biological sample. DNA amplification with PCR allows DNA analysis on biological samples
as small as a few skin cells. With RFLP, DNA samples would have to be about the size of a
quarter. The ability of PCR to amplify such tiny quantities of DNA enables even highly
degraded samples to be analyzed. Great care, however, must be taken to prevent
contamination with other biological materials during the identifying, collecting, and
preserving of a sample.
STR Analysis
Short tandem repeat (STR) technology is used to evaluate specific regions (loci) within
nuclear DNA. Variability in STR regions can be used to distinguish one DNA profile from
another. The Federal Bureau of Investigation (FBI) uses a standard set of 13 specific STR
regions for CODIS. CODIS is a software program that operates local, state, and national
databases of DNA profiles from convicted offenders, unsolved crime scene evidence, and
missing persons. The odds that two individuals will have the same 13-loci DNA profile is
about one in a billion.
Mitochondrial DNA Analysis
Mitochondrial DNA analysis (mtDNA) can be used to examine the DNA from samples that
cannot be analyzed by RFLP or STR. Nuclear DNA must be extracted from samples for use in
RFLP, PCR, and STR; however, mtDNA analysis uses DNA extracted from another cellular
organelle called a mitochondrion. While older biological samples that lack nucleated cellular
material, such as hair, bones, and teeth, cannot be analyzed with STR and RFLP, they can be
analyzed with mtDNA. In the investigation of cases that have gone unsolved for many years,
mtDNA is extremely valuable.
All mothers have the same mitochondrial DNA as their offspring. This is because the
mitochondria of each new embryo comes from the mother's egg cell. The father's sperm
contributes only nuclear DNA. Comparing the mtDNA profile of unidentified remains with
the profile of a potential maternal relative can be an important technique in missing-person
investigations.
Y-Chromosome Analysis
The Y chromosome is passed directly from father to son, so analysis of genetic markers on the
Y chromosome is especially useful for tracing relationships among males or for analyzing
biological evidence involving multiple male contributors.
Human pedigrees
Before we consider human inheritance we need to learn the symbols used to draw pedigrees.
The figure below shows some of the commoner symbols:

Note that the symbols for non-identical twins and for identical twins differ by whether they
descend from a common vertical before bifurcating.
Generations are numberered from the top of the pedigree in uppercase Roman numerals, I, II,
III etc. Individuals in each generation are numbered from the left in arab numberals as
subscripts, III1 , III2, III3 etc. For example, here is a typical autosomal dominant pedigree with
numbered generations and individuals.

15) MONOGENIC DISORDER Monogenic genetic disorders occur as a direct consequence

of a single gene being defective. Such disorders are inherited (passed on from one generation
to another) in a simple pattern according to Mendel's Laws. As such, these disorders are often
referred to as Mendelian disorders.

Meaning:
An inherited disease controlled by a single pair of genes
Classified under:
Nouns denoting stable states of affairs
Synonyms:
monogenic disease; monogenic disorder
Hypernyms ("monogenic disorder" is a kind of...):
congenital disease; genetic abnormality; genetic defect; genetic disease; genetic disorder;
hereditary condition; hereditary disease; inherited disease; inherited disorder (a disease or
disorder that is inherited genetically)
Hyponyms (each of the following is a kind of "monogenic disorder"):
SCID; severe combined immunodeficiency; severe combined immunodeficiency disease (a
congenital disease affecting T cells that can result from a mutation in any one of several
different genes; children with it are susceptible to infectious disease; if untreated it is lethal
within the first year or two of life)
Mediterranean anaemia; Mediterranean anemia; thalassaemia; thalassemia (an inherited form
of anemia caused by faulty synthesis of hemoglobin)

infantile amaurotic idiocy; Sachs disease; Tay-Sachs; Tay-Sachs disease (a hereditary disorder
of lipid metabolism occuring most frequently in individuals of Jewish descent in eastern
Europe; accumulation of lipids in nervous tissue results in death in early childhood)
crescent-cell anaemia; crescent-cell anemia; drepanocytic anaemia; drepanocytic anemia;
sickle-cell anaemia; sickle-cell anemia; sickle-cell disease (a congenital form of anemia
occurring mostly in blacks; characterized by abnormal blood cells having a crescent shape)
neurofibromatosis; von Recklinghausen's disease (autosomal dominant disease characterized
by numerous neurofibromas and by spots on the skin and often by developmental
abnormalities)
dysostosis multiplex; gargoylism; Hurler's disease; Hurler's syndrome; lipochondrodystrophy
(hereditary disease (autosomal recessive) consisting of an error is mucopolysaccharide
metabolism; characterized by severe abnormalities in development of skeletal cartilage and
bone and mental retardation)
Huntington's chorea; Huntington's disease (hereditary disease; develops in adulthood and ends
in dementia)
Gaucher's disease (a rare chronic disorder of lipid metabolism of genetic origin)
CF; cystic fibrosis; fibrocystic disease of the pancreas; mucoviscidosis; pancreatic fibrosis
(the most common congenital disease; the child's lungs and intestines and pancreas become
clogged with thick mucus; caused by defect in a single gene; there is no cure)
familial hypercholesterolemia (congenital disorder characterized by high levels of cholesterol
and early development of atherosclerosis)
Inborn errors of metabolism comprise a large class of genetic diseases involving disorders
of metabolism. The majority are due to defects of single genes that code for enzymes that
facilitate conversion of various substances (substrates) into others (products). In most of the
disorders, problems arise due to accumulation of substances which are toxic or interfere with
normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn
errors of metabolism are now often referred to as congenital metabolic diseases or inherited
metabolic diseases.
The term inborn error of metabolism was coined by a British physician, Archibald Garrod
(18571936), in the early 20th century (1908). He is known for work that prefigured the "one
gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of
alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.
Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate
metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases.
In recent decades, hundreds of new inherited disorders of metabolism have been discovered
and the categories have proliferated. Following are some of the major classes of congenital
metabolic diseases, with prominent examples of each class. Many others do not fall into these
categories. ICD-10 codes are provided where available.

Disorders of carbohydrate metabolism

o E.g., glycogen storage disease

Disorders of amino acid metabolism

o E.g., phenylketonuria , maple syrup urine disease, glutaric acidemia type 1

Disorders of organic acid metabolism (organic acidurias)

o E.g., alcaptonuria

Disorders of fatty acid oxidation and mitochondrial metabolism

o E.g., medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2)

Disorders of porphyrin metabolism

o E.g., acute intermittent porphyria

Disorders of purine or pyrimidine metabolism

o E.g., Lesch-Nyhan syndrome

Disorders of steroid metabolism

o E.g., congenital adrenal hyperplasia

Disorders of mitochondrial function

o E.g., Kearns-Sayre syndrome

Disorders of peroxisomal function

o E.g., Zellweger syndrome

Lysosomal storage disorders

o E.g., Gaucher's disease
o E.g., Niemann Pick disease

16) Haemoglobin and Disease

Decreased levels of haemoglobin, with or without the concomitant decrease in red blood cells,
can cause anaemia. Iron deficiency is one cause of anaemia, as it directly affects the ability to
produce haem molecules, but there are several other causes of anaemia. There can also be
other disease profiles associated with abnormalities in haemoglobin, known generally as

haemoglobinopathies, as well as abnormalities affecting the production of haem molecules,

known as porphyrias. A few examples are described below:
Sickle Cell Anaemia
Sickle Cell Anaemia affects the shape of red blood cells, changing them from a
flattened disc to a sickle or crescent shape. Whereas normal red blood cells are smooth and
move easily through blood vessels, sickle blood cells are hard, inflexible and tend to clump
together, causing them to get stuck in blood vessels as blood clots, thereby blocking the flow
of blood. This can cause pain, blood vessel damage and a low red blood cell count (anaemia)
due to the more fragile nature of sickle blood cells. The abnormal sickle shape is due to the
presence of abnormal haemoglobin (haemoglobin S), which contains abnormal beta
polypeptide with a single amino acid substitution at position 6 along the polypeptide chain
(the alpha chain is normal). The abnormal chain reduces the amount of oxygen inside the
red blood cell, altering its shape.
Thalassaemia
Thalassaemia is caused when the production of haemoglobin chains is impaired, the most
common forms affecting the alpha globin chain (alpha Thalassaemia) or the beta globin chain
(beta Thalassaemia). The chains themselves can be normal, but the amounts produced are
not; sometimes the genes can even be missing. There are four genes needed to make the alpha
globin chain, with moderate to severe anaemia resulting when more than two genes are
affected. With the beta globin chain there are two genes required, the most severe form of the
disease affecting both genes. An equal number of alpha and beta globin proteins are required
to make functional adult haemoglobin, and a deficiency in either chain will cause an
imbalance that damages and destroys red blood cells, thereby producing anaemia. The
deficiency in globin chains can cause the an abnormal association of globin chains: in the case
of alpha Thalassaemia, beta globin chains combine to produce abnormal beta tetramers that
cannot bind oxygen, whereas with beta Thalassaemia no such alpha tetramers exist instead
the alpha globin chains become degraded in the absence of beta globin chains.
Porphyria Porphyria disorders affect the production of functional haem molecules in
haemoglobin. The haem component is composed of a porphyrin ring complex and iron.
Porphyria affects the production of a functional porphyrin complex through a genetic
mutation at any one of the many enzymatic steps involved in its production. While most
haem is in the blood associated with haemoglobin, haem is also required for in several other
tissues, including the liver. Porphyrias can affect either the skin (cutaneous porphyria) or the
nervous system (acute porphyria). Cutaneous porphyria causes the development of blisters,
itching and swelling upon exposure to light, while acute porphyria causes pain, numbness,
paralysis or mental disorders.
Carbon Monoxide Poisoning
Carbon monoxide (CO) binds to haemoglobin with a higher affinity (200x greater) than
oxygen, and at the same binding site. Consequently, carbon monoxide will bind haemoglobin
preferentially over oxygen when both are present in the lungs - even small amounts of carbon
monoxide can dramatically reduce the ability of haemoglobin to transport oxygen. Levels as

low as 0.02% carbon monoxide can cause headaches and nausea, while a concentration of
0.1% can lead to unconsciousness. This accounts for the suffocation caused by carbon
monoxide fumes, such as from the exhaust of a car engine. People who smoke heavily can
block up to 20% of the oxygen binding sites in haemoglobin with carbon monoxide. When
carbon monoxide binds to haemoglobin it becomes a very bright cherry red
(carboxyhaemoglobin), giving the person the appearance of a healthy glow.
By contrast, carbon dioxide (CO2), which is produced as a waste product after aerobic
respiration, binds to haemoglobin at a different site, therefore does not compete with oxygen
for binding to haemoglobin.
The essentials
- Haemoglobinopathies have global importance.
- Carriers of abnormal haemoglobin genes are more resistant to malaria.
- Sickle cell crises can be severe and ultimately fatal.
- The thalassaemias are caused by imbalance in alpha and beta globin.
- Babies with thalassaemia major get severe anaemia in their first year.
1. NORMAL HAEMOGLOBIN STRUCTURE AND FUNCTION
Haemoglobin (Hb) is responsible for the carriage of oxygen throughout the body. When Hb
molecules are reduced in number (resulting in anaemia) or are abnormal in structure (due to
haemoglobinopathy), characteristic symptoms and signs occur.
The term haemoglobinopathy is used here to loosely represent both structural abnormalities of
the Hb molecule, such as sickle cell anaemia, and diseases where globin chains are
imbalanced, such as in thalassaemia syndromes.
The Hb molecule The Hb molecule consists of four subunits, two alpha-like and two beta-like
globins.
Different types of Hb are produced at various stages of life. Fetal haemoglobin (HbF) consists
of two alpha globins and two gamma globins. As the name suggests, HbF is the predominant
haemoglobin found in the fetus. The main adult haemoglobin is HbA (A for adult) which
comprises two alpha globin and two beta globin polypeptide chains (a2b2 haemoglobin).
Even though they have different pathologies, sickle cell disease and thalassaemia share some
features with other anaemias because a reduced oxygen-carrying capacity will have a similar
effect, no matter what the underlying cause may be
The features of anaemia either reflect the fact that less oxygen is being delivered to tissues or
result from the compensatory mechanisms that try to restore oxygen delivery towards normal.
The body is highly adaptable and can cope with anaemia up to a point. The symptoms of
anaemia may be specific or non-specific (see box, below right).

There are a variety of physiological strategies involved, which explain why individuals with
chronically reduced Hb may have few symptoms despite having a low haemoglobin.
If anaemia is of gradual onset, the body has ample time to adapt, and the patient can carry on
working and leading a relatively normal life.
Anaemia of sudden onset, on the other hand, does not allow time for physiological adaptation
and the patient will generally feel unwell.
17) Thalassemia
Thalassemia

ICD-10

D56.

ICD-9

282.4

MedlinePlus

000587

eMedicine

ped/2229 radio/686

MeSH

D013789

Thalassemia (also spelled thalassaemia) is an inherited autosomal recessive blood disease.

