Clinical Features and Molecular

Diagnosis of Most Common

Hereditary Diseases
(Genetic Diseases)

PART I

Dr. Mohamed Ali, M.Sc.. M.Phil., B.Ed., M.S (Sing)., Ph.D (Sing)
Professor & Supervisor
Department of Clinical Biochemistry
Faculty of Medicine
University of Tabuk
•Watson and Crick
started it all in 1953
with the description of
DNA

•63 Year Anniversary

of the paper was in
April.

•Both Won Nobel

Prize
 What are We Looking For?

Earth City Street Address

Human Genome Chromosome Band Gene (DNA)

 640 cubic yards 3,000 MB

1/100 cubic inch 1 x 10-6 MB

It really is like finding a needle in a haystack!

(and a very BIG haystack, at that)
The DNA Between Individuals is Identical.
All differences are in the 0.1% of DNA that varies.

A A
C C
C C
G G
T T
It’s hard to
C G
C C believe sometimes!
A A
G G
G G
 Chromosomal Diseases

• Gametes have abnormal chromosome numbers

and mutations

• Offspring inherit extra chromosome or are

missing a chromosome

• Caused by problems with meiosis

Nondisjunction of chromosomes during meiosis

Based on: Brooks/Cole – Thomson Learning

 Important Points about Inheritance

•Genes have different forms, called alleles

•Each trait is controlled by effects of two alleles

•Some alleles are:

• dominant/recessive
• other alleles are co-dominant
 Hairline Traits
•Allele for Widow’s Peak •Allele for Straight Hairline
is dominant is recessive
•A person with WW or Ww •A person with ww will have
will have Widow’s Peak a Straight Hairline
 Genotype vs. Phenotype
•Genotype refers to the alleles

•Phenotype refers to the appearance

Example: Genotype - Phenotype

WW - person has a widow’s peak
Ww - person has a widow’s peak
ww - person has a straight hair line
 Genetics & Human Diseases
PART I
• About 4,000 human diseases are thought to be
inherited.

• Scientists are making good progress figuring out where

genes are located on chromosomes.

• Genetic diseases are caused by mutations, or

incorrect sequences, in the normal form of the gene.
 Genetic/hereditory diseases
 traditionally - 3 types of diseases
 1. genetically determined
 2. environmentally determined
 3. 1. + 2.
 today - distinctions are blurred
 up to 20% of pediatric in-patients have genetic
abnormality
 about 50% of spontaneous abortuses have chromosomal
aberration
 only mutations that are not lethal are reservoir of genetic
diseases
 CLASSES OF HUMAN
GENETIC DISEASE
• Diseases of Simple Genetic Architecture
– Can tell how trait is passed in a family: follows a recognizable pattern
– One gene per family
– Often called Mendelian disease
– Usually quite rare in population
– “Causative” gene
• Diseases of Complex Genetic Architecture
– No clear pattern of inheritance
– Moderate to strong evidence of being inherited
– Common in population: cancer, heart disease, dementia etc.
– Involves many genes or genes and environment
– “Susceptibility” genes
 Modes of Inheritance

• Autosomal Dominant
– Huntington disease
• Autosomal Recessive
– Cystic fibrosis
• X-linked
– Duchenne muscular dystrophy
• Mitochondrial
– Leber Optic atrophy
• Additive
– HLA-DR in multiple sclerosis
• Combinations of the above
– RP (39 loci), Nonsyndromic deafness
 Terminology
• hereditary = derived from parents
• familial = transmitted in the gametes through
generations
• congenital = present at birth (not always genetically
determined - e.g. congenital syphilis, toxoplasmosis)
• ! not all genetical diseases are congenital - e.g.
Huntington disease - 3rd to 4th decade of life
 Classification
• 3 groups of genetic diseases

