Pedigree o Generations are assigned Roman numerals o individuals within each generation are indicated by Arabic numerals.

o The arrow points at the proband, the person in whom the genetic disorder was first diagnosed. Autosomal recessive inheritance o condition is expressed only in persons who have two copies of (ie, are homozygous for) the mutant allele o often observed with enzyme deficiencies (MCQ) o What is margin of safety effect. heterozygotes express 50% of normal activity. (MCQ) However, 50% of normal enzyme activity in these cases permits normal physiologic function because expression of enzyme from the normal allele is sufficient to provide for the needs of the cell. o Both parents of an affected person must have one normal and one mutant allele, making them obligate carriers barring very rare new mutations. o The likelihood of a person being homozygous for an autosomal recessive trait increases in consanguineous matings because of the existence of a common ancestor. (MCQ) o Rare autosomal recessive diseases also occur with high frequency among genetically isolated populations due to inbreeding. (MCQ) o Pedigree charts show the following: The disease phenotype is expressed by siblings but not by their parents or offspring. (MCQ) Equal occurrence in males and females. (MCQ) Recurrence risk for each sibling is 25%.(MCQ) Possible consanguinity. (MCQ)

Recessive inheritance is shown in pedigrees A and B.

o Autosomal dominant inheritance o this condition is expressed even if a single mutant allele is present, ie, in the heterozygous state o Following are four possible situations by which having one normal copy of a gene is insufficient to prevent disease, leading to a dominant Situation 1 : When the presence of 50% normal activity (ordinarily the margin of safety) is not generous enough to allow normal physiologic function, a condition called haploinsufficiency. (MCQ) Situation 2 : When the defective allele produces a malfunctioning protein product that binds to and interferes with function of the normal gene productthe dominant negative effect. Situation 4 : When the mutant protein has an enhanced function that overrides normal controls or is cytotoxic Situation 5 : When the phenotype appears as dominant inheritance even though the actual allele is recessive at the level of function in individual cells. o The homozygous mutant state usually produces a more severe clinical condition than the heterozygous condition in autosomal dominant diseases. o Pedigree charts for an autosomal dominant disorder The disease phenotype appears in all generations, with each affected person having an affected parent. (MCQ) There is an equal occurrence in males and females, except in cases when ex- pression of the trait is influenced by the persons sex (ie, sex-limited). (MCQ) Risk of transmission of the mutant allele is 50%, but because there usually are so few persons in a family, there may be deviations from this expectation. (MCQ) Potential for some cases to be due to a new mutation, which is more likely for a dominant condition because disease symptoms would be expressed in heterozygotes. (MCQ)

Dominant inheritance is shown in pedigree, in which every affected person has an affected parent.

o An autosomal dominant disorder exhibiting anticipation

o In pedigree , the age of onset, indicated next to the symbols for affected individuals, becomes progressively earlier with each generation. o X-linked recessive inheritance pattern o there can be no male-to-male transmission because the sex of male offspring is determined by contribution of a Y chromosome from the father. (MCQ) o Because they have only one X chromosome, the sons of heterozygous mothers have a 50% chance of being affected. (MCQ) o Pedigree charts

Incidence of disease is higher in males than in females. (MCQ) Female heterozygotes are usually unaffected carriers. (MCQ) Affected men transmit the gene to all daughters, but never to sons. (MCQ) New mutations cause a significant number of isolated cases in males due to unopposed expression of the mutant allele. (MCQ)

o X-linked dominant diseases are relatively rare o Such genes may be transmitted either to sons or daughters by an affected mother but only to daughters by an affected father. o disorders with X linked dominant inheritance Xg blood group vitamin Dresistant rickets. (MCQ) Rett syndrome Most cases of Alport syndrome Incontinentia pigmenti CharcotMarieTooth disease(MCQ) o Pedigree charts All daughters of affected men are affected but never their sons, which may lead to prevalence of affected females over affected males. (MCQ) Recurrence risk is 50% for both male and female offspring of an affected female. (MCQ) Absence of affected males in several generations may suggest prenatal lethality for the hemizygous state. (MCQ)

