CM20 - Modes of Inheritance II

Biomedical Sciences I

What is mosaicism in genetics?

When an individual has at least two genetically different cell lines derived from a single zygote.

What causes mosaicism?

Mutations occurring after conception in a single cell during pre- or postnatal life, leading to clonal descendants that differ genetically from the original zygote.

What is somatic mosaicism?

A mutation during embryogenesis that affects morphogenesis, causing segmental abnormalities, or a mutation in adult dividing cells that may lead to cancer.

What is germline mosaicism?

A mutation in germ cells of an unaffected individual that occurs during embryogenesis, not detectable in blood or buccal DNA, but can be passed to offspring, causing autosomal dominant or X-linked diseases.

What are dynamic mutations?

Mutations involving unstable repeat expansions—repeating nucleotide sequences that expand across generations, often causing neurological diseases.

What is anticipation in dynamic mutations?

A phenomenon where symptoms appear earlier and more severely in successive generations.

What is parental transmission bias in repeat expansion disorders?

Repeat expansions and anticipation are often more severe when inherited from either the mother or the father

What is the repeat threshold for Huntington’s disease?

Normal: 5–35 repeats; Mild: 36–39; Severe: >40 CAG repeats.

• Huntington’s = more severe when inherited from the father

What causes Fragile X syndrome?

An X-linked dominant disorder caused by >200 CGG repeats in the 5′-UTR of the FMR1 gene, leading to methylation and gene silencing.

What is the inheritance pattern of mitochondrial disorders?

Follow strict maternal inheritance and do not follow Mendelian patterns.

What is replicative segregation in mitochondrial DNA?

Random distribution of mtDNA copies during cell division, leading to variability in disease expression.

What is the difference between homoplasmy and heteroplasmy?

Homoplasmy: all mtDNA copies are identical

Heteroplasmy: a mix of normal and mutant mtDNA copies.

What is the mitochondrial genetic bottleneck?

A reduction in mtDNA number in developing oocytes before expansion, causing variability in mutant mtDNA in offspring.

What characterizes multifactorial diseases?

They show familial clustering but do not follow Mendelian inheritance, resulting from multiple genes and environmental factors.

What are qualitative vs. quantitative traits?

Qualitative traits are discrete (present or not); quantitative traits are continuous and measurable (e.g., height, blood pressure). Quantitative traits usually follow a normal curve model.

What is the liability threshold model?

A model for qualitative traits where disease occurs only if a threshold of genetic and environmental liability is crossed.

What increases recurrence risk in multifactorial inheritance?

Having more affected relatives, a severely affected proband, or a proband of the less commonly affected sex.

What is heritability in genetics?

The proportion of phenotypic variation in a trait that is due to genetic variation in a population.

What do twin studies reveal about heritability?

Greater concordance in monozygotic (MZ) twins compared to dizygotic (DZ) twins indicates a stronger genetic component.

What are limitations of twin studies?

Assumptions of equal environments, somatic mutations, and epigenetic differences like methylation and X-inactivation.

What do adoption studies show about genetic influence?

Higher disease rates in adopted children of affected biological parents suggest a genetic component.

What is the prevalence of congenital malformations?

About 2% of births, mostly due to multifactorial causes.

What are the key features of cleft lip and palate? (Multifactorial disorder)

• Occur in about 2.5 per 1000 births

• Can be syndromic (genetic, part of a syndrome) or non-syndromic (isolated).

• Environmental risk factors: Maternal smoking, folic acid and vitamin A deficiency, certain medications like ibuprofen and barbiturates.

What are the key features of congenital heart defects? (Multifactorial disorder)

The most common congenital malformations (8 per 1000 births), often show familial aggregation, may present as different types of defects (e.g., VSD, ASD, aortic stenosis).

What are the key features of coronary artery disease (CAD)? (Multifactorial disorder)

CAD risk is higher in males and influenced by environmental factors like obesity, smoking, and diet. Genetic factors include mutations in LDL receptor and apolipoprotein genes. Risk increases with early-onset or female relatives affected.

What are the key features of stroke? (Multifactorial disorder)

Stroke risk is 2–3 times higher if a parent had a stroke. Genetic factors include mutations in coagulation genes (e.g., factor V), while environmental risks include obesity, diabetes, and smoking.

What are the key features of hypertension? (A multifactorial disorder)

Hypertension has a heritability of about 0.5 (50%). Genetic causes include mutations in the renin-angiotensin system, and environmental factors include stress, obesity, and low physical activity.

What are the key features of breast cancer? (Multifactorial disorder)

Breast cancer risk doubles with a first-degree relative affected and increases with early-onset or multiple affected relatives. Genetic factors include BRCA1/2 and DNA repair genes; environmental risks include nulliparity (never giving birth), high-fat diet, and hormone therapy.

What are the key features of colorectal cancer? (A multifactorial disorder)

Colorectal cancer risk is 2–3 times higher with affected relatives. Genetic causes include APC and mismatch repair gene mutations; environmental risks include a high-fat, low-fiber diet and sedentary lifestyle.

What are the key features of prostate cancer as a multifactorial disorder?

Prostate cancer risk is 2–3 times higher with an affected relative. It has a heritability of about 0.4. Genetic analysis is difficult due to late onset; SNPs near the MYC oncogene are implicated. High-fat diet is a non-genetic risk factor.

What are the key features of type 1 diabetes mellitus (T1DM) as a multifactorial disorder?

T1DM shows familial clustering with MZ concordance of 50%. Genetic factors include HLA class II (DR3, DR4) and insulin gene; environmental triggers include viral infections.

What are the key features of type 2 diabetes mellitus (T2DM) as a multifactorial disorder?

T2DM has a recurrence risk of 15–30%, with MZ concordance >90%. Genetic factors include TCF7L2, PPAR-γ, and KCNJ11; environmental factors include obesity and poor diet.

What are the key features of obesity as a multifactorial disorder?

Obesity has a strong genetic component (heritability 0.6–0.8). Genes include leptin, leptin receptor, MC4R, and FTO. Adoption studies show stronger correlation with biological than adoptive parents.

What are the key features of Alzheimer’s disease as a multifactorial disorder?

Alzheimer’s risk doubles with a first-degree relative affected. Early-onset forms are autosomal dominant (presenilin 1/2, APP), while late-onset is linked to APOE-e4. Environmental risks include head trauma and DDT exposure.

What are the key features of alcoholism as a multifactorial disorder?

Alcoholism risk is 5x higher in children of alcoholics. MZ concordance is >60%. Type I is later-onset and less severe; Type II is early-onset and more severe. Genes include ADH and ALDH.

What are the key features of schizophrenia as a multifactorial disorder?

Schizophrenia has a recurrence risk of 8–10% in children of affected parents. MZ concordance is 50%. Over 100 candidate genes are involved, especially in glutamatergic and dopaminergic pathways.

What are the key features of autism spectrum disorder (ASD) as a multifactorial disorder?

ASD is 3–4 times more common in males and has heritability >0.7. Many mutations are inherited paternally, with increased risk in children of older fathers.