• 1. Disorders with multifactorial inheritance

(polygenic)
• 2. Monogenic (mendelian) disorders
• 3. Chromosomal aberrations
 1. Disorders with multifactorial
inheritance (polygenic)
• influence of multiple genes + environmental factors
• relatively frequent
• Diabetes mellitus (see Endocrine pathology)
• Hypertension (see Circulation)
• Gout (discussed here + see Crystals)
• Schizophrenia (Psychiatry)
• Congenital heart disease - certain forms (see Heart)
• Some types of cancer (ovarian, breast, colon) (see
Neoplasms)
• often familial occurrence - probability of disease is in 1st
degree relatives about 5-10%; 2nd degree relatives - 0,5-1%
 Gout
• genetically impaired metabolism of uric acid (end
product of purine metabolism)
• tissue accumulation of excessive amounts of UA
crystals
• recurrent episodes of acute arthritis - precipitation of
monosodium urate crystals inside the joints
• formation of large crystalline aggregates - tophi
• chronic destruction of joints - joint deformity
• renal injury
• M>F
• Primary gout (90% of cases)
• unknown enzymatic defect

• Secondary gout (10%)

• known cause of hyperuricemia (increased
turnover of nucleic acids - e.g. leukemias;
chronic renal disease; increased intake -
game, red wine)
 Morphology
• Acute arthritis
• any joint, mostly hallux - abrupt and intense pain
• reason??? - lower temperature?
• Chronic arthritis
• permanent precipitation - tophi - inflammation
(lymphocytes, histiocytes)
• destruction of cartilage, fibrosis of synovial
membrane, ankylosis
• Kidneys - 3 forms
• medulla (papillae), tophi, kidney stones
• tophi are formed in the vicinity of joints, bursa olecrani, bursa
preapatellaris, auricle
• less frequently kidneys, other tissues
• urate crystals are soluble in water! - fixation in absolute alcohol
(biopsy!!!)
• turns polarized light
• patients with gout - obese, increased risk of hypertension,
arteriosclerosis
• Clinical presentation - 3 stages
• 1. asymptomatic hyperuricaemia
• 2. acute arthritis - attacks of acute pain (days-weeks), silent
periods (months-years)
• 3. chronic changes - tophi, ankylosis, in 20% chronic renal
failure
 2. Monogenic (mendelian) disorders
• mutation of 1 gene, mendelian type of
inheritance
• today about 5000 diseases
• Autosomal dominant
• Autosomal recessive
• X-linked
 Autosomal dominant disorders
• both homozygotes and heterozygotes are
affected
• usually heterozygotes (inherited from one
parent)
• both males and females are affected
• transmission from one generation to the other
• 50% of children are affected
 Familial hypercholesterolemia
• (= subgroup of hyperlipoproteinemia)
• most frequent mendelian disorder - 1:500
• mutation of gene encoding LDL-receptor (70% of plasma
cholesterol)
• heterozygotes 2-3× elev. of plasma cholesterol levels
• homozygotes 5× elevation of plasma cholesterol levels
• heterozygotes asymptomatic until adulthood - xanthomas
along tendon sheets, coronary AS
• homozygotes - xanthomas in childhood, death due to MI by
the age of 15Y
 Marfan syndrome
• French pediatrician Marfan - 1896 - young girl
with typical habitus
• abnormal protein fibrillin - secreted by
fibroblasts, part of ECM
• impairment of collagenous and elastic tissue -
decreased firmness of connective tissue
• principal clinical manifestations - 3 systems
 1. skeleton
• slender, elongated habitus
• long legs, arms and fingers (arachnodactyly) -
El Greco!
• high, arched (Gothic) palate
• hyperextensibility of joints
• spinal deformities, pectus excavatum, pigeon
breast - pres. Lincoln???
 2. ocular changes
• dislocation or subluxation of the lens
(weakness of suspensory ligaments)

