Introduction to Mendelian Inheritance

• Mendelian inheritance denotes genetic transmission patterns based on single genes located on chromosomes within the nucleus.
• Transmission follows three fundamental laws defined by Mendel: Law of Segregation, Law of Independent Assortment, and Law of Dominance.

Autosomal Dominant Inheritance

Characteristics

• Demonstrates vertical transmission, appearing in multiple successive generations without skipping.
• Affected individuals possess a 50% chance of passing the deleterious gene to each offspring.
• Males and females are equally likely to be affected and transmit the trait.
• Presence of male-to-male transmission confirms autosomal dominant inheritance and differentiates it from X-linked inheritance.

Clinical Nuances

• De novo mutations frequently account for isolated cases and are often associated with advanced paternal age.
• Variable expressivity causes differing phenotypic severity among individuals harboring the identical genotype within the same family.
• Incomplete penetrance occurs when an individual inherits the pathogenic variant but fails to manifest clinical symptoms, leading to skipped generations in pedigrees.
• Pleiotropy involves a single gene defect resulting in multiple, apparently unrelated phenotypic anomalies across different organ systems.

Clinical Examples

• Achondroplasia, Neurofibromatosis Type 1, Marfan syndrome, and Tuberous Sclerosis.

Autosomal Recessive Inheritance

Characteristics

• Exhibits horizontal transmission, typically restricting phenotypic manifestation to a single sibship within one generation.
• Carrier parents face a 25% risk for an affected child, 50% risk for a carrier child, and 25% risk for a genetically normal child per pregnancy.
• Males and females are affected in equal proportions.
• Increased prevalence is noted in consanguineous unions due to a higher probability of both parents inheriting the identical mutant allele from a common ancestor.

Clinical Nuances

• Frequently associated with enzymatic defects and inborn errors of metabolism, since 50% enzyme activity in carriers is generally sufficient for normal function.
• Pseudodominance occurs when a homozygous affected individual mates with a heterozygous carrier, producing a dominant-like vertical transmission pattern.

Clinical Examples

• Cystic Fibrosis, Sickle Cell Anemia, Thalassemia, Phenylketonuria, and Spinal Muscular Atrophy.

X-Linked Recessive Inheritance

Characteristics

• Incidence is significantly higher in males than in females.
• Affected males transmit the mutant gene to 100% of their daughters, making them obligate carriers, and to 0% of their sons, demonstrating an absence of male-to-male transmission.
• Carrier females face a 50% chance of transmitting the mutant allele to their sons, who will be affected, and to their daughters, who will be carriers.
• Follows a criss-cross inheritance pattern from affected grandfather through carrier daughter to affected grandson.

Clinical Nuances

• Heterozygous females may occasionally display symptoms due to skewed X-inactivation, known as Lyonization.
• Females with Turner syndrome can express X-linked recessive traits due to the presence of only a single X chromosome.

Clinical Examples

• Duchenne Muscular Dystrophy, Hemophilia A and B, and Glucose-6-Phosphate Dehydrogenase deficiency.

X-Linked Dominant Inheritance

Characteristics

• Affects both sexes, but females are affected more frequently, often presenting with a milder phenotype compared to hemizygous males.
• Affected males transmit the trait to 100% of their daughters and 0% of their sons.
• Affected females carry a 50% transmission risk for both sons and daughters.

Clinical Nuances

• Several conditions exhibit male lethality in utero, leading to pedigrees exclusively featuring affected females and an increased incidence of spontaneous abortions.

Clinical Examples

• Vitamin D Resistant Rickets, Rett Syndrome, and Incontinentia Pigmenti.

Y-Linked Inheritance

Characteristics

• Demonstrates strict male-to-male transmission.
• Affected males pass the specific trait to all sons and no daughters.

Clinical Examples

• Y-chromosome infertility and traits involving male sex determination.

Summary of Risk Assessment