In thalassemia the genetic defect, which could be either mutation or deletion, results in
reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin.
This can cause the formation of abnormal hemoglobin molecules, thus causing anemia, the
characteristic presenting symptom of the thalassemias.
Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell
anemia (a hemoglobinopathy) is a qualitative problem of synthesis of an incorrectly
functioning globin. Thalassemias usually result in underproduction of normal globin proteins,
often through mutations in regulatory genes. Hemoglobinopathies imply structural
abnormalities in the globin proteins themselves.[1] The two conditions may overlap, however,
since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also
affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but
most are not. Either or both of these conditions may cause anemia.
The two major forms of the disease, alpha- and beta- (see below), are prevalent in discrete
geographical clusters around the world - probably associated with malarial endemicity in
ancient times. Alpha is prevalent in peoples of Western African descent, and is nowadays
found in populations living in Africa and in the Americas. Beta is particularly prevalent
among Mediterranean peoples, and this geographical association was responsible for its
naming: Thalassa () is Greek for the sea, Haema () is Greek for blood. In

Europe, the highest concentrations of the disease are found in Greece, coastal regions in
Turkey, in particular, Aegean Region such as Izmir, Balikesir, Aydin, Mugla and
Mediterranean Region such as Antalya, Adana, Mersin, in parts of Italy, in particular,
Southern Italy and the lower Po valley. The major Mediterranean islands (except the
Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus and Crete are heavily affected in
particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean,
also have high rates of thalassemia, including people from the West Asia and North Africa.
Far from the Mediterranean, South Asians are also affected, with the world's highest
concentration of carriers (16% of the population) being in the Maldives.
The thalassemia trait may confer a degree of protection against malaria, which is or was
prevalent in the regions where the trait is common, thus conferring a selective survival
advantage on carriers, and perpetuating the mutation. In that respect the various thalassemias
resemble another genetic disorder affecting hemoglobin, sickle-cell disease(ref?).
Pathophysiology
Normal hemoglobin is composed of two chains each of and globin. Thalassemia patients
produce a deficiency of either or globin, unlike sickle-cell disease which produces a
specific mutant form of globin.
The thalassemias are classified according to which chain of the hemoglobin molecule is
affected. In thalassemias, production of the globin chain is affected, while in thalassemia
production of the globin chain is affected.
globin chains are encoded by a single gene on chromosome 11; globin chains are encoded
by two closely linked genes on chromosome 16. Thus in a normal person with two copies of
each chromosome, there are two loci encoding the chain, and four loci encoding the
chain. Deletion of one of the loci has a high prevalence in people of African or Asian
descent, making them more likely to develop thalassemias. thalassemias are common in
Africans, but also in Greeks and Italians.
Alpha () thalassemias
The thalassemias involve the genes HBA1[2] and HBA2,[3] inherited in a Mendelian
recessive fashion. There are two gene loci and so four alleles. It is also connected to the
deletion of the 16p chromosome. thalassemias result in decreased alpha-globin production,
therefore fewer alpha-globin chains are produced, resulting in an excess of chains in adults
and excess chains in newborns. The excess chains form unstable tetramers (called
Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves.
[edit] Beta () thalassemias
Beta thalassemias are due to mutations in the HBB gene on chromosome 11 ,[4] also inherited
in an autosomal-recessive fashion. The severity of the disease depends on the nature of the
mutation. Mutations are characterized as (o or thalassemia major) if they prevent any

formation of chains (which is the most severe form of thalassemia); they are characterized
as (+ or thalassemia intermedia) if they allow some chain formation to occur. In either
case there is a relative excess of chains, but these do not form tetramers: rather, they bind to
the red blood cell membranes, producing membrane damage, and at high concentrations they
form toxic aggregates.
Delta () thalassemia
As well as alpha and beta chains being present in hemoglobin about 3% of adult hemoglobin
is made of alpha and delta chains. Just as with beta thalassemia, mutations can occur which
affect the ability of this gene to produce delta chains.
In combination with other hemoglobinopathies
Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:

hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India;

clinically similar to thalassemia major or thalassemia intermedia.

hemoglobin S/thalassemia, common in African and Mediterranean populations;

clinically similar to sickle cell anemia, with the additional feature of splenomegaly

hemoglobin C/thalassemia: common in Mediterranean and African populations,

hemoglobin C/o thalassemia causes a moderately severe hemolytic anemia with
splenomegaly; hemoglobin C/+ thalassemia produces a milder disease.

Cause
and thalassemia are often inherited in an autosomal recessive fashion although this is not
always the case. Cases of dominantly inherited and thalassemias have been reported, the
first of which was in an Irish family who had a two deletions of 4 and 11 bp in exon 3
interrupted by an insertion of 5 bp in the -globin gene. For the autosomal recessive forms of
the disease both parents must be carriers in order for a child to be affected. If both parents
carry a hemoglobinopathy trait, there is a 25% chance with each pregnancy for an affected
child. Genetic counseling and genetic testing is recommended for families that carry a
thalassemia trait.
Treatment
Patients with thalassemia minor usually do not require any specific treatment.[citation needed]
Treatment for patients with thalassemia major includes chronic blood transfusion therapy, iron
chelation, splenectomy, and allogeneic hematopoietic transplantation.[citation needed]
Medication
Medical therapy for beta thalassemia primarily involves iron chelation. Deferoxamine is the
intravenously or subcutaneously administered chelation agent currently approved for use in
the United States. Deferasirox (Exjade) is an oral iron chelation drug also approved in the US

in 2005. Deferoprone is an oral iron chelator that has been approved in Europe since 1999 and
many other countries. It is available under compassionate use guidelines in the United States.
Carrier detection

A screening policy exists in Cyprus to reduce the incidence of thalassemia, which

since the program's implementation in the 1970s (which also includes pre-natal
screening and abortion) has reduced the number of children born with the hereditary
blood disease from 1 out of every 158 births to almost zero.[6]

In Iran as a premarital screening, the man's red cell indices are checked first, if he has
microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the
woman is tested. When both are microcytic their hemoglobin A2 concentrations are
measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait)
they are referred to the local designated health post for genetic counseling.[7]

Being a carrier of the disease may confer a degree of protection against malaria, as it is quite
common among people of Italian or Greek origin, and also in some African and Indian
regions. This is probably by making the red blood cells more susceptible to the less lethal
species Plasmodium vivax, simultaneously making the host's red
18) Monogenic diseases
Monogenic diseases result from modifications in a single gene occurring in all cells of the
body. Though relatively rare, they affect millions of people worldwide. Scientists currently
estimate that over 10,000 of human diseases are known to be monogenic. Pure genetic
diseases are caused by a single error in a single gene in the human DNA. The nature of
disease depends on the functions performed by the modified gene. The single-gene or
monogenic diseases can be classified into three main categories:

Dominant

Recessive

X-linked

All human beings have two sets or copies of each gene called allele; one copy on each side
of the chromosome pair. Recessive diseases are monogenic disorders that occur due to
damages in both copies or allele. Dominant diseases are monogenic disorders that involve
damage to only one gene copy. X linked diseases are monogenic disorders that are linked to
defective genes on the X chromosome which is the sex chromosome. The X linked alleles can
also be dominant or recessive. These alleles are expressed equally in men and women, more
so in men as they carry only one copy of X chromosome (XY) whereas women carry two
(XX).

Monogenic diseases are responsible for a heavy loss of life. The global prevalence of all
single gene diseases at birth is approximately 10/1000. In Canada, it has been estimated that
taken together, monogenic diseases may account for upto 40% of the work of hospital based
paediatric practice (Scriver, 1995).
Thalassaemia
Sickle cell anemia
Haemophilia
Cystic Fibrosis
Tay sachs disease
Fragile X syndrome
Huntington's disease
Osteogenesis imperfecta (OI and sometimes known as brittle bone disease, or "Lobstein
syndrome"[1]) is a genetic bone disorder. People with OI are born with defective connective
tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen.[2]
This deficiency arises from an amino acid substitution of glycine to bulkier amino acids in the
collagen triple helix structure. The larger amino acid side-chains create steric hindrance that
creates a bulge in the collagen complex, which in turn influences both the molecular
nanomechanics as well as the interaction between molecules, which are both compromised.[3]
As a result, the body may respond by hydrolyzing the improper collagen structure. If the body
does not destroy the improper collagen, the relationship between the collagen fibrils and
hydroxyapatite crystals to form bone is altered, causing brittleness.[4] Another suggested
disease mechanism is that the stress state within collagen fibrils is altered at the locations of
mutations, where locally larger shear forces lead to rapid failure of fibrils even at moderate
loads as the homogeneous stress state found in healthy collagen fibrils is lost.[3] These recent
works suggest that OI must be understood as a multi-scale phenomenon, which involves
mechanisms at the genetic, nano-, micro- and macro-level of tissues.
As a genetic disorder, OI is an autosomal dominant defect. Most people with OI receive it
from a parent but it can be an individual (de novo or "sporadic") mutation.
Type Description

Gene

OMIM

mild

COL1A1, COL1A2

166240 (IA), 166200

(IB)

II

severe and usually lethal in the

perinatal period

COL1A1, COL1A2,
CRTAP

166210 (IIA), 610854

(IIB)

III

considered progressive and deforming COL1A1, COL1A2

259420

IV

deforming, but with normal scleras

166220

COL1A1, COL1A2

Marfan syndrome (also called Marfan's syndrome) is a genetic disorder of the connective
tissue.

It is sometimes inherited as a dominant trait. It is carried by a gene called FBN1, which

encodes a connective protein called fibrillin-1.[1][2] People have a pair of FBN1 genes. Because
it is dominant, people who have inherited one affected FBN1 gene from either parent will
have Marfan's. This syndrome can run from mild to severe.
People with Marfan's are typically tall, with long limbs and long thin fingers.
The most serious complications are the defects of the heart valves and aorta. It may also affect
the lungs, eyes, the dural sac surrounding the spinal cord, skeleton and the hard palate.
EhlersDanlos syndrome (EDS) (also known as "Cutis hyperelastica"[1]) is a group of
inherited connective tissue disorders, caused by a defect in the synthesis of collagen (a protein
in connective tissue). The collagen in connective tissue helps tissues to resist deformation
(decreases its elasticity). In the skin, muscles, ligaments, blood vessels and visceral organs,
collagen plays a very significant role and with increased elasticity, secondary to abnormal
collagen, pathology results. Depending on the individual mutation, the severity of the
syndrome can vary from mild to life-threatening. There is no cure, and treatment is
supportive, including close monitoring of the digestive, excretory and particularly the
cardiovascular systems. Corrective surgery may help with some of the problems that may
develop in certain types of EDS, although the condition means that extra caution is advised
and special practices observed.[2]
19) Cystic fibrosis (also known as CF or mucoviscidosis) is a common disease which affects
the entire body, causing progressive disability and often early death. The name cystic fibrosis
refers to the characteristic scarring (fibrosis) and cyst formation within the pancreas, first
recognized in the 1930s.[1] Difficulty breathing is the most serious symptom and results from
frequent lung infections that is treated with, though not cured by, antibiotics and other
medications. A multitude of other symptoms, including sinus infections, poor growth,
diarrhea, and infertility result from the effects of CF on other parts of the body.
CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane
conductance regulator (CFTR). This gene is required to regulate the components of sweat,
digestive juices, and mucus. Although most people without CF have two working copies of
the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene
works normally. Therefore, CF is considered an autosomal recessive disease.
CF is most common among Caucasians; one in 25 people of European descent carry one gene
for CF. Approximately 30,000 Americans have CF, making it one of the most common lifeshortening inherited diseases. Individuals with cystic fibrosis can be diagnosed before birth by
genetic testing, or by a sweat test in early childhood. Ultimately, lung transplantation is often
necessary as CF worsens.
The hallmark symptoms of cystic fibrosis are salty tasting skin,[3] poor growth and poor
weight gain despite a normal food intake,[4] accumulation of thick, sticky mucus,[5] frequent
chest infections and coughing or shortness of breath.[6] Males can be infertile due to

congenital absence of the vas deferens.[7] Symptoms often appear in infancy and childhood,
such as bowel obstruction due to meconium ileus in newborn babies.[8] As the child grows, he
or she will need to exercise to release mucus in the alveoli.[9] Ciliated epithelial cells in the
patient have a mutated protein that leads to abnormally viscous mucus production.[5] The poor
growth in children typically presents as an inability to gain weight or height at the same rate
as their peers and is occasionally not diagnosed until investigation is initiated for poor growth.
The causes of growth failure are multi-factorial and include chronic lung infection, poor
absorption of nutrients through the gastrointestinal tract, and increased metabolic demand due
to chronic illness.[4]
In rare cases, cystic fibrosis can manifest itself as a coagulation disorder. Young children are
especially sensitive to vitamin K malabsorptive disorders because only a very small amount of
vitamin K crosses the placenta, leaving the child with very low reserves. Because factors II,
VII, IX, and X (clotting factors) are vitamin Kdependent, low levels of vitamin K can result
in coagulation problems. Consequently, when a child presents with unexplained bruising, a
coagulation evaluation may be warranted to determine whether there is an underlying disease.
[10]