3. cardiovascular system
• fragmentation of elastic fibers in tunica media
- aorta
• aneurysmal dilatation - aortic dissection -
rupture (35-45% of pts.)
• incompetence (dilatation) - aortic valve
• tricuspidal and/or mitral valve - floppy valve
 Ehlers-Danlos syndrome
• similar to Marfan syndrome
• genetic defect of collagen fibrils - several types
- both autosomal dominant and recessive
• hyperextensibility of skin, hypermobility of
joints - contortionist!
• joint dislocations, vulnerability
• rupture of large vessels, colon, cornea
 2. Autosomal recessive
• majority of mendelian disorders
• only homozygotes are affected, heterozygotes
(parents) are only carriers
• 25% of descendants are affected
• if the mutant gene occurs with low frequency - high
probability in consanguineous marriages
• onset of symptoms often in childhood
• frequently enzymatic defect
• testing of parents and amnial cells
 Cystic fibrosis
• 1:2000 live births - most common lethal genetic
disease in white population
• defect in the transport of chloride ions across
epithelia - increased absorption of Na+ and water to
the blood
• widespread defect in the exocrine glands -
abnormally viscid mucous secretions
• blockage of airways, pancreatic ducts, biliary ducts
• Pancreatic abnormalities (85%) - dilatation of
ducts, atrophy of exocrine part, fibrosis
• Pulmonary lesions - dilatation of bronchioles,
mucus retention, repeated inflammation,
bronchiectasis, lung abscesses, emphysema and
atelectasis (100%), cor pulmonale chronicum
• GIT - meconium ileus (newborns) (25%), biliary
cirrhosis (2%)
• Male genital tract - sterility (obstruction of vas
deferens, epididymis, seminal vesicles) (95%)
 Clinical symptomatology
• recurrent pulmonary infections
• pancreatic insufficiency, malabsorption syndrome
(large, foul stool), hypovitaminosis A, D, E, K, poor
weight gain
• high level of sodium in the sweat - "salty" children -
mother's diagnosis
• death usually in 3. decade due to respiratory failure
 Phenylketonuria (PKU)

• absence of enzyme phenylalanine-hydroxylase (PAH) Phe -

>Tyr
• increase of plasmatic Phe since birth - rising levels - impairs
brain development
• after 6M - severe mental retardation - IQ under 50
• decreased pigmentation of hair and skin - absence of Tyr
• EARLY SCREENING TEST!!!
• DIET!!!
• mothers with PKU - increased levels of Phe - transplacental
transport - child with severe mental defect (although
heterozygous!) - maternal PKU - DIET!!!
 Galactosemia

• defect of galactose metabolism

• lactose -> Gal+Glc
• Gal -> Glc - defect - accumulation of Gal in blood
• liver, eyes, brain are affected
• hepatomegaly (fatty change - fibrosis - cirrhosis)
• lens - opacification - cataracts
• brain - loss of neurons, gliosis, edema
• Symptomatology - from birth
• vomiting, diarrhea, jaundice, hepatomegaly
• later - cataracts, mental retardation
• DIET!
 Glycogen storage diseases
(glycogenoses)
• deficiency of any one of the enzymes involved in
degradation or synthesis
• depending on the type of defect - tissue distribution,
type of accumulated product
• 12 forms - most important:
• type I. - von Gierke disease - hepatorenal type
• type II. - Pompe disease - generalized type (liver,
heart, skeletal muscle)
• type V. - McArdle syndrome - skeletal muscle only
• biopsy: PAS, Best's carmine
 Lysosomal storage diseases
• defect of lysosomal enzymes, hydrolyzing
various substances (a.o. sphingolipids,
mucopolysacharides) - storage of insoluble
metabolites in lysosomes
• extremely rare

Sphingolipidoses
• more frequent in Ashkenazi Jews
 Gaucher disease
• defect of glucocerebrosidase - 3 types (type 1
- survival, type 2 - lethal, type 3 -
intermediate)
• accumulation of glucocerebroside (Glc-
ceramide) - kerasin
• Gaucher cells - spleen (red pulp), liver
(sinuses), bone marrow
 Niemann-Pick disease
• defect of sphingomyelinase
• accumulation of cholesterol and
sphingomyelin in spleen, liver, BM, LN, lungs -
massive visceromegaly
• CNS (foamy cells) - severe neurological
deterioration
• death during first 4-5 years
Tay-Sachs disease (gangliosidosis)

