Q&A: Modes of Inheritance II - Atypical and Multifactorial Inheritance

Forty practice flashcards in Question and Answer format covering atypical modes of inheritance, dynamic repeat expansion disorders, mitochondrial biology, and multifactorial disorders.

What is mosaicism?

An individual with at least $2$ cell lines that differ genetically, but are derived from a single zygote.

What are the primary clinical consequences of somatic mosaicism depending on when and where the mutation occurs?

A mutation occurring during embryogenesis affects morphogenesis leading to a segmental abnormality, while a mutation in adult dividing cells leads to carcinogenesis.

Why can unaffected individuals with germline mosaicism be at risk of having offspring with highly penetrant autosomal dominant or X-linked disorders?

Because the disease-causing mutation is present in their germline cells but is not detected in DNA from buccal swabs or peripheral blood cells.

What is the genetic mechanism underlying polyglutamine disorders such as Huntington's disease?

An unstable repeat expansion consisting of a string of consecutive glutamine ($CAG$) repeats of variable length in the mutant protein.

What is anticipation in dynamic repeat expansion disorders?

A phenomenon where the disease exhibits an earlier age of onset and increased severity with each successive generation as the number of repeats expands.

What are the CAG repeat count ranges for normal individuals, mild late-onset Huntington's disease, and severe Huntington's disease?

Normal: $5\text{--}35$ repeats; Mild late-onset HD: $36\text{--}39$ repeats; Severe HD: $>40$ repeats.

What molecular mutation and epigenetic mechanism cause Fragile X syndrome?

A massive repeat expansion ($>200$ $CGG$) in the $5'\text{-UTR}$ of the $FMR1$ gene, leading to increased CpG methylation and gene silencing.

What inheritance pattern, expressivity, and penetrance in females characterize Fragile X syndrome?

X-linked dominant inheritance with variable expressivity and low penetrance ($50\%$ in females).

What are two distinct features of mitochondrial DNA (mtDNA) structure and cellular distribution?

Each cell contains several hundred mitochondria with several copies of $mtDNA$ per mitochondrion, and $mtDNA$ contains no introns.

Based on the mitochondrial genome map, what functional gene categories are encoded by human mtDNA?

Genes for Complex I, Complex III, Complex IV, Complex V (ATP synthase), transfer RNA (tRNA) genes, and ribosomal RNA (rRNA) genes.

Why do mitochondrial disorders follow strict maternal inheritance?

Because sperm mitochondria are not present in the zygote.

What is replicative segregation in mitochondrial biology?

The process during cell division where $mtDNA$ replicates and copies are distributed randomly among newly synthesized mitochondria and daughter cells.

How are homoplasmy and heteroplasmy defined in mitochondrial genetics?

Homoplasmy is a pure population of either wild-type or mutant $mtDNA$, whereas heteroplasmy is a mixed population of wild-type and mutant $mtDNA$.

As shown in the heteroplasmy diagram, what determines whether a cell or tissue expresses a mitochondrial disease phenotype?

The phenotype depends on the relative proportions of wild-type and mutant $mtDNA$ crossing the threshold for phenotypic expression.

What is the mitochondrial genetic bottleneck?

The reduction of the number of mitochondria in developing oocytes before expansion in mature oocytes, causing variability in the proportion of mutant $mtDNA$ passed to offspring.

How are multifactorial traits classified into discrete and continuous categories?

Discrete qualitative traits (either present or absent) and continuous quantitative traits (measurable physiological or biochemical parameters that vary continuously).

What distribution curve do most continuous quantitative multifactorial traits follow?

A normal (Gaussian) distribution.

How does the liability threshold model explain the occurrence of discrete qualitative multifactorial diseases?

An individual expresses the disease only when their total liability (combined additive genetic variants and environmental factors) crosses a specific threshold.

What criteria increase the recurrence risk for a multifactorial disorder in a family?

Recurrence risk is higher if more than $1$ family member is affected, if the proband has a severe form of the disease, or if the proband belongs to the less commonly affected sex.

How does relationship distance affect the recurrence risk of a multifactorial disorder?

The recurrence risk decreases rapidly in distant relatives.