20) Alpha 1-antitrypsin deficiency (1-antitrypsin deficiency, A1AD or simply Alpha-1)

is an autosomal recessive genetic disorder caused by defective production of alpha 1antitrypsin (A1AT), leading to decreased A1AT activity in the blood and lungs, and deposition
of excessive abnormal A1AT protein in liver cells.[1][2] There are several forms and degrees of
deficiency. Severe A1AT deficiency causes panacinar emphysema or COPD in adult life in
many people with the condition (especially if they are exposed to cigarette smoke), as well as
various liver diseases in a minority of children and adults, and occasionally more unusual
problems.[3] It is treated by avoidance of damaging inhalants, by intravenous infusions of the
A1AT protein, by transplantation of the liver or lungs, and by a variety of other measures, but
it usually produces some degree of disability and reduced life expectancy.[1]
Symptoms of alpha-1 antitrypsin deficiency include shortness of breath, wheezing, rhonchi,
and rales. The patient's symptoms may resemble recurrent respiratory infections or asthma
that does not respond to treatment. Individuals with A1AD may develop emphysema during
their thirties or forties even without a history of significant smoking, though smoking greatly
increases the risk for emphysema.[1] A1AD also causes impaired liver function in some
patients and may lead to cirrhosis and liver failure (15%). It is a leading cause of liver
transplantation in newborns.
Alpha 1-antitrypsin (A1AT) is produced in the liver, and one of its functions is to protect the
lungs from the neutrophil elastase enzyme, which can disrupt connective tissue.[1] Normal
blood levels of alpha-1 antitrypsin are 1.5-3.5 g/l. In individuals with PiSS, PiMZ and PiSZ
phenotypes, blood levels of A1AT are reduced to between 40 and 60% of normal levels. This
is usually sufficient to protect the lungs from the effects of elastase in people who do not
smoke. However, in individuals with the PiZZ phenotype, A1AT levels are less than 15% of
normal, and patients are likely to develop panacinar emphysema at a young age; 50% of these

patients will develop liver cirrhosis, because the A1AT is not secreted properly and instead
accumulates in the liver. A liver biopsy in such cases will reveal PAS-positive, diastaseresistant granules.
21) Familial hypercholesterolemia (abbreviated FH, also spelled familial
hypercholesterolaemia) is a genetic disorder characterized by high cholesterol levels,
specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood
and early cardiovascular disease. Many patients have mutations in the LDLR gene that
encodes the LDL receptor protein, which normally removes LDL from the circulation, or
apolipoprotein B (ApoB), which is the part of LDL that binds with the receptor; mutations in
other genes are rare. Patients who have one abnormal copy (are heterozygous) of the LDLR
gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal
copies (being homozygous) may cause severe cardiovascular disease in childhood.
Heterozygous FH is a common genetic disorder, occurring in 1:500 people in most countries;
homozygous FH is much rarer, occurring in 1 in a million births.[1]
Heterozygous FH is normally treated with statins, bile acid sequestrants or other
hypolipidemic agents that lower cholesterol levels. New cases are generally offered genetic
counseling. Homozygous FH often does not respond to medical therapy and may require other
treatments, including LDL apheresis (removal of LDL in a method similar to dialysis) and
occasionally liver transplantation.[1]
Genetics
The most common genetic defects in FH are LDLR mutations (prevalence 1 in 500, depending
on the population), ApoB mutations (prevalence 1 in 1000), PCSK9 mutations (less than 1 in
2500) and LDLRAP1. The related disease sitosterolemia, which has many similarities with FH
and also features cholesterol accumulation in tissues, is due to ABCG5 and ABCG8 mutations.
[1]

LDL receptor
The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It
comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids
in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease
by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes
accelerated atherosclerosis in childhood, including its complications. The plasma LDL levels
are inversely related to the activity of LDL receptor (LDLR). Homozygotes have LDLR
activity of less than 2%, while heterozygotes have defective LDL processing with receptor
activity being 225%, depending on the nature of the mutation. Over 1000 different mutations
are known.[1]
There are five major classes of FH due to LDLR mutations:[12]

Class I: LDLR is not synthesized at all.

Class II: LDLR is not properly transported from the endoplasmic reticulum to the
Golgi apparatus for expression on the cell surface.

Class III: LDLR does not properly bind LDL on the cell surface because of a defect in
either apolipoprotein B100 (R3500Q) or in LDL-R.

Class IV: LDLR bound to LDL does not properly cluster in clathrin-coated pits for
receptor-mediated endocytosis.

Class V: LDLR is not recycled back to the cell surface.

ApoB
ApoB, in its ApoB100 form, is the main apoprotein, or protein part of the lipoprotein particle.
Its gene is located on the second chromosome (2p24-p23) and is between 21.08 and 21.12 Mb
long. FH is often associated with the mutation of R3500Q, which causes replacement of
arginine by glutamine at position 3500. The mutation is located on a part of the protein that
normally binds with the LDL receptor, and binding is reduced as a result of the mutation. Like
LDLR, the number of abnormal copies determines the severity of the hypercholesterolemia.[1]
[13]

[edit] PCSK9
Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to
autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report.[1][14] The
gene is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid protein
that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly by reducing
the number of LDL receptors on liver cells.[15]
[edit] LDLRAP1
Abnormalities in the ARH gene, also known as LDLRAP1, were first reported in a family in
1973.[16] In contrast to the other causes, two abnormal copies of the gene are required for FH
to develop (autosomal recessive). The mutations in the protein tend to cause the production of
a shortened protein. Its real function is unclear, but it seems to play a role in the relation
between the LDL receptor and clathrin-coated pits. Patients with autosomal recessive
hypercholesterolemia tend to have more severe disease than LDLR-heterozygotes but less
severe than LDLR-homozygotes.[1]
22) Familial adenomatous polyposis (FAP) is an inherited condition in which numerous
polyps form mainly in the epithelium of the large intestine. While these polyps start out
benign, malignant transformation into colon cancer occurs when not treated.

Signs and symptoms

From early adolescence and onwards, patients with this condition develop hundreds to
thousands of polyps. These may bleed, leading to blood in the stool. If the blood is not visible,
it is still possible for the patient to develop anemia due to gradually developing iron
deficiency. If malignancy develops, this may present with weight loss, altered bowel habit, or
even metastasis to the liver or elsewhere.
The genetic determinant in familial polyposis may also predispose carriers to other
malignancies, e.g., of the duodenum and stomach. Other signs that may point to FAP are
pigmented lesions of the retina ("CHRPE - congenital hypertrophy of the retinal pigment
epithelium"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The
combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner's
syndrome (with or without abnormal scarring).[1]
Familial adenomatous polyposis can have different inheritance patterns and different genetic
causes. When this condition results from mutations in the APC gene, it is inherited in an
autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause
the disorder. The incidence of malignancy in these cases approaches 100%. In most cases, an
affected person has one parent with the condition.
Mutations in the MUTYH gene are inherited in an autosomal recessive pattern, which means
two copies of the gene must be altered for a person to be affected by the disorder. Most often,
the parents of a child with an autosomal recessive disorder are not affected but are carriers of
one copy of the altered gene.
Prenatal testing is possible if a disease-causing mutation is identified in an affected family
member; however, prenatal testing for typically adult-onset disorders is uncommon and
requires careful genetic counseling.
Because of the genetic nature of FAP, polyposis registries have been developed around the
world. The purpose of these registries is to increase knowledge about the transmissibility of
FAP, but also to document, track, and notify family members of affected individuals. One
study has shown that the use of a registry to notify family members (call-ups) significantly
reduced mortality when compared with probands.[2] The St. Mark's polyposis registry is the
oldest in the world, started in 1924, and many other polyposis registries now exist.
Retinoblastoma (Rb) is a rapidly developing cancer which develops in the cells of retina, the
light detecting tissue of the eye.[1] In the developed world, Rb has one of the best cure rates of
all childhood cancers (95-98%), with more than nine out of every ten sufferers surviving into
adulthood. Retinoblastoma is a very treatable cancer.
Classification
There are two forms of the disease; a genetic, heritable form and a non-genetic, non-heritable
form. Approximately 55% of children with Rb have the non-genetic form. If there is no

history of the disease within the family, the disease is labelled "sporadic", but this does not
necessarily indicate that it is the non-genetic form.
In about two thirds of cases,[2] only one eye is affected (unilateral retinoblastoma); in the other
third, tumours develop in both eyes (bilateral retinoblastoma). The number and size of
tumours on each eye may vary. In certain cases, the pineal gland is also affected (trilateral
retinoblastoma). The position, size and quantity of tumours are considered when choosing the
type of treatment for the disease.
The most common and obvious sign of retinoblastoma is an abnormal appearance of the pupil,
leukocoria.[1] Other less common and less specific signs and symptoms are: deterioration of
vision, a red and irritated eye, faltering growth or delayed development. Some children with
retinoblastoma can develop a squint,[3] commonly referred to as "cross-eyed" or "wall-eyed"
(strabismus). Retinoblastoma presents with advanced disease in developing countries and eye
enlargement is a common finding.
23) Neurofibromatosis (commonly abbreviated NF) is a genetically-inherited disorder in
which the nerve tissue grows tumors (i.e., neurofibromas) that may be harmless or may cause
serious damage by compressing nerves and other tissues. The disorder affects all neural crest
cells (Schwann cells, melanocytes, endoneurial fibroblasts). Cellular elements from these cell
types proliferate excessively throughout the body forming tumors and the melanocytes
function abnormally resulting in disordered skin pigmentation. The tumors may cause bumps
under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other
neurological problems.[1]
Neurofibromatosis is autosomal dominant, which means that it affects
males and females equally and is dominant (only one copy of the affected
gene is needed to get the disorder). Therefore, if only one parent has
neurofibromatosis, his or her children have a 50% chance of developing
the condition as well. The severity in affected individuals, however, can
vary (this is called variable expressivity). Moreover, in around half of cases
there is no other affected family member bNeurofibromatosis type 1
Neurofibromatosis type 1 - mutation of neurofibromin chromosome 17q11.2. The diagnosis of
NF1 is made if any two of the following seven criteria are met:

Two or more neurofibromas on the skin or under the skin or one plexiform
neurofibroma (a large cluster of tumors involving multiple nerves); Neurofibromas are
the subcutaneous bumps that are characteristic of the disease and increase in number
with age.

Freckling of the groin or the axilla (arm pit).

Caf au lait spots (pigmented, most often a shade of brown, smooth edges(coast of
California)[2] birthmarks). Six or more measuring 5 mm in greatest diameter in

prepubertal individuals and over 15 mm in greatest diameter in postpubertal

individuals

Skeletal abnormalities, such as sphenoid dysplasia or thinning of the cortex of the long
bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)

Lisch nodules (hamartomas of iris), freckling in the iris.

Tumors on the optic nerve, also known as an optic glioma

Patient with multiple small cutaneous neurofibromas and a 'caf au lait spot' (bottom of photo,
to the right of centre). A biopsy has been taken of one of the lesions
Neurofibromatosis type 2
Neurofibromatosis type 2 - mutation of NF2 (Merlin) in chromosome 22q12
bilateral tumors, acoustic neuromas on the vestibulocochlear nerve (the eighth cranial
nerve) leading to hearing loss
o In fact, the hallmark of NF 2 is hearing loss due to acoustic neuromas around
the age of twenty
o the tumors may cause:

headache

balance problems, and Vertigo

facial weakness/paralysis

patients with NF2 may also develop other brain tumors, as well as
spinal tumors

Deafness and Tinnitus

Any relative with NF-2.

Li-Fraumeni syndrome is a rare autosomal dominant hereditary disorder. It is named

after Frederick Pei Li and Joseph F. Fraumeni, Jr., the American physicians who first
recognized and described the syndrome.[1] Li-Fraumeni syndrome greatly increases
susceptibility to cancer. The syndrome is linked to germline mutations of the p53
tumor suppressor gene,[2] which normally helps control cell growth. Mutations can be
inherited or can arise de novo early in embryogenesis or in one of the parent's germ
cells.

Persons with LFS are at risk for a wide range of malignancies, with particularly high
occurrences of breast cancer, brain tumors, acute leukemia, soft tissue sarcomas, bone
sarcomas, and adrenal cortical carcinoma.

Characteristics
What makes Li-Fraumeni Syndrome unusual is that

several kinds of cancer are involved,

cancer often appears at a young age, and

cancer often appears several times throughout the life of an affected person.