• neurons and glial cells of CNS - mental

retardation, blindness
 Mucopolysacharidoses

• MP synthesized in the connective tissue by fibroblasts -

part of the ground substance
• several clinical variants (I-VII)
• involvement of liver, spleen, heart (valves, coronary
arteries), blood vessels
• Symptoms: coarse facial features (gargoylism), clouding
of the cornea, joint stiffness, mental retardation
• usually death in childhood (cardiac complications)
• most frequent Hurler syndrome and Hunter syndrome
(X-linked!)
 X-linked diseases
• transmitted by heterozygous mother to sons
• daughters - 50% carriers, 50% healthy
• sons - 50% diseased, 50% healthy
• Children of diseased father - sons are healthy, all
daughters are carriers
• Hemophilia A (defect of Factor VIII)
• Hemophilia B (defect of Factor IX)
• Muscle dystrophy (Duchen disease)
 3. Chromosomal aberrations
(cytogenetic disorders)
• alternations in the number or structure of chromosomes
• autosomes or sex chromosomes
• studied by cytogenetics
• cell cycle arrested in metaphase (colchicin) - staining by
Giemsa method (G-bands) - photographing - karyotype
• 2 sets of 23 chromosomes
• 22 pairs of autosomes, 2 sex chromosomes (XX or XY)
• cytogenetic disorders are relatively frequent! (1:160
newborns; 50% of spontaneous abortions)
 Numerical abnormalities
• euploidy - normal 46 (2n)
• polyploidy (3n or 4n) - spontaneous abortion
• aneuploidy
• trisomy (2n+1) - 47 - compatible with life
• monosomy (2n-1) - autosomal - incompatible
with life
• - sex chromosomal -
compatible with life
 Structural abnormalities

• breakage followed by loss or rearrangement

• deletion, translocation
Generally:
• loss of chromosomal material is more dangerous than
gain
• abnormalities of sex chromosomes are better tolerated
than autosomal
• abnormalities of sex chromosomes sometimes
symptomatic in adult age (e.g. infertility)
• usually origin de novo (both parents and siblings are
normal)
 Autosomal disorders
Trisomy 21 (Down syndrome)
• most frequent - 1:700 births; parents have
normal karyotype
• maternal age has a strong influence: <20 y.
1:1550 live births, >45 y. 1:25 live births
• most frequently is abnormality in ovum (ovum
is under long-time influence of enviroment)
 Clinical symptoms
• mental retardation (IQ 25-50)
• flat face + epicanthus
• congenital heart defects
• neck skin folds
• skeletal muscle hypotonia
• hypermobility of joints
• increased risk of acute leukemias
• mortality 40% until 10Y (cardiac complications)
 Less frequent disorders

• Trisomy 18 (Edwards syndrome) 1:8000

• Trisomy 13 (Patau syndrome) 1:15000
 Sex chromosomal disorders
• a number of karyotypes from 45(X0) to 49
(XXXXY) - compatible with survival
• normally - in females 1 of X is inactivated (all
somatic cells contain Barr body)
• ! male phenotype is encoded by Y
 Klinefelter syndrome (47, XXY)

