Genetics

1. Modes of Inheritance

•    Autosomal Dominant (AD)

o    Only one mutated allele needed; vertical transmission (seen in every generation).

o    Equal male and female transmission.

o    Examples:

    Marfan syndrome (FBN1 mutation)

    Huntington's disease

    Familial hypercholesterolaemia

    Adult polycystic kidney disease (PKD1)

•    Autosomal Recessive (AR)

o    Two mutated alleles needed; often skips generations.

o    Increased risk with consanguinity.

o    Examples:

    Cystic fibrosis

    Sickle cell disease

    Phenylketonuria

    Wilson’s disease

•    X-Linked Recessive

o    Mainly affects males; no male-to-male transmission.

o    Carrier females may have mild manifestations.

o    Examples:

    Haemophilia A and B

    Duchenne muscular dystrophy

    G6PD deficiency

•    Mitochondrial Inheritance

o    Maternal inheritance only; all children of affected mothers may inherit.

o    Examples:

    MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes)

    Leber's hereditary optic neuropathy

2. Penetrance and Expressivity

•    Penetrance

o    Probability that a gene mutation results in clinical expression.

o    Example: Retinoblastoma — ~90% penetrance.

•    Expressivity

o    Variability in severity among individuals with the same genotype.

o    Example: Neurofibromatosis type 1 (café-au-lait spots vs plexiform neurofibromas).

3. Anticipation

•    Disease manifests at an earlier age or with increased severity in successive generations.

•    Often due to trinucleotide repeat expansions.

•    Examples:

o    Myotonic dystrophy (CTG repeat)

o    Huntington’s disease (CAG repeat)

o    Fragile X syndrome (CGG repeat)

4. Basic Genetic Terminology

•    Allele: Variant form of a gene.

•    Locus: Specific location of a gene on a chromosome.

•    Polymorphism: Common DNA sequence variation in the population (>1% frequency).

•    Mutation types:

o    Missense: single amino acid change.

o    Nonsense: premature stop codon.

o    Frameshift: insertion/deletion altering reading frame.

o    Splice site: affects mRNA processing.

5. Population Genetics

•    Hardy–Weinberg Principle

o    Allele and genotype frequencies remain constant in a large, 

                            randomly mating population without selection, mutation, or migration.

o    Basic equation: p² + 2pq + q² = 1

    p = frequency of normal allele

    q = frequency of mutant allele

    p² = homozygous normal

    2pq = heterozygous carriers

    q² = homozygous affected

•    Applications

o    Estimate carrier rates in recessive conditions.

o    Predict population-level disease prevalence.

Extra Revision Pearls

•    X-linked dominant disorders (rarer): e.g. Alport syndrome (can also be AR).

•    Mitochondrial diseases often have high phenotypic variability due to heteroplasmy 

                                                                                            (mixture of normal and mutant mtDNA).

•    In consanguinity, risk of AR disorders increases due to shared ancestry increasing homozygosity.