Diagnosis and treatment

Li-Fraumeni Syndrome is diagnosed if the following three criteria are met:
1. the patient has been diagnosed with a sarcoma at a young age (below 45),
2. a first-degree relative has been diagnosed with any cancer at a young age (below 45),
3. and another first-degree or a second-degree relative has been diagnosed with any
cancer at a young age (below 45) or with a sarcoma at any age.
Genetic counseling and genetic testing are used to confirm that somebody has this gene
mutation. Once such a person is identified, early and regular screenings for cancer are
recommended for him or her. If caught early the cancers can often be successfully treated.
Unfortunately, people with Li-Fraumeni are likely to develop another primary malignancy at a
future time.
24) In genetics, a dynamic mutation is an unstable heritable element where the probability of
mutation is a function of the number of copies of the mutation. That is, the replication product
of a dynamic mutation has a different likelihood of mutation than its predecessor. These
mutations, typically short sequences repeated many times, give rise to numerous known
diseases including the Trinucleotide repeat disorders.
Robert I. Richards and Grant R. Sutherland called these phenomena, in the framework of
dynamical genetics, dynamic mutations. Triplet expansion is caused by slippage during DNA
replication. Due to the repetitive nature of the DNA sequence in these regions 'loop out'
structures may form during DNA replication while maintaining complementary base paring
between the parent strand and daughter strand being synthesized. If the loop out structure is
formed from sequence on the daughter strand this will result in an increase in the number of
repeats. However if the loop out structure is formed on the parent strand a decrease in the
number of repeats occurs. It appears that expansion of these repeats is more common that
reduction. Generally the larger the expansion the more likely they are to cause disease or
increase the severity of disease. This property results in the characteristic of anticipation seen
in trinucleotide repeat disorders. Anticipation describes the tendency of age of onset to

decrease and severity of symptoms to increase through successive generations of an affected

family due to the expansion of these repeats.
Common features

Most of these diseases have neurological symptoms.

Anticipation/The Sherman paradox refers to progressively earlier or more severe

expression of the disease in more recent generations.

Repeats are usually polymorphic in copy number, with mitotic and meiotic instability.

Copy number related to the severity and/or age of onset

Imprinting effects

Reverse mutation - The mutation can revert to normal or to a premutation carrier state.

25) Mitochondrial disease

,
Mitochondrial disease
Classification and external resources
ICD-9

277.87

DiseasesDB

28840

MeSH

D028361

Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the

organelles that are the "powerhouses" found in most eukaryotic cells. Mitochondria convert
the energy of food molecules into the ATP that powers most cell functions.
Mitochondrial diseases are often caused by mutations to mitochondrial DNA that affect
mitochondria function. Mitochondrial diseases take on unique characteristics both because of
the way the diseases are often inherited and because mitochondria are so critical to cell
function. The subclass of these diseases that have neuromuscular disease symptoms are often
called a mitochondrial myopathy.
Classification
Diabetes mellitus and deafness (DAD)

o this combination at an early age can be due to mitochondrial disease

o Diabetes mellitus and deafness can also be found together for other reasons

Leber's hereditary optic neuropathy (LHON)

o visual loss beginning in young adulthood
o eye disorder characterized by progressive loss of central vision due to
degeneration of the optic nerves and retina
o Wolff-Parkinson-White syndrome
o multiple sclerosis-type disease
o affects 1 in 50,000 people in Finland

Leigh syndrome, subacute sclerosing encephalopathy

o after normal development the disease usually begins late in the first year of
life, although onset may occur in adulthood
o a rapid decline in function occurs and is marked by seizures, altered states of
consciousness, dementia, ventilatory failure

Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)

o progressive symptoms as described in the acronym
o dementia

Myoneurogenic gastrointestinal encephalopathy (MNGIE)

o gastrointestinal pseudo-obstruction
o neuropathy

Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

o progressive myoclonic epilepsy
o "Ragged Red Fibers" clumps of diseased mitochondria accumulate in the
subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers"
when muscle is stained with modified Gmri trichrome stain
o short stature

o hearing loss
o lactic acidosis
o exercise intolerance

Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms

(MELAS)

Conditions such as Friedreich's ataxia can affect the mitochondria, but are not associated with
mitochondrial proteins.
Symptoms
Symptoms include poor growth, loss of muscle coordination, muscle weakness, visual
problems, hearing problems, learning disabilities, mental retardation, heart disease, liver
disease, kidney disease, gastrointestinal disorders, respiratory disorders, neurological
problems, and dementia.
Causes
Mitochondrial disorders may be caused by mutations, acquired or inherited, in mitochondrial
DNA (mtDNA) or in nuclear genes that code for mitochondrial components. They may also
be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections,
or other environmental causes (see MeSH).
Mitochondrial DNA inheritance behaves differently from autosomal and sex-linked
inheritance. Nuclear DNA has two copies per cell (except for sperm and egg cells), and one
copy is inherited from the father and the other from the mother. Mitochondrial DNA,
however, is strictly inherited from the mother and each mitochondrial organelle typically
contains multiple mtDNA copies (see Heteroplasmy). During cell division the mitochondrial
DNA copies segregate randomly between the two new mitochondria, and then those new
mitochondria make more copies. If only a few of the mtDNA copies inherited from the
mother are defective, mitochondrial division may cause most of the defective copies to end up
in just one of the new mitochondria (for more detailed inheritance patterns, see Human
mitochondrial genetics). Mitochondrial disease may become clinically apparent once the
number of affected mitochondria reaches a certain level; this phenomenon is called "threshold
expression".
Treatment
Although research is ongoing, treatment options are currently limited; vitamins are frequently
prescribed, though the evidence for their effectiveness is limited.[3] Pyruvate has been
proposed recently as a treatment option.[4]
Spindle transfer, where the nuclear DNA is transferred to another healthy egg cell leaving the
defective mitochondrial DNA behind, is a potential treatment procedure that has been

successfully carried out on monkeys.[5] [6] Using a similar pronuclear transfer technique,
researchers at Newcastle University successfully transplanted healthy DNA in human eggs
from women with mitochondrial disease into the eggs of women donors who were unaffected.
[7] [8]
Human genetic engineering is already being used on a small scale to allow infertile
women with genetic defects in their mitochondria to have children.[9]
Embryonic mitochondrial transplant and protofection have been proposed as a possible
treatment for inherited mitochondrial disease, and allotopic expression of mitochondrial
proteins as a radical treatment for mtDNA mutation load.
26) Multifactorial and polygenic (complex) disorders
Genetic disorders may also be complex, multifactorial, or polygenic, meaning that they are
likely associated with the effects of multiple genes in combination with lifestyle and
environmental factors. Multifactorial disorders include heart disease and diabetes. Although
complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance.
This makes it difficult to determine a persons risk of inheriting or passing on these disorders.
Complex disorders are also difficult to study and treat because the specific factors that cause
most of these disorders have not yet been identified.
On a pedigree, polygenic diseases do tend to run in families, but the inheritance does not fit
simple patterns as with Mendelian diseases. But this does not mean that the genes cannot
eventually be located and studied. There is also a strong environmental component to many of
them (e.g., blood pressure).

asthma

autoimmune diseases such as multiple sclerosis

cancers

ciliopathies

cleft palate

diabetes

heart disease

hypertension

inflammatory bowel disease

mental retardation

mood disorder

obesity

refractive error

infertility

27) Introduction to Chromosome Diseases

Chromosome diseases are genetic diseases where a large part of the genetic code has
been disrupted. Chromosomes are long sequences of DNA that contain hundreds or
thousands of genes. Every person has 2 copies of each of the 23 chromosomes, called
chromosomes 1..22 and the 23rd is the sex chromosome, which is either X and Y. Men
are XY and women are XX in the 23rd chromosome pair.
Causes of chromosome diseases: Chromosomal diseases arise from huge errors in the
DNA that result from having extra chromosomes, large missing sequences, or other
major errors. These are usually caused by a random physical error during reproduction
and are not inherited diseases (i.e. both parents are usually free of the condition).
Spontaneous chromosome errors: Most chromosomal diseases arise spontaneously
from parents where neither has the disease. A large genetic mistake typically occurs in
the woman's egg, which may partially explain why older women are more likely to have
babies with Down syndrome.
Many chromosome errors cause the fetus to be aborted before birth, but some
syndromes can be born and survive, though all typically suffer severe mental and
physical defects. Down syndrome is the most common and well-known chromosome
defect, but there are many.
Types of chromosome diseases: There are several common types of chromosome errors
that cause disease. The effects of errors in the sex chromosomes (X and Y) differ greatly
from errors in the autosomes (chromosomes 1..22). The following major classes of
chromosome diseases can occur:
Trisomy conditions: Most people have 2 copies of each chromosome, but some
people are born with 3 copies, which is called trisomy. Trisomy can occur in

chromosomes 1..22 (autosomal trisomy) and also in the sex chromosome (see
below). Down syndrome is a trisomy affecting the autosome chromosome 21.
Monosomy conditions: When a person has only one of a given chromosome, rather
than a pair, this is called monosomy. These conditions are very rare for autosomes
(chromosomes 1..22) because body cells without pairs do not seem to survive, but
can occur in the sex chromosome (monosomy X is Turner syndrome).
Sex chromosome conditions: Typically men are XY and women are XX in the pair
for the 23rd chromosome. However, sometimes people are born with only one sex
chromosome (monosomy of the sex chromosome), or with three sex chromosomes
(trisomy of the sex chromosome).
Rarer types of chromosome diseases: There are also some other rarer types of
chromosome conditions that may lead to diseases:
Translocation disorders: Partial errors in chromosomes can occur, where a person
still only has a pair, but accidentally has entire sequences misplaced. These can lead
to diseases similar to trisomy. For example, Translocation Down Syndrome is a
subtype of Down Syndrome caused by translocation of a large sequence of a
chromosome.
Subtraction disorders: The process of translocation can also cause large sequences of
DNA to be lost from chromosomes. This creates diseases similar to monosomy
conditions.
Mosaicisim: This refers to the bizarre situation where people have two types of cells
in the body. Some cells have normal chromosomes, and some cells have a disorder
such as a trisomy.
One-sided chromosome disorders: For these unusual diseases it matters whether the
chromosomes were inherited from the father or mother.
Non-contagiousness of chromosome diseases: All types of genetic diseases occur at
birth including chromosome diseases. You cannot catch the disease from someone else
who has the disease. You are either born with the error in your chromosomes or not
Genetic tests can determine whether or not a person has a chromosome disease, even as
early as in the fetus by antenatal testing for genetic diseases.
28) Introduction to Chromosome Diseases
Chromosome diseases are genetic diseases where a large part of the genetic code has been
disrupted. Chromosomes are long sequences of DNA that contain hundreds or thousands of
genes. Every person has 2 copies of each of the 23 chromosomes, called chromosomes 1..22

and the 23rd is the sex chromosome, which is either X and Y. Men are XY and women are XX
in the 23rd chromosome pair.
Causes of chromosome diseases: Chromosomal diseases arise from huge errors in the DNA
that result from having extra chromosomes, large missing sequences, or other major errors.
These are usually caused by a random physical error during reproduction and are not
inherited diseases (i.e. both parents are usually free of the condition).
Spontaneous chromosome errors: Most chromosomal diseases arise spontaneously from
parents where neither has the disease. A large genetic mistake typically occurs in the woman's
egg, which may partially explain why older women are more likely to have babies with Down
syndrome.
Many chromosome errors cause the fetus to be aborted before birth, but some syndromes can
be born and survive, though all typically suffer severe mental and physical defects. Down
syndrome is the most common and well-known chromosome defect, but there are many.
Types of chromosome diseases: There are several common types of chromosome errors that
cause disease. The effects of errors in the sex chromosomes (X and Y) differ greatly from
errors in the autosomes (chromosomes 1..22). The following major classes of chromosome
diseases can occur:

Trisomy conditions: Most people have 2 copies of each chromosome, but some
people are born with 3 copies, which is called trisomy. Trisomy can occur in
chromosomes 1..22 (autosomal trisomy) and also in the sex chromosome (see below).
Down syndrome is a trisomy affecting the autosome chromosome 21.

Monosomy conditions: When a person has only one of a given chromosome, rather
than a pair, this is called monosomy. These conditions are very rare for autosomes
(chromosomes 1..22) because body cells without pairs do not seem to survive, but can
occur in the sex chromosome (monosomy X is Turner syndrome).

Sex chromosome conditions: Typically men are XY and women are XX in the pair
for the 23rd chromosome. However, sometimes people are born with only one sex
chromosome (monosomy of the sex chromosome), or with three sex chromosomes
(trisomy of the sex chromosome).

Rarer types of chromosome diseases: There are also some other rarer types of chromosome
conditions that may lead to diseases:

Translocation disorders: Partial errors in chromosomes can occur, where a person

still only has a pair, but accidentally has entire sequences misplaced. These can lead to
diseases similar to trisomy. For example, Translocation Down Syndrome is a subtype
of Down Syndrome caused by translocation of a large sequence of a chromosome.

Subtraction disorders: The process of translocation can also cause large sequences of
DNA to be lost from chromosomes. This creates diseases similar to monosomy
conditions.

Mosaicisim: This refers to the bizarre situation where people have two types of cells
in the body. Some cells have normal chromosomes, and some cells have a disorder
such as a trisomy.

One-sided chromosome disorders: For these unusual diseases it matters whether the
chromosomes were inherited from the father or mother.

Non-contagiousness of chromosome diseases: All types of genetic diseases occur at birth

including chromosome diseases. You cannot catch the disease from someone else who has the
disease. You are either born with the error in your chromosomes or not Genetic tests can
determine whether or not a person has a chromosome disease, even as early as in the fetus by
antenatal testing for genetic diseases.
Sex Chromosome Conditions
Sex chromosome defects: There are various defects of the sex chromosomes. Normally a
man has XY and a woman XX. But the wrong combinations can arise with extra sex
chromosomes or missing ones:

Turner syndrome (XO syndrome, monosomy X, missing Y): This should just be called
the "X syndrome" because the person has an X, but no second sex chromosome. Such
people are female, as there is no male Y chromosome. It is a 1-in-5000 syndrome,
involving some relatively minor conditions, but usually sterility.