• 1:1000 males
• additional X is either of paternal or maternal origin
• advanced maternal age, history of irradiation of
either of parents
• wide range of clinical manifestations
• distinctive body habitus - increase length between
soles and pubic bone
• reduced body and facial hair
• gynecomastia
• testicular atrophy - impaired spermatogenesis -
sterility (rarely fertility! - mosaics)
 Turner syndrome (45, X0)
• 1:3000 females
• primary hypogonadism in phenotypic female
• growth retardation (short stature, webbing of
the neck, low posterior hairline, broad chest,
cubitus valgus)
• streak ovaries - infertility, amenorrhea,
infantile genitalia, little pubic hair
 Prenatal diagnostics
• amniocentesis - analysis of amniotic fluid
• cytogenetic analysis (karyotype - e.g. Down)
• biochemical activity of various enzymes (e.g. Tay-
Sachs)
• analysis of various specific genes (CF gene - PCR)
• sex of the fetus (X-linked disorders - hemophilia)
 Pediatric diseases
• infants and children
• first year of life - high mortality
• highest mortality - neonatal period (first 4W;
perinatal first 1W)
• between 1Y and 15Y of age - the leading cause
of death = injuries from accidents
 Congenital malformations
• structural defects present at birth - some may
become apparent later!
• etiology is either genetic or environmental
• viral infections (rubella, CMV) - during first 3M
• other infectious (toxoplasmosis, syphilis, HIV)
• drugs (thalidomide, alcohol, cytostatics)
• irradiation
• in 40-60% is the cause unknown!
 Perinatal infections

• ascending (transcervical) - in utero or

during birth (HSV, HIV)
• transplacental - syphilis, toxoplasmosis,
rubella, CMV
 Prematurity
• higher morbidity and mortality than in full term babies
• before 37.-38. W
• high risk - weight <2500g
• intracerebral bleeding (immature vessels in basal ganglia)
• infant respiratory distress syndrome RDS - decrease in
surfactant synthesis; 15-20% 32.-36.W vs. 60% <28.W
• SIDS - sudden infant death syndrome (crib death, cot
death)
• Erythroblastosis fetalis - hemolysis due to ABO or Rh
incompatibility between mother and fetus
 Tumors
• benign vs. malignant
• benign (hemangioma - nevus flammeus - port wine
stains, lymphangioma - hygroma colli cysticum,
sacrococcygeal teratoma)
• malignant (hematopoietic - malignant lymphomas,
leukemias - see Hematopathology; neurogenic
(neuroblastoma, Ewing sarcoma, primitive
neuroectodermal tumor - PNET, CNS-
medulloblastoma), sarcomas (rhabdo-, osteo-),
kidneys (Wilms' tu), thyroid (papillary ca)
• specialized diagnostic-therapeutic pediatric centers
Molecular Diagnostics :
Hype or Hope ?

PART II
We now know how God
wrote the book of life
Bill Clinton
 But do we know
how to read the book ?
 Genetic Diagnostics

• Cytogenetic tests

• FISH

• Molecular tests
 Molecular Diagnostics

- Diagnosis of infectious diseases

- Genetic identification

- Diagnosis of genetic diseases

Diagnosis of infectious diseases

HPV
Chlamydia
Hepatitis
HIV
Toxoplasmosis
Genetic Identification

- Paternity Testing

- Forensics
Paternity Testing
Forensic testing
 Diagnosis of genetic diseases

- Somatic rearrangements in cancer

- Genetic risk factors

- Pharmacogenetics

- Mutations in monogenic diseases

Molecular Diagnosis

Example In Oncology
&
Genetics
 Diagnostic Molecular Pathology

• USE OF:
– Sequence Specific INFORMATION
• in
– MACROMOLECULES
• for
– Risk identfication
– Diagnosis
– Prognosis
– Prediction of response to therapy
– Montoring therapeutic responses
 Macromolecules

• Peptides/proteins
• Polysaccharides
• Polynucleotides/nucleic acids
 “Nucleic Acid Diagnosis”

• Use of specific sequence information in

• nucleic acids
– DNA and RNA
• for clinical diagnosis
 Analysis Of Information In Nucleic Acids

• Sequencing
• Hybridization
• Amplification
– with specific primers
• Restriction enzyme digestion
– Recognize specific sequences
• Electrophoretic mobility
• Translation
 Molecular Oncology

• DIAGNOSITC/PROGNOSTIC INFORMATION PROVIDED BY:

– Gross alterations in DNA content of tumors
– Cell cycle information
– Molecular Markers of Clonality
– Oncogene/Tumor Suppressor gene mutations
– Tumor Specific Translocations
– “Tissue specific” mRNA in tumor staging
– Minimal residual disease determination
 Identification Of Clonal Proliferations

• Antigen receptor gene rearrangements.

