Autosomal Dominant Inheritance

Autosomal dominant (AD) inheritance requires only one pathogenic allele on an autosome to cause disease. Affected individuals typically have one affected parent, and the condition is transmitted vertically through generations with a 50% recurrence risk for each offspring.

For the carrier and recurrence-risk math (penetrance corrections, Bayesian updates, worked pedigree examples), see Autosomal Dominant Risk Assessment.

• Vertical transmission: Affected individuals appear in every generation. Each child of an affected heterozygous parent has a 50% chance of inheriting the pathogenic variant.
• Sex-independent: Males and females are equally likely to be affected and to transmit the condition. Male-to-male transmission is possible (distinguishing AD from X-linked).
• Penetrance: The proportion of individuals with a pathogenic variant who show any clinical features. Reduced penetrance means some carriers appear unaffected (e.g., BRCA1 has ~70% cumulative penetrance for breast cancer by age 80).
• Variable expressivity: Different individuals with the same pathogenic variant may show different severity or features. For example, neurofibromatosis type 1 (NF1) ranges from cafe-au-lait spots only to severe plexiform neurofibromas.
• De novo mutations: A new pathogenic variant arising in the affected individual, not inherited from either parent. Common in conditions with reduced reproductive fitness (e.g., ~80% of achondroplasia cases are de novo, with advanced paternal age as a risk factor).
• Age-dependent penetrance: Penetrance increases with age. Huntington disease shows virtually no symptoms before age 20 in typical expansions but approaches full penetrance by age 70.
• Dominant negative effect: The abnormal protein interferes with the function of the normal protein (e.g., the severe forms of osteogenesis imperfecta, where a mutant collagen chain disrupts the assembly of normal collagen).
• Haploinsufficiency: One functional copy of the gene is insufficient for normal function (e.g., PAX3 in Waardenburg syndrome type 1).
• Gain of function: The mutant protein acquires a new or enhanced activity (e.g., FGFR3 in achondroplasia).

• Marfan syndrome (FBN1): Classic AD with variable expressivity. Aortic root dilation, lens subluxation, and skeletal features can vary widely even within the same family
• Huntington disease (HTT): Demonstrates age-dependent penetrance and anticipation (through CAG repeat expansion)
• Familial hypercholesterolemia (LDLR): Heterozygotes have elevated LDL; homozygotes are severely affected, demonstrating dosage sensitivity
• Hereditary breast/ovarian cancer (BRCA1/2): Reduced penetrance means not all carriers develop cancer, complicating risk counseling