Klinefelter syndrome (XXY syndrome, also rarely XXXY): a 1-in-1000 disorder

where the person is usually male (because of the Y chromosome), but has lower levels
of testosterone and may have some female-like features (because there are two X
chromosomes), and is usually sterile. The rarer XXXY syndrome may lead to
retardation.

Jacobs syndrome (XYY syndrome): The person has an extra Y male chromosome. He
will be male and may be largely normal, or may suffer from minor features such as
excess acne and may be very tall, and in some cases behavioral complaints such as
aggression. Frequency around 1-in-2000.

Triple-X (XXX, also XXXX or XXXXX): These people are females with an
additional X chromosome. In rarer cases, there can even be 4 or 5 X chromosomes.
They can be largely normal, or may suffer from problems such as infertility (some but
not all), and reduced mental acuity. Occurs with a frequency around 1-in-700.

Note that there is no ordering, and XYX would be the same as XXY.

So there are viable combinations: XX (male), XY (female), XXY (Klinefelter), XXX, XYY,
and XO (Turner). They all contain the X chromosome. Interestingly, there has been no
combinations found that contain only Y: YO (Y, missing X), YY, or YYY syndromes. Not
even aborted fetal embryo cells with this combination have been found. It has been suggested
that there is something fundamental on the X chromosome that is needed for life.
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Down's syndrome

Extra chromosomes

Klinefelter

Inherited diseases

XYY

Trisomies

Chromosomal diseases

Monosomy

Syndromes
29) Autosomal Trisomy Chromosome Diseases
The 22 non-sex autosome chromosomes (autosomes) can also exhibit disorders, of which the
most common is trisomy (having 3 copies rather than a pair). Because these are disorders of
the autosomes and not the sex chromosomes, these disorders can occur with males or females.
These chromosome diseases arise rather surprisingly from an extra copy of the DNA, which
makes you wonder why having 3 copies of the code bad even when the DNA code on the
extra chromosome is actually correct. The condition of having 3 chromosomes is called
trisomy and the most common example for autosomes is Down syndrome.
Here is some details about particular autosome disorders:

Down syndrome (trisomy 21): an extra autosome creating a triplet at chromsome 21.
These people are usually mentally retarded, and have physical characteristics such as
an enlarged tongue and rounded flattened facial features. Frequency is around 1-in800 but risk increases with the age of the mother to around 1-in-25 for a 45-year-old
mother. The extra chromosome occurs because the mother's egg (or less commonly
father's sperm) has wrongly kept both of its autosome 21 pair.

Edwards syndrome (trisomy 18): an extra autosome at chromosome 18. Most fetuses
are aborted before term, but a live birth with this condition occurs with a frequency
around 1-in-3000. Edwards syndrome is more severe than Down's syndrome, and
includes mental retardation and numerous physical defects that often cause an early
death.

Patau syndrome (trisomy 13): a very severe disorder leading to mental retardation and
physical defects, occurring with a frequency around 1-in-5000. It is so severe that
many babies die soon after birth.

Miscarriages caused by trisomy: So we have seen trisomies at autosomes 13, 15, 18, and
21. Trisomy at the other autosomes seems to be fatal in embryos leading to spontaneous
miscarriage. The high frequency of natural miscarriages, around 1-in-5, occurs to a large
extent because of chromosome errors.
Causes of trisomy: Since Down syndrome occurs more frequently in older women, one
might theorize of the reason why. The most likely idea is that the problem is not during the
pregnancy, but at the start, with more eggs created with poorly separated chromosomes in
older women (about 1-in-5 for young women, compared to 3-in-4 for 40-year-old women).
However, another possibility is that the female body gradually loses its ability to recognize
wrong cells in a fetus. But it is not an immune issue because the uterus is an immuneprivileged site during pregnancy.
Partial trisomy: Down syndrome can be caused not only by a full trisomy, but also by a
partial trisomy at autosome 21. Due to errors in a process called "translocation", a part of a
chromosome can be wrongly attached to another pair. This creates a partial trisomy.
Another possible variant of Down's syndrome is a translocation between two pairs of
chromosomes, usually part of 21 gets add to the 14th. This also causes a variant known as
Translocation Down syndrome.
Mosaicism: Yet another chromosome oddity is mosaicism, where a person has different sets
of chromosomes in different cells. If some cells are normal and others have trisomy 21, then
Down syndrome results. Mosaicism can result from two paths. In the first method, the fetus
started with trisomy 21, and then one line of cells lost the trisomy. In the second method, the
fetus started normal, but somehow a cell line gained trisomy 21.
So why chromosome 21? It is one of the smaller chromosomes, and has relatively few genes
(maybe 200-250). Research continues into determining why having too many of these genes,
and consequent gene overexpression, leads to Down syndrome's characteristic mental and
physical features.
Monosomy and Autosome Subtraction Disorders
Monosomy occurs when there is only one of a pair of chromosomes and is usually nonviable. For example, the opposite of Down syndrome is monosomy-21, which is fatal. More

common are "subtraction disorders" which occur due to missing genetic material within
chromosomes, typically when a sequence of a chromosome is missing. The creation of
reproductive sperm and egg cells involves a complex process that can sometimes misplace
parts of a chromosome, such that one cell has an extra sequence (perhaps leading to one of the
trisomy disorders if this cell becomes a child), but if a child is generated from the other cell, it
may get a subtraction disorder.
Genomic imprinting is an epigenetic process that involves methylation and histone
modifications in order to achieve monoallelic gene expression without altering the genetic
sequence. These epigenetic marks are established in the germline and are maintained
throughout all somatic cells of an organism.
Appropriate expression of imprinted genes is important for normal development, with
numerous genetic diseases associated with imprinting defects including Beckwith-Wiedemann
syndrome, Silver-Russell Syndrome, Angelman Syndrome and Prader-Willi Syndrome.
PraderWilli syndrome (abbreviated PWS) is a rare genetic disorder in which seven genes
(or some subset thereof) on chromosome 15 (q 11-13) are deleted or unexpressed
(chromosome 15q partial deletion) on the paternal chromosome. It was first described in 1956
by Andrea Prader, Heinrich Willi, Alexis Labhart, Andrew Ziegler, and Guido Fanconi of
Switzerland.[1] The incidence of PWS is between 1 in 25,000 and 1 in 10,000 live births. The
paternal origin of the genetic material that is affected in the syndrome is important because
the particular region of chromosome 15 involved is subject to parent of origin imprinting,
meaning that for a number of genes in this region only one copy of the gene is expressed
while the other is silenced through imprinting. For the genes affected in PWS it is the paternal
copy that is usually expressed, while the maternal copy is silenced. This means that while
most people have a single working copy of these genes, people with PWS have no working
copy. PWS has the sister syndrome Angelman syndrome in which maternally derived genetic
material is affected in the same genetic region.
Signs and symptoms
patient with the syndrome, showing characteristic facial appearance, with elongated face,
prominent nose, and smooth philtrum
Clinical features and signs
Holm et al. (1993) describe the following features and signs as pretest indicators of PWS,
although not all will be present.
In utero:

Reduced fetal movement

Frequent abnormal fetal position

Occasional polyhydramnios (excessive amniotic fluid)

At birth:

Often breech or caesarean births

Lethargy Hypotonia

Feeding difficulties (due to poor muscle tone affecting sucking reflex)

Difficulties establishing respiration Hypogonadism

Infancy:

Failure to thrive (continued feeding difficulties) Delayed milestones/intellectual delay

Excessive sleeping Strabismus

Scoliosis (often not detected at birth)

Childhood:

Speech delay

Poor physical coordination

Hyperphagia (over-eating) from age 2 8 years. Note change from feeding difficulties
in infancy

Excessive weight gain

Sleep disorders

Scoliosis

General physical appearance (adults)

Prominent nasal bridge

Small hands and feet with tapering of fingers

Soft skin, which is easily bruised

Excess fat, especially in the central portion of the body

High, narrow forehead

Almond-shaped eyes with thin, down-turned lids

Light skin and hair relative to other family members

Lack of complete sexual development

Frequent skin picking

Striae

Delayed motor development

Angelman syndrome (AS) is a neuro-genetic disorder characterized by intellectual

and developmental delay, sleep disturbance, seizures, jerky movements (especially
hand-flapping), frequent laughter or smiling, and usually a happy demeanor.

AS is a classic example of genomic imprinting in that it is usually caused by deletion

or inactivation of genes on the maternally inherited chromosome 15 while the paternal
copy, which may be of normal sequence, is imprinted and therefore silenced. The
sister syndrome, Prader-Willi syndrome, is caused by a similar loss of paternally
inherited genes and maternal imprinting. AS is named after a British pediatrician, Dr.
Harry Angelman, who first described the syndrome in 1965.[1] An older, alternative
term for AS, happy puppet syndrome, is generally considered pejorative and
stigmatizing so it is no longer the accepted term, though it is sometimes still used as an
informal term of diagnosis. People with AS are sometimes known as "angels", both
because of the syndrome's name and because of their youthful, happy appearance.

31) terms pharmacogenomics and pharmacogenetics tend to be used interchangeably, and a

precise, consensus definition of either remains elusive. Pharmacogenetics is generally
regarded as the study or clinical testing of genetic variation that gives rise to differing
response to drugs, while pharmacogenomics is the broader application of genomic
technologies to new drug discovery and further characterization of older drugs.
Pharmacogenetics refers to genetic differences in metabolic pathways which can affect
individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.[1]
Genetic polymorphism
Since all polymorphism has a genetic basis, genetic polymorphism has a particular meaning:

Genetic polymorphism is the simultaneous occurrence in the same locality of two or

more discontinuous forms in such proportions that the rarest of them cannot be
maintained just by recurrent mutation.[7][14]:11

The definition has three parts: a) sympatry: one interbreeding population; b) discrete forms;
and c) not maintained just by mutation.
Genetic polymorphism is actively and steadily maintained in populations by natural selection,
in contrast to transient polymorphisms where a form is progressively replaced by another.[15]:6-7
By definition, genetic polymorphism relates to a balance or equilibrium between morphs. The
mechanisms that conserve it are types of balancing selection.

32) Conventional therapies are the treatments that doctors use as part of medical care to treat
people with cancer. These are surgery, radiotherapy, chemotherapy, hormonal and biological
therapies. They are also referred to as orthodox treatments. These treatments are usually tested
using scientific reasoning and research methods to prove their benefits and possible side
effects.

2.4.1 Techniques for inserting genes into cells

The ideal technique would repair or replace a faulty gene at its normal position in the
chromosome. While this is possible under certain conditions in the laboratory, the process
is still much too inefficient to be useful in treatment. Some of the better-developed
methods that are available do insert the normal gene into a chromosome, but have no
control over the location of insertion.
Genes can be inserted into cells in culture in the laboratory by a number of physical or
chemical techniques [for example, micro injection, attached to micro bullets,
precipitation on cells with calcium phosphate, in a lipid coat (liposome)], or can be
carried into the chromosomes by genetically modified viruses, including certain
retroviruses and parvoviruses. At present the use of genetically modified viruses holds
the most immediate promise. The retroviral technique will be described, as it has been the
most widely investigated to date.
The retroviruses include HIV and some viruses which cause tumours in mice. When
these viruses infect a cell they permanently insert their genetic material into the
chromosomes of the host cell. By removing the virus own genes and replacing them with
a human gene, the virus can be converted into a harmless but effective vehicle for
carrying the gene into a cell and for depositing it in one of the host cells chromosomes.
Because the virus has had its own genes removed it is no longer capable of replicating
within the cell or causing disease. While relatively safe, this process is not absolutely free
of risk, as there remains a small possibility that the process of gene insertion might
disrupt the function of a normal gene or switch on one that should normally be inactive.
One of the early limitations with retroviral vectors was that they were only effective in
cells that were actively dividing. This severely limited their potential, as many cell types
affected by genetic disease (such as nerve and muscle cells) do not normally undergo cell
division. Recently however, retroviral vectors derived from HIV and other closely related
viruses have been found to be capable of genetically modifying non-dividing cells, and
these vectors are currently being investigated and evaluated for possible clinical
application. Similarly, vectors based on the parvovirus, adeno-associated virus (AAV),
have been shown to be capable of successfully delivering genes into non-dividing cells

and appear particularly promising in nerve and muscle cells.