– Southern Blotting: IgH, TCR; EBV termini.
– PCR: Ig and TCR gene rearrangement.
• X-inactivation.
– Human androgen receptor assay.
• Microsatellite allelotyping.
 TRANSLOCATIONS: DETECTION
METHODS
• No fusion product:
– detect at DNA level.
• In situ hybridizaton
• Southern Blotting:
– Probe to translocated sequence hybridizes to altered band size.
(multiple probes)
– Problems: Quantity, quality of DNA, labor intensive.
• PCR
– If recurrent breakpoints in small DNA region
» Available for BCL2 (60% detected); BCL1 (40-60% detected).
– ? Long-range PCR – need for high quality DNA.
 TRANSLOCATIONS: DETECTION
METHODS
• Fusion product:
– Detect at DNA or RNA level.
• DNA level: FISH, Southern blotting.
• RNA detection: RT-PCR
– Highly sensitive.
– Cheaper
– “Real-time” detection.
– Semi-quantitative detection – minimal residual
disease/quantification.
– Chimeric transcript detectable during “complete remission” :
rising titer - impending relapse.
– Need for fresh tissue (in general)
 Spectral Karyotyping (SKY)
• FISH w/multiple probes to identify all
chromosomes
– Identify any translocations, markers etc. w/one
test.
– Need for special equipment
– Need for metaphases.
 Gene Amplifications & Specific
Mutations
• Amplification
– n-Myc: neuroblastoma.
– Her2/Neu: breast cancer.
• Mutations:
– C-Kit: gastrointestinal stromal tumors.
– EGFR: Lung CA response to Iressa.
– p53: poor prognosis, reduced chemosensitivity.
 Tumor Suppressor Gene
Mutations
“loss of function mutations”
– many possible mutations
– “hot-spots”
• e.g., p53: Exons 6, 7, 8, 9 > 90% of mutations
– truncated protein: “protein truncation test”
– “whole gene sequencing”
• Tumor precentage.
 “Oncogene” Mutations
• :“gain of function mutations.”
– limited number for each gene.
• “regulatory site mutations” - “constitutive
activation.”
• “active site mutations” - “constitutive
activation/altered substrate.
• Often recurrent - test for known mutations.
» e.g., c-Kit; c-RAS; Ret, EGFR, etc.
 Tumor Classification/diagnosis W/ Microarrays

• Label total RNA from a tumor

• hybridize to chip w/  25,0000
cDNAs/oligonucleotides.
– Expression profile unique to tumor type.
– ? Predict behavior
– ? Identify origin of mets
– ? Identify targets for therapy.
 Molecular Genetic Tests
• Genetic test:
– Analyis of human
• DNA
• RNA
• chromosomes
• proteins
• metabolites
– to detect heritable disease-related
• genotype,
• phenotype
• karyotype
– for clinical purposes.
 Genetic Diagnosis
“Purpose”

