Autosomal Inheritance and Complicating Mechanisms

Flashcards covering basic pedigree structures, autosomal dominant and recessive inheritance characteristics, disease examples, and mechanisms that complicate standard Mendelian patterns.

What is the difference between occurrence risk and recurrence risk in genetic counseling?

Occurrence risk applies to parents who have not yet had an affected child, whereas recurrence risk applies to parents who have already had one or more affected children.

How do genotype and phenotype differ?

Genotype refers to the genetic constitution at a specific locus, whereas phenotype is the physically or clinically observed manifestation of a trait.

How does Phenylketonuria (PKU) demonstrate that genotype does not uniquely dictate phenotype?

PKU is caused by mutations in the $PAH$ gene encoding phenylalanine hydroxylase, but avoiding dietary phenylalanine prevents the intellectual disability phenotype from developing despite the individual having the homozygous mutant genotype.

What are the key pedigree characteristics of autosomal dominant inheritance?

Vertical transmission (no skipped generations), equal proportions of affected males and females, and the presence of male-to-male (father to son) transmission.

What is the average proportion of affected offspring when a person with an autosomal dominant disorder ($Aa$) mates with an unaffected individual ($aa$)?

On average, $50\%$ ($1/2$) of the offspring will be affected.

How does phenotypic severity generally compare between homozygotes and heterozygotes in autosomal dominant diseases?

The homozygous state is typically more severe than the heterozygous state, often resulting in early mortality or severely reduced fertility.

How does deep venous thrombosis (DVT) risk differ between heterozygotes and homozygotes for the Factor V Leiden ($F5$) mutation?

Heterozygotes have a $5\text{--}7 \times$ greater risk for DVT, while homozygotes have up to an $80 \times$ greater risk.

What is a sex-limited autosomal disorder, and how does $BRCA1/BRCA2$ illustrate this concept?

A sex-limited disorder occurs when both biological sexes inherit the mutant allele at equal frequencies, but the phenotype is expressed predominantly or exclusively in one sex. For example, males can inherit and transmit $BRCA1/BRCA2$ mutations without typically developing breast cancer themselves.

What are the primary pedigree characteristics of autosomal recessive inheritance?

Horizontal transmission (skipped generations), equal frequencies of affected males and females, potential father-to-son allele transmission, and affected individuals almost always having two heterozygous carrier parents.

What is the expected prevalence of affected offspring from a cross between two carrier parents ($Aa$) of an autosomal recessive disease?

$25\%$ ($1/4$) of the children are expected to be affected.

What is a compound heterozygote in autosomal recessive disease?

An individual who carries two different mutant alleles at the same disease locus (such as two distinct mutations in the $CFTR$ gene) rather than two identical mutant alleles.

What is consanguinity, and what proportion of genes do first cousins share?

Consanguinity is the mating of closely related individuals (most commonly first cousins). First cousins share approximately $1/8$ ($12.5\%$) of their genes.

What clinical feature shown in this eye image is associated with Wilson disease?

A Kayser-Fleischer ring, which results from excessive copper accumulation due to mutations in the $ATP7B$ gene.

How is reduced penetrance defined?

Reduced penetrance is an all-or-nothing phenomenon where less than $100\%$ of individuals with a disease-causing mutant genotype express the clinical phenotype.

What is the penetrance rate of hereditary retinoblastoma, and why is it described as inherited dominantly but expressed recessively at the cellular level?

Penetrance is $90\%$. It is inherited as an autosomal dominant trait, but at the cellular level, tumor formation requires a second somatic hit to the remaining functional $RB$ gene, making it recessively expressed cellularly.

How does variable expression differ from reduced penetrance?

Variable expression describes the degree of severity of the phenotype in individuals who express the disease (ranging from mild to severe), whereas reduced penetrance determines whether the disease phenotype manifests at all.

What are the penetrance and expressivity characteristics of Neurofibromatosis type 1 ($NF1$)?

Neurofibromatosis type 1 has $100\%$ penetrance, but shows variable expression ranging from mild hyperpigmentation to severe neurofibromas and malignancy in fewer than $10\%$ of affected individuals.

What genetic mutation causes Huntington disease, and how does parental origin affect its age of onset?

Huntington disease is caused by a $CAG$ trinucleotide repeat expansion in the $HTT$ gene. The age of onset tends to be earlier when the disease gene is inherited from an affected father.

What is pleiotropy, and how is it demonstrated in Marfan syndrome?

Pleiotropy occurs when a single gene mutation affects multiple anatomical or physiological systems. In Marfan syndrome, mutations in the $FBN1$ gene encoding fibrillin-1 affect the cardiovascular system (aorta), ocular system (lens suspensory ligament), and skeletal system (periosteum).

What is locus heterogeneity, and what is an example involving bone collagen?

Locus heterogeneity occurs when mutations at different gene loci produce the same clinical phenotype. Osteogenesis imperfecta is an example, as autosomal dominant forms can be caused by mutations in either the $COL1A1$ or $COL1A2$ gene.

What proportion of achondroplasia cases arise from new spontaneous mutations in the $FGFR3$ gene?

Approximately $7/8$ ($87.5\%$) of achondroplasia cases result from new spontaneous mutations.

What mechanism explains two or more offspring presenting with an autosomal dominant disease born to unaffected parents without a family history?

Germline mosaicism, in which a mutation occurs in a parent's germline cells (sperm or oocytes) but is absent from their somatic cells.

How do Prader-Willi syndrome and Angelman syndrome illustrate genomic imprinting via Chromosome 15 deletions?

A 3-4 Mb deletion on chromosome 15 results in Prader-Willi syndrome when inherited from the father, but results in Angelman syndrome when inherited from the mother.