33) Antisense therapy is a form of treatment for genetic disorders or infections. When the
genetic sequence of a particular gene is known to be causative of a particular disease, it is
possible to synthesize a strand of nucleic acid (DNA, RNA or a chemical analogue) that will
bind to the messenger RNA (mRNA) produced by that gene and inactivate it, effectively
turning that gene "off". This is because mRNA has to be single stranded for it to be translated.
Alternatively, the strand might be targeted to bind a splicing site on pre-mRNA and modify
the exon content of an mRNA.[1]
This synthesized nucleic acid is termed an "anti-sense" oligonucleotide because its base
sequence is complementary to the gene's messenger RNA (mRNA), which is called the
"sense" sequence (so that a sense segment of mRNA " 5'-AAGGUC-3' " would be blocked by
the anti-sense mRNA segment " 3'-UUCCAG-5' ").
Antisense drugs are being researched to treat cancers (including lung cancer, colorectal
carcinoma, pancreatic carcinoma, malignant glioma and malignant melanoma), diabetes,
ALS, Duchenne muscular dystrophy and diseases such as asthma and arthritis with an
inflammatory component. Most potential therapies have not yet produced significant clinical
results, though one antisense drug, fomivirsen (marketed as Vitravene), has been approved by
the US Food and Drug Administration (FDA) as a treatment for cytomegalovirus retinitis.

Human adenovirus (Ad) vectors are extensively used as gene transfer vehicles. However, a
serious obstacle for the use of these vectors in clinical applications is due to pre-existing
immunity to human Ads affecting the efficacy of gene transfer. One of the approaches to
circumvent host immune response could be the development of vectors based on non-human
Ads that are able to transduce genes into human cells. In this study, we explored the
possibility of using avian Ad CELO vectors as gene-transfer vehicles. For this purpose, we
constructed a set of recombinant CELO viruses and demonstrated that they are able to deliver
transgenes into various organs on the background of pre-existing immunity to human Ad5.
The created CELO-p53 vector restored the function of the p53 tumor suppressor both in
cultured human tumor cells in vitro and in their xenografts in nude mice in vivo. The latter
effect was accompanied by inhibition of tumor growth. Noteworthily, the delivery of CELOp53 led to activation of p53 target genes in cells showing inactivation of endogenous p53 by
three different mechanisms, that is, in the human epidermoid carcinoma A431, lung
adenocarcinoma H1299, and cervical carcinoma HeLa.
However, despite the above potential advantages of CELO vectors to date, there were no
detailed studies devoted to testing their application in vivo. As the first step in this direction,
we characterized the abilities of CELO vectors (i) to deliver transgenes into different tissues,
(ii) to transfer transgenes into hosts bearing preformed anti-hAd5 antibodies, and (iii) to

achieve the inhibition of tumor growth following delivery of the p53 tumor-suppressor gene
into mice bearing human tumors.
The recombinant CELO viruses were constructed as described earlier17 by homologous
recombination between the CELO virus genome digested with SwaI restriction endonuclease
and a plasmid containing CMV promoter-driven cassettes expressing green fluorescent
protein (GFP), secreted alkaline phosphatase (SEAP) or p53 tumor suppressor, flanked by a
fragment of CELO virus DNA. The details of the design and the scheme of the resulting
recombinant CELO viruses are shown in Figure 1.
34) Genetic counselors
Genetic counseling or counselling (British English) is the process by which patients or
relatives, at risk of an inherited disorder, are advised of the consequences and nature of the
disorder, the probability of developing or transmitting it, and the options open to them in
management and family planning in order to prevent, avoid or ameliorate it. This complex
process can be separated into diagnostic (the actual estimation of risk) and supportive aspects.
[1]

The National Society of Genetic Counselors officially defines genetic counseling as the
process of helping people understand and adapt to the medical, psychological and familial
implications of genetic contributions to disease [2]. This process integrates:

Interpretation of family and medical histories to assess the chance of disease

occurrence or recurrence.

Education about inheritance, testing, management, prevention, resources and research.

Counseling to promote informed choices and adaptation to the risk or condition.

A genetic counselor is an expert with a Master of Science degree in genetic counseling. In the
United States they are certified by the American Board of Genetic Counseling.[1] Most enter
the field from a variety of disciplines, including biology, genetics, nursing, psychology, public
health and social work.[citation needed] Genetic counselors must be expert educators, skilled in
translating the complex language of genomic medicine into terms that are easy to understand.
Genetic counselors work as members of a health care team and act as a patient advocate as
well as a genetic resource to physicians. Genetic counselors provide information and support
to families who have members with birth defects or genetic disorders, and to families who
may be at risk for a variety of inherited conditions. They identify families at risk, investigate
the problems present in the family, interpret information about the disorder, analyze
inheritance patterns and risks of recurrence, and review available genetic testing options with
the family.

Genetic counselors are present at high risk or specialty prenatal clinics that offer prenatal
diagnosis, pediatric care centers, and adult genetic centers. Genetic counseling can occur
before conception (i.e. when one or two of the parents are carriers of a certain trait) through to
adulthood (for adult onset genetic conditions, such as Huntington's disease or hereditary
cancer syndromes).
Patients
Any person may seek out genetic counseling for a condition they may have inherited from
their biological parents.
A woman, if pregnant, may be referred for genetic counseling if a risk is discovered through
prenatal testing (screening or diagnosis). Some clients are notified of having a higher
individual risk for chromosomal abnormalities or birth defects. Testing enables women to
make the decision whether to continue with their pregnancy or facilitate the earliest
opportunity for treatment immediately after their baby is born.
A person may also undergo genetic counseling after the birth of a child with a genetic
condition. In these instances, the genetic counselor explains the condition to the patient along
with recurrence risks in future children. In all cases of a positive family history for a
condition, the genetic counselor can evaluate risks, recurrence and explain the condition itself.
[ Counseling session structure
The goals of genetic counseling are to increase understanding of genetic diseases, discuss
disease management options, and explain the risks and benefits of testing.[3] Counseling
sessions focus on giving vital, unbiased information and avoid sensitive topics. Seymour
Kessler, in 1979, first categorized sessions in five phases: an intake phase, an initial contact
phase, the encounter phase, the summary phase, and a follow-up phase.[4] The intake and
follow-up phases occur outside of the actual counseling session.
Reasons and results
Families may choose to attend counseling or undergo prenatal testing for a number of reasons.
[5]

Family history of a chromosome abnormality

Molecular test for single gene disorder

Increased maternal age (>35 years)

Abnormal serum screening results or ultrasound findings

Increased nuchal translucency

Detectable conditions

Most disorders cannot occur unless both the mother and father pass on their genes, such as
Cystic Fibrosis. Some diseases can be inherited from one parent, such as Huntingtons
disease. Other genetic disorders are the cause of an error or mutation occurring during the cell
division process (trisomy). Testing can reveal conditions that are easily treatable as long as
they are detected (Phenylketonuria or PKU). Results from genetic testing may also reveal:

Down syndrome

Sickle-cell anemia

Tay-Sachs disease

Spina bifida

Muscular dystrophy

Mental retardation

Genetic counselors as support

Genetic Alliance states that counselors provide supportive counseling to families, serve as
patient advocates and refer individuals and families to community or state support services.
They serve as educators and resource people for other health care professionals and for the
general public. Many engage in research activities related to the field of medical genetics and
genetic counseling. The field of genetic counseling is rapidly expanding and many counselors
are taking on "non-traditional roles" which includes working for genetic companies and
laboratories.[citation needed] When communicating increased risk, counselors anticipate the likely
distress and prepare women for the results. Counselors help clients cope with the emotional,
psychological, medical, social, and economic consequences of the test results.
[edit] Prenatal genetic counseling
If an initial noninvasive screening test reveals a risk to the fetus, clients are encouraged to
attend genetic counseling to learn about their options. Further prenatal investigation is
beneficial and provides helpful details regarding the status of the fetus, contributing to the
decision-making process. Decisions made by clients are affected by factors including timing,
accuracy of information provided by tests, and risk and benefits of the tests. Counselors
present a summary of all the options available. Clients may accept the risk and have no future
testing, proceed to diagnostic testing, or take further screening tests to refine the risk. Invasive
diagnostic tests possess a small risk of miscarriage (1-2%) but provide more definitive results.
Increased risk result is commonly presented in positively and negatively ways. While families
seek direction and suggestions from the counselors, they are reassured that no right or wrong
answer exists. When discussing possible choices, counselor discourse predominates and is
characterized by examples of what some people might do. Discussion enables people to place
the information and circumstances into the context of their own lives.[7] Clients are given a
decision-making framework they can use to situate themselves. The outcomes of tests may

reveal normal results but chromosomal anomaly and fetal death are possibilities. Counselors
focus on the importance of individual choice and do not encourage deliberation during their
informative sessions. Testing is offered because some diagnosed conditions cannot be
changed in any way and there is no therapy or treatment available to make it better. Therefore,
women must decide how they should proceed in their pregnancy after learning that their fetus
has a potential condition.
35) Prenatal diagnosis
Prenatal diagnosis or prenatal screening is testing for diseases or conditions in a fetus or
embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down
syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina
bifida, cleft palate, Tay Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, and
fragile x syndrome. Screening can also be used for prenatal sex discernment. Common testing
procedures include amniocentesis, ultrasonography including nuchal translucency ultrasound,
serum marker testing, or genetic screening. In some cases, the tests are administered to
determine if the fetus will be aborted, though physicians and patients also find it useful to
diagnose high-risk pregnancies early so that delivery can be scheduled in a tertiary care
hospital where the baby can receive appropriate care.
Fetal screening has also been done to determine characteristics generally not considered birth
defects, and avail for e.g. sex selection. The rise of designer babies and parental selection for
specific traits raises a host of bioethical and legal issues that will dominate reproductive rights
debates in the 21st century.
Invasiveness
Diagnostic prenatal testing can be by invasive or non-invasive methods. An invasive method
involves probes or needles being inserted into the uterus, e.g. amniocentesis, which can be
done from about 14 weeks gestation, and usually up to about 20 weeks, and chorionic villus
sampling, which can be done earlier (between 9.5 and 12.5 weeks gestation) but which may
be slightly more risky to the fetus. However since chorionic villus sampling is performed
earlier in the pregnancy than amniocentesis, typically during the first trimester, it can
reasonably be expected that there will be a higher rate of miscarriage after chorionic villus
sampling than after amniocentesis. Non-invasive techniques include examinations of the
woman's womb through ultrasonography and maternal serum screens (i.e. Alpha-fetoprotein)
and also genetic analysis on fetal cells isolated from maternal blood [1]. Non-invasive genetic
tests for Down Syndrome,
Fetal versus maternal
Some screening tests performed on the woman are intended to detect traits or characteristics
of the fetus. Others detect conditions in the woman that may have an adverse effect on the
fetus, or that threaten the pregnancy. For example, abnormally low levels of the serum marker
PAPP-A have been shown to correspond to an increased risk of pre-eclampsia, in which the

mother's high blood pressure can threaten the pregnancy, though many physicians find regular
blood-pressure monitoring to be more reliable.
[edit] Reasons for prenatal diagnosis
There are three purposes of prenatal diagnosis: (1) to enable timely medical or surgical
treatment of a condition before or after birth, (2) to give the parents the chance to abort a fetus
with the diagnosed condition, and (3) to give parents the chance to "prepare" psychologically,
socially, financially, and medically for a baby with a health problem or disability, or for the
likelihood of a stillbirth.
Having this information in advance of the birth means that healthcare staff as well as parents
can better prepare themselves for the delivery of a child with a health problem. For example,
Down Syndrome is associated with cardiac defects that may need intervention immediately
upon birth
Many expectant parents would like to know the sex of their baby before birth. Methods
include amniocentesis with karyotyping, and prenatal ultrasound. In some countries, health
care providers are expected to withhold this information from parents, while in other countries
they are expected to give this information.[citation needed]
[edit] Qualifying risk factors
Because of the miscarriage and fetal damage risks associated with amniocentesis and CVS
procedures, many women prefer to first undergo screening so they can find out if the fetus'
risk of birth defects is high enough to justify the risks of invasive testing. ACOG guidelines
currently recommend that all pregnant women, regardless of age, be offered invasive testing
to obtain a definitive diagnosis of certain birth defects. Therefore, most physicians offer
diagnostic testing to all their patients, with or without prior screening and let the patient
decide.
The following are some reasons why a patient might consider her risk of birth defects already
to be high enough to warrant skipping screening and going straight for invasive testing.

Women over the age of 35

Women who have previously had premature babies or babies with a birth defect,
especially heart or genetic problems

Women who have high blood pressure, lupus, diabetes, asthma, or epilepsy

Women who have family histories or ethnic backgrounds prone to genetic disorders, or
whose partners have these

Women who are pregnant with multiples (twins or more)

Women who have previously had miscarriages

Methods of prenatal screening and diagnosis

There are multiple ways of classifying the methods available, including the invasiveness and
the time performed.
Invasiveness Test

Comments

Time

Fetal Cells in
Non-invasive Maternal Blood
(FCMB)

Based on enrichment of fetal cells which

circulate in maternal blood. Since fetal cells
hold all the genetic information of the
First trimester
developing fetus they can be used to perform
prenatal diagnosis. [3]

During in vitro fertilization (IVF) procedures,

it is possible to sample cells from human
Preimplantation
embryos prior the implantation.[4] PGD is in prior to
Non-invasive Genetic Diagnosis
itself non-invasive, but IVF usually involves implantation
(PGD)
invasive procedures such as transvaginal
oocyte retrieval
External
Non-invasive
examination

Examination of the woman's uterus from

outside the body.