• Diagnostic Testing
• Screening
• Presymptomatic Testing
• Prenatal testing
• Preimplantation Diagnosis
• Pharmacogenetic testing
• Susceptibility to environmental agents
 Conventional Cytogenetics
(Karyotyping)
• Detect numerical structural chromosomal
alterations
– trisomy
– monosomy
– duplications
– translocations, etc.
 Conventional Cytogenetics
(Karyotyping)
• evaluate all chromosomes
– prior specification of chromosome unnecessary
– detect unsuspected abnormality
– detect balanced alterations
• (No gain or loss of genetic material)
• FISH may be performed.
– characterize unxpected alterations
 Conventional Cytogenetics
(Karyotyping)
• Disadvantages:
– Need for live cells to grow in culture
• (ACMG standards, failure <1%).
– Turnaround time - up to 10 days
• (ACMG standards - 90% of results w/in 14 days)
– Labor Intensive
 FISH
• Use of fluorescently labeled probes to
specifically visualize
– entire chromosomes (chr. paint probes)
– centromeres (centromeric probes)
– specific loci (locus-specific probes)
• Metaphase
– All types of probes
• Interphase
– Centromeric and locus-specific probes only
 FISH
• Identify:
– translocations
– marker chromosomes
– Small deletions/duplications w/ locus-sopecific
probes
• e.g., DiGeorge’s syndrome.
 Molecular Tests
• Test for:
– karyotpye
– gain or loss of genetic material (“dosage”)
– genetic linkage
– known/recurrent mutations
– variations in lengths of repeat sequences
– alterations in DNA methylation
– unknown mutations in multiple genetic segments
 Types of mutations-gene
• Point mutations
– Missense (change an amino acid)
– Nonsense (premature termination)
– Silent
• Deletion
– Large variation in size
• Insertion
• Duplication
• Splice site
• Regulatory
• Expanded repeat
 Deletions
• Complete/partial gene deletion
– Duchenne Muscular Dystrophy
– Alpha thalassemia
• Multiple genes (“contiguous gene
syndromes”
– DiGeorge Syndrome
– TSC2-PKD1
– WAGR syndrome
 Insertions
• Tay Sachs Disease
– 4bp insertion in Ashkenazi Jews
• Hemophilia A
– L1 insertion in FVIII gene (1% of patients)
 Real-Time PCR
• New instruments can monitor PCR during
thermocycling
– intercalating dye:
• non-specific increase in fluorescence with increased
double-stranded DNA
• “Melting curve” analysis - monitor denaturation of
double-stranded DNA
– Probes using Fluorescence Resonance Energy
Transfer (“FRET”)
• Monitor binding of probe to wild-type or mutatnt
allele.
 Mutation Scanning Methods
• Test one or more genes for unknown
variation in.
– Exons
– Introns
– splice sites
– Promoters/enhancers
– “locus control region”
 Disease Mutations
Single mutations Fragile X
Sickle Cell Anemia

Common mutations Deafness

Hemochromatosis

Panel of mutations Cystic Fibrosis

Private mutations Breast Cancer

Colorectal cancer
 DNA Sequencing

1980-1990 1990-2005 > 2005

Radio - gel Fluorescent - capillary Next generation
Thousand bp / day Million bp / day Billion bp / day
 What Can The Genes Tell Us?
• Give us a better understanding of the underlying
biology of the trait in question
• Serve as direct targets for better treatments
– Pharmacogenetics
– Interventions
• Give us better predictions of who might develop
disease
• Give us better predictions of the course of the
disease
• Lead to knowledge that can help find a cure or
prevention
Sickle Cell Disease- recessive allele
•Red blood cells are sickle shaped, issues with circulation causing
anemia and pain

Based on: Harvard Family Health Guide, 1999

 Sickle cell disease
(sickle cell anemia)

• Codominant disorder found in

African Americans.
– 1 in 400 African Americans
• Can be fatal.
• Possible cure: bone-marrow
transplants
• The sickle cell trait can prevent
Malaria
 Hemophilia
• A disorder in which a
person’s blood does
not clot properly.
• It is a recessive sex-
linked, X-chromosome
disorder.
• 1 in 10,000 males
born are afflicted.
“Royalty Disease”
 Characteristics of a child with Down
Syndrome
-wide, rounded face -equal length fingers
-Lower cognitive ability -webbed neck
-enlarged tongue

Normal female Down syndrome karyotype

karyotype with 46 with an extra chromosome
chromosomes 21

Based on: Mader, S., Inquiry Into Life, McGraw-Hill