Mendelian inheritance patterns

Mendelian Basics - Pea Plant Power Play

• Foundation: Gregor Mendel's experiments with pea plants established the fundamental laws of inheritance.
  • Law of Segregation: Paired alleles separate into different gametes.
  • Law of Independent Assortment: Genes for different traits sort independently.
• Key Concepts:
  • Genotype vs. Phenotype: Genetic code vs. expressed trait.
  • Allele: A variant form of a gene.
  • Homozygous vs. Heterozygous: Two identical alleles (AA) vs. two different alleles (Aa).

⭐ While foundational, true Mendelian inheritance is uncommon for complex human diseases (e.g., hypertension), which are typically multifactorial.

Autosomal Dominant - One Allele to Rule

• One mutated allele is sufficient to cause disease.
• Affects males and females equally; transmitted vertically through generations.
• Each offspring of an affected heterozygote has a 50% chance of inheritance.
• Unaffected individuals do not transmit the trait.
• Key features:
  • Pleiotropy: One gene, multiple effects (e.g., Marfan syndrome).
  • Variable expressivity: Severity differs (e.g., Neurofibromatosis type 1).
  • Incomplete penetrance: Genotype present, but no phenotype.

⭐ Look for de novo mutations in a patient with no family history, common in conditions like Achondroplasia.

Autosomal Recessive - Two to Tango

• Requires two copies of the mutated gene (aa) for disease expression. Affects males & females equally.
• Parents are typically asymptomatic heterozygous carriers (Aa).
• Disease often "skips" generations, appearing unexpectedly.
• Recurrence risk for offspring of two carriers is 25% for an affected child, 50% for a carrier, and 25% for an unaffected non-carrier.
• Consanguinity significantly ↑ the risk of AR disorders.

⭐ With a disease frequency of 1/10,000, the carrier frequency is ~1/50, calculated using the Hardy-Weinberg equation ($q^2$ and $2pq$).

X-Linked Patterns - It's a Guy Thing

• X-Linked Recessive:
  • Affects males >> females; females are typically carriers.
  • Skips generations (unaffected carrier females pass to sons).
  • Affected mothers have a 50% chance of passing the trait to each son.
  • Affected fathers have all daughters as carriers.
• X-Linked Dominant:
  • Affects females > males.
  • Transmitted from father to ALL daughters.
  • Does not skip generations.

⭐ No male-to-male transmission occurs in X-linked inheritance, as fathers pass the Y chromosome to sons.

Genetic Curveballs - Beyond the Basics

• Codominance: Both alleles fully and separately expressed (e.g., AB blood type).
• Incomplete Dominance: Heterozygous phenotype is a blend of two homozygous phenotypes.
• Pleiotropy: One gene affects multiple organ systems (e.g., Marfan syndrome).
• Penetrance vs. Expressivity:
  • Incomplete Penetrance: Not all individuals with a mutant genotype express the phenotype.
  • Variable Expressivity: Individuals with the same genotype have varying phenotypic presentations.

⭐ Germline Mosaicism: A mutation in germ cells but not somatic cells can cause disease in offspring of unaffected parents, mimicking recessive patterns.

• Autosomal Dominant inheritance shows vertical transmission with a 50% risk to each offspring.
• Autosomal Recessive conditions often skip generations, with a 25% recurrence risk for carrier parents.
• X-linked Recessive disorders exhibit no male-to-male transmission and primarily affect males.
• X-linked Dominant traits are passed from an affected father to all his daughters.
• Mitochondrial inheritance is transmitted exclusively from the mother to all her children.
• Remember penetrance (all-or-none) vs. variable expressivity (severity range).