First or
second
trimester

Ultrasound
Non-invasive
detection

Commonly dating scans (sometimes known

as booking scans) from 7 weeks to confirm
pregnancy dates and look for twins. The
specialised nuchal scan at 1113 weeks may
be used to identify higher risks of Downs
syndrome. Later morphology scans from 18
weeks may check for any abnormal
development.

First or
second
trimester

Non-invasive Fetal heartbeat

Listening to the fetal heartbeat (see

stethoscope)

First or
second
trimester

Non-invasive Non-stress test

Use of cardiotocography during the third

trimester to monitor fetal wellbeing

Third
trimester

Maternal serum
Less invasive screening (triple
test)

Second trimester maternal serum screening

(AFP screening, triple screen, quad screen, or
Second
penta screen) can check levels of alpha
trimester
fetoprotein, -hCG, inhibin-A, estriol, and hhCG

Advances in Prenatal Screening

Measurement of fetal proteins in maternal serum is a part of standard prenatal screening for
fetal aneuploidy and neural tube defects.[9] [10] Computational predictive model shows that
extensive and diverse feto-maternal protein trafficking occurs during pregnancy and can be
readily detected non-invasively in maternal whole blood.[11] This computational approach
circumvented a major limitation, the abundance of maternal proteins interfering with the
detection of fetal proteins, to fetal proteomic analysis of maternal blood. Entering fetal gene
transcripts previously identified in maternal whole blood into a computational predictive
model helped develop a comprehensive proteomic network of the term neonate. It also shows
that the fetal proteins detected in pregnant womans blood originate from a diverse group of
tissues and organs from the developing fetus. Development proteomic networks dominate the
functional characterization of the predicted proteins, illustrating the potential clinical
application of this technology as a way to monitor normal and abnormal fetal development.
Typical screening sequence
California provides a useful guide to most of the currently available screening paradigms.[12]
At early presentation of pregnancy at around 6 weeks, early dating ultrasound scan may be
offered to help confirm the gestational age of the embryo and check whether a single or twin
pregnancy, but such a scan is unable detect common abnormalities. Details of prenatal
screening and testing options may be provided.
Around weeks 10-11, nuchal thickness scan (NT) may be offered which can be combined with
blood tests for PAPP-A and beta-hCG, two serum markers that correlate with chromosomal
abnormalities, in what is called the First Trimester Combined Test. The results of the blood
test are them combined with the NT ultrasound measurements, maternal age, and gestational
age of the fetus to yield a risk score for Down Syndrome, Trisomy 18, and Trisomy 13. First
Trimester Combined Test has a sensitivity (i.e. detection rate for abnormalities) of 82-87%
and a false-positive rate around 5%.
Alternatively, a second trimester Quad blood test may be taken (the triple test is widely
considered obsolete but in some states, such as Missouri, where Medicaid only covers the
Triple test, that's what the patient typically gets). With integrated screening, both a First
Trimester Combined Test and a Triple/Quad test is performed, and a report is only produced

after both tests have been analyzed. However patients may not wish to wait between these two
sets of test. With sequential screening, a first report is produced after the first trimester sample
has been submitted, and a final report after the second sample. With contingent screening,
patients at very high or very low risks will get reports after the first trimester sample has been
submitted. Only patients with moderate risk (risk score between 1:50 and 1:2000) will be
asked to submit a second trimester sample, after which they will receive a report combining
information from both serum samples and the NT measurement. The First Trimester
Combined Test and the Triple/Quad test together have a sensitivity of 88-95% with a 5%
false-positive rate for Down Syndrome, though they can also be analyzed in such a way as to
offer a 90% sensitivity with a 2% false-positive rate.
Conditions typically tested for
Use of NT ultrasound will screen for Down Syndrome (Trisomy 21), Edwards Syndrome
(Trisomy 18), and Patau Syndrome (Trisomy 13), whilst screens that only use serum markers
will screen for Down Syndrome and Trisomy 18, but not Trisomy 13. Considering that
Trisomy 13 is extremely rare, maybe 1:5000 pregnancies and 1:16000 births, this difference is
probably not significant. The AFP marker, whether alone or as part of the Quad test, can
identify 80% of spina bifida, 85% of abdominal wall defects, and 97% of anencephaly.
Frequently women will receive a detailed 2nd trimester ultrasound in Weeks 18-20
(Morphology scan) regardless of her AFP level, which makes the AFP score unnecessary.
Morphology ultrasound scans being undertaken on larger sized fetuses than in earlier scans,
detect other structural abnormalities such as cardiac and renal tract abnormailities.
Ethical issues of prenatal testing

The option to continue or abort a pregnancy is the primary choice after most prenatal
testing. Rarely, fetal intervention corrective procedures are possible.

Are the risks of prenatal diagnosis, such as amniocentesis worth the potential benefit?

Some fear that this may lead to being able to pick and choose what children parents
would like to have. This could lead to choice in sex, physical characteristics, and
personality in children. Some feel this type of eugenic abortion is already underway
(for example, sex selection)[citation needed].

Knowing about certain birth defects such as spina bifida and teratoma before birth
may give the option of fetal surgery during pregnancy, or assure that the appropriate
treatment and/or surgery be provided immediately after birth.

Questions of the value of mentally or physically disabled people in society.

How to ensure that information about testing options is given in a non-directive and
supportive way.

That parents are well informed if they have to consider abortion vs. continuing a
pregnancy. See wrongful abortion.

Will the result of the test affect treatment of the fetus?

In some genetic conditions, for instance cystic fibrosis, an abnormality can only be detected if
DNA is obtained from the fetus. Usually an invasive method is needed to do this.
If a genetic disease is detected, there is often no treatment that can help the fetus until it is
born. However in the US, there are prenatal surgeries for spina bifida foetus. Early diagnosis
gives the parents time to research and discuss post-natal treatment and care, or in some cases,
abortion. Genetic counselors are usually called upon to help families make informed decisions
regarding results of prenatal diagnosis.
False positives and false negatives
Ultrasound of a fetus, which is considered a screening test, can sometimes miss subtle
abnormalities. For example, studies show that a detailed 2nd trimester ultrasound, also called
a level 2 ultrasound, can detect about 97% of neural tube defects such as spina bifida[citation
needed]
. Ultrasound results may also show "soft signs," such as an Echogenic intracardiac focus
or a Choroid plexus cyst, which are usually normal, but can be associated with an increased
risk for chromosome abnormalities.
Both false positives and false negatives will have a large impact on a couple when they are
told the result, or when the child is born. Diagnostic tests, such as amniocentesis, are
considered to be very accurate for the defects they check for, though even these tests are not
perfect, with a reported 0.2% error rate (often due to rare abnormalities such as mosaic Down
Syndrome where only some of the fetal/placental cells carry the genetic abnormality).
A higher maternal serum AFP level indicates a greater risk for anencephaly and open spina
bifida. This screening is 80% and 90% sensitive for spina bifida and anencephaly,
respectively.[citation needed]
Amniotic fluid acetylcholinesterase and AFP level are more sensitive and specific than AFP in
predicting neural tube defects.
Many maternal-fetal specialists do not bother to even do an AFP test on their patients because
they do a detail ultrasound on all of them in the 2nd trimester, which has a 97% detection rate
for neural tube defects such as anencephaly and open spina bifida.
No prenatal test can detect all forms of birth defects and abnormalities.
36) Prenatal diagnosis
Prenatal diagnosis or prenatal screening is testing for diseases or conditions in a fetus or
embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down
syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina
bifida, cleft palate, Tay Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, and
fragile x syndrome. Screening can also be used for prenatal sex discernment. Common testing

procedures include amniocentesis, ultrasonography including nuchal translucency ultrasound,

serum marker testing, or genetic screening. In some cases, the tests are administered to
determine if the fetus will be aborted, though physicians and patients also find it useful to
diagnose high-risk pregnancies early so that delivery can be scheduled in a tertiary care
hospital where the baby can receive appropriate care.
Fetal screening has also been done to determine characteristics generally not considered birth
defects, and avail for e.g. sex selection. The rise of designer babies and parental selection for
specific traits raises a host of bioethical and legal issues that will dominate reproductive rights
debates in the 21st century.
Invasiveness
Diagnostic prenatal testing can be by invasive or non-invasive methods. An invasive method
involves probes or needles being inserted into the uterus, e.g. amniocentesis, which can be
done from about 14 weeks gestation, and usually up to about 20 weeks, and chorionic villus
sampling, which can be done earlier (between 9.5 and 12.5 weeks gestation) but which may
be slightly more risky to the fetus. However since chorionic villus sampling is performed
earlier in the pregnancy than amniocentesis, typically during the first trimester, it can
reasonably be expected that there will be a higher rate of miscarriage after chorionic villus
sampling than after amniocentesis. Non-invasive techniques include examinations of the
woman's womb through ultrasonography and maternal serum screens (i.e. Alpha-fetoprotein)
and also genetic analysis on fetal cells isolated from maternal blood [1]. Non-invasive genetic
tests for Down Syndrome,
Some screening tests performed on the woman are intended to detect traits or characteristics
of the fetus. Others detect conditions in the woman that may have an adverse effect on the
fetus, or that threaten the pregnancy. For example, abnormally low levels of the serum marker
PAPP-A have been shown to correspond to an increased risk of pre-eclampsia, in which the
mother's high blood pressure can threaten the pregnancy, though many physicians find regular
blood-pressure monitoring to be more reliable.
Reasons for prenatal diagnosis
There are three purposes of prenatal diagnosis: (1) to enable timely medical or surgical
treatment of a condition before or after birth, (2) to give the parents the chance to abort a fetus
with the diagnosed condition, and (3) to give parents the chance to "prepare" psychologically,
socially, financially, and medically for a baby with a health problem or disability, or for the
likelihood of a stillbirth.
Having this information in advance of the birth means that healthcare staff as well as parents
can better prepare themselves for the delivery of a child with a health problem. For example,
Down Syndrome is associated with cardiac defects that may need intervention immediately
upon birth

Advances in Prenatal Screening

Measurement of fetal proteins in maternal serum is a part of standard prenatal screening for
fetal aneuploidy and neural tube defects.[9] [10] Computational predictive model shows that
extensive and diverse feto-maternal protein trafficking occurs during pregnancy and can be
readily detected non-invasively in maternal whole blood.[11] This computational approach
circumvented a major limitation, the abundance of maternal proteins interfering with the
detection of fetal proteins, to fetal proteomic analysis of maternal blood. Entering fetal gene
transcripts previously identified in maternal whole blood into a computational predictive
model helped develop a comprehensive proteomic network of the term neonate. It also shows
that the fetal proteins detected in pregnant womans blood originate from a diverse group of
tissues and organs from the developing fetus. Development proteomic networks dominate the
functional characterization of the predicted proteins, illustrating the potential clinical
application of
Will the result of the test affect treatment of the fetus?
In some genetic conditions, for instance cystic fibrosis, an abnormality can only be detected if
DNA is obtained from the fetus. Usually an invasive method is needed to do this.
If a genetic disease is detected, there is often no treatment that can help the fetus until it is
born. However in the US, there are prenatal surgeries for spina bifida foetus. Early diagnosis
gives the parents time to research and discuss post-natal treatment and care, or in some cases,
abortion. Genetic counselors are usually called upon to help families make informed decisions
regarding results of prenatal diagnosis.
No prenatal Abstract
Introduction
Preimplantation genetic diagnosis (PGD) is widely used for women heterozygous for a
Robertsonian translocation. Preconceptional diagnosis (PCD), performed before fertilization,
may be an alternative to PGD, especially in countries where PGD is restricted or prohibited,
as in France. It could also give different information and clarify the influence of reproductive
and obstetric history.
Methods
In our study, translocation was diagnosed before ICSI in five cases (group A), and after
newborn or fetal aneuploidy or miscarriage in two cases, (group B).
Results
First polar body (PB1) analysis using acrocentric centromeric probes was done for 85 PB1s,
and aneuploidy rate was at 42.4%. Oocyte aneuploidy rate differed (p < 0.0001) between
groups A and B (30% vs 84%). Despite the small group sizes, we demonstrate a correlation (p

= 0.0358) of aneuploidy rate in polar bodies after 2 or more attempts. Three live births were
recorded, all in group A.
Discussion
PCD could thus be an alternative to PGD. This pilot study also provides new prognostic
information taking into account the womens natural history, but further confirmation is
required.
Keywords: First polar body biopsy, Robertsonian translocation, Previous aneuploidy,
Preconceptional diagnosis, FISH
37) Genetic testing
From Wikipedia, the free encyclopedia
Genetic Testing : Gene tests (also called DNA-based tests), the newest and most
sophisticated of the techniques used to test for genetic disorders, involve direct examination
of the DNA molecule itself. Other genetic tests include biochemical tests for such gene
products as enzymes and other proteins and for microscopic examination of stained or
fluorescent chromosomes. Genetic tests are used for several reasons, including:

carrier screening, which involves identifying unaffected individuals who carry one
copy of a gene for a disease that requires two copies for the disease to be expressed

preimplantation genetic diagnosis (see the side bar, Screening Embryos for Disease)

prenatal diagnostic testing

newborn screening

presymptomatic testing for predicting adult-onset disorders such as Huntington's

disease

presymptomatic testing for estimating the risk of developing adult-onset cancers and
Alzheimer's disease

confirmational diagnosis of a symptomatic individual

forensic/identity testing

Genetic testing allows the genetic diagnosis of vulnerabilities to inherited diseases, and can
also be used to determine a child's paternity (genetic father) or a person's ancestry. Normally,
every person carries two copies of every gene, one inherited from their mother, one inherited
from their father. The human genome is believed to contain around 20,000 - 25,000 genes. In
addition to studying chromosomes to the level of individual genes, genetic testing in a broader
sense includes biochemical tests for the possible presence of genetic diseases, or mutant forms
of genes associated with increased risk of developing genetic disorders. Genetic testing
identifies changes in chromosomes, genes, or proteins.[1] Most of the time, testing is used to
find changes that are associated with inherited disorders. The results of a genetic test can
confirm or rule out a suspected genetic condition or help determine a person's chance of

developing or passing on a genetic disorder. Several hundred genetic tests are currently in use,
and more are being developed.[2][3]
Since genetic testing may open up ethical or psychological problems, genetic testing is often
accompanied by genetic counseling.
Types
Genetic testing is "the analysis of, chromosomes (DNA), proteins, and certain metabolites in
order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for
clinical purposes."[4] It can provide information about a person's genes and chromosomes
throughout life. Available types of testing include:

Newborn screening: Newborn screening is used just after birth to identify genetic
disorders that can be treated early in life. The routine testing of infants for certain
disorders is the most widespread use of genetic testingmillions of babies are tested
each year in the United States. All states currently test infants for phenylketonuria (a
genetic disorder that causes mental illness if left untreated) and congenital
hypothyroidism (a disorder of the thyroid gland).