What formula calculates heritability (H^2) using monozygotic (CMZ) and dizygotic (CDZ) twin concordance rates?

$$H^2 = \frac{C_{MZ} - C_{DZ}}{1 - C_{DZ}}$$

What does it signify when monozygotic (MZ) twin concordance is significantly higher than dizygotic (DZ) twin concordance?

It indicates that the trait or behavior is partly due to nature (genetics).

What are three major limitations of twin studies when estimating heritability?

The assumption of equally similar environments for MZ and DZ twins, different somatic mutations occurring after cleavage, and differing methylation or X-inactivation patterns.

How do adoption studies help establish a genetic component for a multifactorial disease?

By comparing disease rates among adopted offspring of affected parents with disease rates among adopted offspring of unaffected parents.

What is the overall incidence of congenital malformations, and what is the most common specific defect?

Approximately $2\%$ of births; congenital heart defects are the most common, occurring in $8/1000$ births.

What non-genetic environmental factors are associated with cleft lip and palate?

Ibuprofen, aspirin, barbiturates, maternal smoking, deficiency in folic acid and vitamin A, and exposure to chemicals.

What factors indicate an increased familial risk for coronary artery disease (CAD)?

Having more than $1$ affected relative, an affected relative of female sex, or an affected relative with onset age $<55$ years.

What are the twin concordance rates for stroke, and what genetic category is involved?

$C_{MZ} = 10\%$ and $C_{DZ} = 5\%$; genes encoding coagulation factors (such as clotting factor V).

What is the estimated heritability of hypertension, and which genetic system is primarily implicated?

Heritability is approximately $0.5$ for both systolic and diastolic hypertension; genes regulating the angiotensin system (angiotensinogen, ACE II, angiotensin receptor).

How much does having a first-degree affected relative increase a woman's breast cancer risk, and what environmental factors contribute?

Risk increases $2\times$; environmental factors include nulliparity, first child at $>30$ years, high-fat diet, alcohol abuse, and estrogen replacement therapy.

Which gene mutations and environmental factors are associated with colorectal cancer?

Mutations in the $APC$ gene or DNA mismatch repair genes; environmental factors include sedentarism and a high-fat, low-fiber diet.

Why is genetic analysis of prostate cancer difficult, and what non-coding genomic association has been identified?

Difficult due to late age of onset (past $70$ years); associated with several SNPs located in an area surrounding an enhancer for the $MYC$ oncogene.

How do monozygotic twin concordance rates (CMZ) compare between Type 1 and Type 2 Diabetes Mellitus?

Type 1 Diabetes Mellitus has $C_{MZ} = 50\%$, whereas Type 2 Diabetes Mellitus has $C_{MZ} > 90\%$.

Which genetic loci are strongly linked to Type 1 Diabetes Mellitus susceptibility?

HLA class II genes (with high incidence in $DR3$ and $DR4$ homozygotes) and the insulin gene.

What three key genes are associated with Type 2 Diabetes Mellitus risk?

$TCF7L2$ (regulating insulin production), $PPAR\text{-}\gamma$ (adipocyte differentiation and glucose metabolism), and $KCNJ11$ (K channel for insulin secretion).

What is the heritability of obesity, and what gene mutation in homozygotes increases risk by 70%?

Heritability is $0.6\text{--}0.8$; homozygosity for mutations in the $FTO$ gene increases risk by $70\%$.

Which three genes are associated with early-onset autosomal dominant Alzheimer's disease?

Presenilin 1 ($PSEN1$), Presenilin 2 ($PSEN2$), and Amyloid-beta precursor protein ($APP$).

Which gene allele is associated with an increased risk for late-onset Alzheimer's disease?

The $\varepsilon4$ allele of Apolipoprotein E ($APOE\text{-}\varepsilon4$).

What are the differences in age of onset, sex ratio, and severity between Type I and Type II alcoholism?

Type I has onset $>25$ years, affects males and females equally, and is less severe; Type II occurs in males $<25$ years, is more severe, and is harder to treat.

What are the male-to-female ratio, heritability, and paternal age factor associated with Autism Spectrum Disorder (ASD)?

ASD is $3\text{--}4\times$ more common in males, has a heritability $>0.7$, and carries higher risk in offspring of older fathers due to paternally inherited mutations.