Pedigrees illustrating X-linked recessive (A) and dominant (B) inheri- tance patterns. Note the absence of male-to-male transmission in both pedigrees and the predominance of affected males over females in the X-linked recessive pedigree. o Incompletely dominant disorders o occur in cases where the heterozygous genotype produces a different phenotype from that seen in the homozygous genotype. o The effect is often of intermediate severity between the unaffected and fully affected phenotypes. o For example, in sickle cell anemia, the normal allele is incompletely dominant in heterozygotes. (MCQ) o Mitochondrial disorders o The mitochondrial chromosome (mtDNA) is a 16.5 kb circular plasmid. o The mtDNA bears 37 genes encoding rRNAs, tRNAs, and some genes for o proteins involved in oxidative phosphorylation. (MCQ) o are maternally transmitted because the ovum provides all mitochondria to the fertilized embryo o What is heteroplasmy(MCQ) In these disorders, affected cells usually have a mixture of mitochondria, some with mutant mtDNA and others with wildtype mtDNA, a condition called heteroplasmy. o Segregation of mitochondria during cell division is not as tightly controlled as for nuclear chromosomes, leading to random distribution of mitochondria carrying normal and mutant mtDNA to ova. o This contributes to variable expression and reduced penetrance of the phenotype among persons within kindreds with mitochondrial disorders.

inheritance of a mitochondrial disorder . note the similarity to the X-linked

dominant inheritance pattern but incomplete penetrance as exemplified by individuals II-4 and III-4.
o Major Concepts in Human Genetics o When similar phenotypes or disease conditions can be caused by different geno- types, this may produce heterogeneity. o Allelic heterogeneity (MCQ) occurs when different alleles of the same gene produce clinically similar conditions. Allelic heterogeneity may account for phenotypic variability in some families with genetic disease. o Locus heterogeneity (MCQ) refers to the condition when mutations of more than one gene or locus can produce similar disease states. This genotypic variability is responsible for different inheritance patterns of some disorders. For example, Ehlers-Danlos syndrome may be caused by mutations at more than 10 known loci, producing inheritance patterns ranging from autosomal recessive or dominant to Xlinked. (MCQ) o Variable expression arises when the nature and severity of the phenotype for a genetic condition varies from one person to another. o Pleiotropy refers to a condition in which a mutant allele may have different phenotypic effects in various organ systems in an affected person. o Genomic imprinting expression of an allele differs depending on whether it is inherited from the mother or the father. A gene that is shut off when inherited from the mother is maternally imprinted. (MCQ) A gene that is silenced when inherited from the father is paternally imprinted. (MCQ)

Imprinting involves an epigenetic mechanism, ie, an alteration in phenotype that does not result from a change in the genotype. (MCQ) Expression of the imprinted genes is silenced or shut off by methylation of certain chromatin regions after DNA replication during gametogenesis. The imprint is reversible upon passage through gametogenesis in the nextgeneration. o Genetic Anticipation Certain inherited disorders exhibit increased severity of phenotype or decreased age of onset as the disease gene is passed from one generation to the next, an effect known as anticipation Examples of genetic diseases that show anticipation are Huntington disease, Fragile X syndrome(MCQ) disorders that arise from trinucleotide repeat expansion show Genetic anticipation(MCQ) Disease symptoms occur only when the length of the trinucleotide repeat region exceeds a threshold. o Mosaicism It is defined as the presence of cells in the body that are genetically different. Somatic mosaicism mutation of a gene occurs in a non-germline (somatic) cell at some point during early development of the person, and all cells descendent from that progenitor are genetically distinct. Germline mosaicism a mutation that occurred in the parents gonadal make-up is transmitted through some gametes, but not all. All females are technically mosaic for the genes of their X chromosomes due to inactivation of one or the other X chromosomes early in development, a phenomenon termed the Lyon hypothesis or lyonization. (MCQ) Because X inactivation is random, this phenomenon accounts for variable expression of some X-linked disorders, depending on whether the disease allele or wildtype allele was inactivated. (MCQ) Distribution of cells from the early embryo to the tissues may be imbalanced, so that expression of the disease phenotype is not uniform among the organs. Up to 25% of patients with Turner syndrome exhibit a mosaic karyotype, in which only some cells have the 45,X karyotype classically associated with the condition. (MCQ) o Uniparental disomy refers to a condition in which one or more cells of the body have two identical chromosomes derived from a single parent, which increases the likelihood of expression of recessive alleles inherited from that parent. (MCQ)