Diagnostic testing: Diagnostic testing is used to diagnose or rule out a specific genetic
or chromosomal condition. In many cases, genetic testing is used to confirm a
diagnosis when a particular condition is suspected based on physical mutations and
symptoms. Diagnostic testing can be performed at any time during a person's life, but
is not available for all genes or all genetic conditions. The results of a diagnostic test
can influence a person's choices about health care and the management of the disease.

Carrier testing: Carrier testing is used to identify people who carry one copy of a gene
mutation that, when present in two copies, causes a genetic disorder. This type of
testing is offered to individuals who have a family history of a genetic disorder and to
people in ethnic groups with an increased risk of specific genetic conditions. If both
parents are tested, the test can provide information about a couple's risk of having a
child with a genetic condition.

Prenatal testing: Prenatal testing is used to detect changes in a fetus's genes or

chromosomes before birth. This type of testing is offered to couples with an increased
risk of having a baby with a genetic or chromosomal disorder. In some cases, prenatal
testing can lessen a couple's uncertainty or help them decide whether to abort the
pregnancy. It cannot identify all possible inherited disorders and birth defects,
however.

Preimplantation genetic diagnosis: Genetic testing procedures that are performed on

human embryos prior to the implantation as part of an in vitro fertilization procedure.

Predictive and presymptomatic testing: Predictive and presymptomatic types of testing

are used to detect gene mutations associated with disorders that appear after birth,
often later in life. These tests can be helpful to people who have a family member with
a genetic disorder, but who have no features of the disorder themselves at the time of
testing. Predictive testing can identify mutations that increase a person's chances of

developing disorders with a genetic basis, such as certain types of cancer. For
example, an individual with a mutation in BRCA1 has a 65% cumulative risk of breast
cancer [1]. Presymptomatic testing can determine whether a person will develop a
genetic disorder, such as hemochromatosis (an iron overload disorder), before any
signs or symptoms appear. The results of predictive and presymptomatic testing can
provide information about a persons risk of developing a specific disorder and help
with making decisions about medical care.

Forensic testing: Forensic testing uses DNA sequences to identify an individual for
legal purposes. Unlike the tests described above, forensic testing is not used to detect
gene mutations associated with disease. This type of testing can identify crime or
catastrophe victims, rule out or implicate a crime suspect, or establish biological
relationships between people (for example, paternity).

Parental testing: This type of genetic test uses special DNA markers to identify the
same or similar inheritance patterns between related individuals. Based on the fact that
we all inherit half of our DNA from the father, and half from the mother, DNA
scientists test individuals to find the match of DNA sequences at some highly
differential markers to draw the conclusion of relatedness.

Research testing: Research testing includes finding unknown genes, learning how
genes work and advancing our understanding of genetic conditions. The results of
testing done as part of a research study are usually not available to patients or their
healthcare providers.

Pharmacogenomics: type of genetic testing that determines the influence of genetic

variation on drug response.

Medical procedure
Genetic testing is often done as part of a genetic consultation and as of mid-2008 there were
more than 1,200 clinically applicable genetic tests available.[5] Once a person decides to
proceed with genetic testing, a medical geneticist, genetic counselor, primary care doctor, or
specialist can order the test after obtaining informed consent.
Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that
surrounds a fetus during pregnancy), or other tissue. For example, a medical procedure called
a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside
surface of the cheek. Alternatively, a small amount of saline mouthwash may be swished in
the mouth to collect the cells. The sample is sent to a laboratory where technicians look for
specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder.
The laboratory reports the test results in writing to a person's doctor or genetic counselor.
Interpreting results
The results of genetic tests are not always straightforward, which often makes them
challenging to interpret and explain. When interpreting test results, healthcare professionals
consider a persons medical history, family history, and the type of genetic test that was done.

A positive test result means that the laboratory found a change in a particular gene,
chromosome, or protein of interest. Depending on the purpose of the test, this result may
confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify
an increased risk of developing a disease (such as cancer) in the future, or suggest a need for
further testing. Because family members have some genetic material in common, a positive
test result may also have implications for certain blood relatives of the person undergoing
testing. It is important to note that a positive result of a predictive or presymptomatic genetic
test usually cannot establish the exact risk of developing a disorder. Also, health professionals
typically cannot use a positive test result to predict the course or severity of a condition.
Risks and limitations
The physical risks associated with most genetic tests are very small, particularly for those
tests that require only a blood sample or buccal smear (a procedure that samples cells from the
inside surface of the cheek). The procedures used for prenatal testing carry a small but real
risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or
tissue from around the fetus.
Direct-to-Consumer genetic testing
Direct-to-Consumer (DTC) genetic testing is a type of genetic test that is accessible directly to
the consumer without having to go through a health care professional. Usually, to obtain a
genetic test, health care professionals such as doctors acquire the permission of the patient and
order the desired test. DTC genetic tests, however, allow consumers to bypass this process
and order one themselves. There are a variety of DTC tests, ranging from testing for breast
cancer alleles to mutations linked to cystic fibrosis. Benefits of DTC testing are the
accessibility of tests to consumers, promotion of proactive healthcare and the privacy of
genetic information. Possible additional risks of DTC testing are the lack of governmental
regulation and the potential misinterpretation of genetic information.
38) A genetic screen (often shortened to screen) is a procedure or test to identify and select
individuals who possess a phenotype of interest. A genetic screen for new genes is often
referred to as forward genetics as opposed to reverse genetics, the term for identifying
mutant alleles in genes that are already known. Mutant alleles that are not tagged for rapid
cloning are mapped and cloned by positional cloning.
What is newborn genetic screening?
Newborn genetic screening is a health program that identifies treatable genetic disorders in
newborn infants. Early intervention to treat these disorders can eliminate or reduce symptoms
that might otherwise cause a lifetime of disability.
Who performs newborn screening?
Newborn genetic screening programs are conducted worldwide. In the United States, newborn
screening programs are developed and run by individual states. Each state decides which

disorders to test for and how to cover the costs of screening.

Who is screened?
In most cases, newborn infants are automatically screened in the hospital shortly after
delivery.
Who pays for screening?
Individual states in the United States finance their newborn screening programs in different
ways. Most states collect a fee for screening, which ranges from less than $15 to nearly $60
per newborn. Health insurance or other programs can pay this fee for the newborn's parents.
Often, the fee charged does not fully cover the cost of screening, so public health system
funding is used to supplement the program. Financing a screening program comes with an
expectation that the benefits of testing - early detection and treatment - will equal or exceed
the cost.
Who decides?
Lawmakers in each state have enacted legislation that defines the state's newborn screening
program. From time to time, these programs need review and revision to incorporate new
technologies, address financial issues and ensure that the screening program is meeting the
needs of the state's residents.
Prenatal Genetic Information - Disclaimer
This site is designed to provide an introduction to basic genetics and genetic testing for
patients who are pregnant or are considering a pregnancy. The information included on this
site is not intended to cover all situations in which genetic testing and/or genetic counseling
are appropriate. Any questions you have should be directed to your family physician or
genetic counselor. Publications, links, and other communications found on this site are
provided for general informational purposes only; they are not intended as a substitute for
medical advice and/or consultation with an appropriate physician or technical expert.
LabCorp is not responsible for the content of any sites or non-LabCorp materials that are
linked to this site. Please consult your family physician for matters relating to your personal
health. Please keep in mind that the field of genetics is constantly changing; therefore, it is
important to involve your physician to ensure that you receive the latest available information.
39) Genetic screening by DNA technology: a systematic review of health economic
evidence.
OBJECTIVES: The Human Genome Project has led to a multitude of new potential
screening targets on the level of human DNA. The aim of this systematic review is to
critically summarize the evidence from health economic evaluations of genetic screening in
the literature.

METHODS: Based on an extensive explorative search, an appropriate algorithm for a

systematic database search was developed. Twenty-one health economic evaluations were
identified and appraised using published quality criteria.
RESULTS: Genetic screening for eight conditions has been found to be investigated by
health economic evaluation: hereditary breast and ovarian cancer, familial adenomatous
polyposis (FAP) colorectal cancer, hereditary nonpolyposis colorectal carcinoma (HNPCC),
retinoblastoma, familial hypercholesterolemia, hereditary hemochromatosis, insulindependent diabetes mellitus, and cystic fibrosis. Results range from dominated to cost-saving.
Population-wide genetic screening may be considered cost-effective with limited quality of
evidence only for three conditions. The methodology of the studies was of varying quality.
Cost-effectiveness was primarily influenced by mutation prevalence, genetic test costs,
mortality risk, effectiveness of treatment, age at screening, and discount rate.
CONCLUSIONS: Health economic evidence on genetic screening is limited: Only few
conditions have properly been evaluated. Based on the existing evidence, healthcare decision
makers should consider the introduction of selective genetic screening for FAP and HNPCC.
As genetic test costs are declining, the existing evaluations may warrant updating. Especially
in the case of hereditary hemochromatosis, genetic population screening may be about to turn
from a dominated to a cost-effective or even cost-saving intervention. INTRODUCTION
As we near a new millennium, technology changes the world at an astonishing rate. Almost no
aspect of our world is as it was only a few years ago. Included within this change is the advent
of new reproductive technologies which influence the choices available to prospective
parents.
Among these new technologies is the ability for science to accurately predict the genetic
make-up of a fetus. 2
40) SOME ETHICAL ISSUES IN HUMAN GENETICS 23
FAC T S H E E T
Produced by the Centre for Genetics Education. Internet: http://www.genetics.edu.au
Important points
Ethical issues need to be considered if the benefits are maximised and the harms minimised
from the increasing ability to use

genetic testing to analyse an individuals genetic information. Ethical issues that arise are
generated from:
The shared nature and ownership of genetic information. The doctors ethical
responsibilities include balancing the privacy
and confidentiality of the individual and prevention of harm to others (the duty of care). The
individual tested also has family
responsibilities and obligations including dissemination of genetic test results within the
family to enable informed decisionmaking
by their at-risk relatives.
Limitations of genetic testing. While in some cases, genetic tests provide reliable and
accurate information on which people
can make decisions, in other cases it may not be possible to obtain a definitive result. An
individual is much more than the
sum of their genes: the individuals environment can modify the expression of genetic
messages to the body and many factors
are not genetic that make an individual who they are
The discovery of a change in a particular gene may provide some information about the
nature of the condition that the
person has, will develop or for which they may be at increased risk, but can rarely predict the
severity of the condition
or the age at which symptoms will first onset and in prenatal testing, the potential for quality
of life for the child or the
severity of a particular condition
Inappropriate applications of genetic testing such as for the sole purpose of family
balancing (sexing of a fetus for this reason)
or its use in paternity testing without the informed consent of all parties involved
The potential for discrimination especially with the use of information generated by the
use of predictive/presymptomatic
testing results - generally for adult-onset conditions - in life insurance applications and
employment (see Genetics Fact Sheet
23A for more information and about genetic testing and life insurance products in Australia)
Setting boundaries in applications of the genetics technology. This is one of the greatest
challenges to find the way to
implement regulations internationally such as in the areas of reproductive cloning and genetic
testing for enhancement.
It is also important to recognise and respect the moral, religious and cultural beliefs that
underpin the decision-making by
individuals, couples, families or communities
Forensic DNA databanks. Ensuring that they are used for the purpose for which they were
collected and protected from
misuse. Also, where the public has also assisted the police by volunteering genetic samples to
assist in the investigations of
unsolved crimes, ensure that special protections are put in place for the DNA samples and the
information generated