Autosomal Dominant Risk Assessment

Autosomal dominant (AD) conditions require only one pathogenic variant for disease expression. Risk assessment must account for penetrance, variable expressivity, and the possibility of de novo mutations.

For the underlying biology and pedigree pattern (vertical transmission, anticipation, age-dependent penetrance), see Autosomal Dominant Inheritance.

• Each child of an affected parent has a 1/2 (50%) chance of inheriting the variant
• Penetrance modifies the risk: if penetrance is 80%, the risk of being clinically affected = 1/2 x 0.8 = 40%
• De novo mutations account for a significant fraction of some AD conditions (e.g., ~80% of achondroplasia cases)
• Age-dependent penetrance: For late-onset conditions (e.g., BRCA1, Huntington disease), risk of manifesting increases with age

Example 1: Risk with reduced penetrance

Problem: A parent has a variant in a gene causing an AD condition with 70% penetrance. What is the chance their child will be clinically affected?

Solution:

• P(inheriting variant) = 1/2
• P(affected | has variant) = 0.70 (penetrance)
• Risk = 1/2 x 0.70 = 35%

Example 2: Non-penetrant parent

Problem: Two unaffected parents have a child with an AD condition. The father is found to carry the same variant. What is the recurrence risk for future children?

Solution:

• Father is a non-penetrant carrier
• Each future child has a 1/2 chance of inheriting the variant
• If the condition has 80% penetrance: risk of being affected = 1/2 x 0.80 = 40%
• Risk of having the variant but not being affected = 1/2 x 0.20 = 10%

Example 3: Gonadal mosaicism

Problem: An unaffected couple has two children with an AD condition. Neither parent carries the variant in blood. What is the most likely explanation and recurrence risk?

Solution:

• Most likely: gonadal mosaicism in one parent
• Empiric recurrence risk is typically quoted as up to 5-10% (varies by condition)
• Not 50% because the mosaic parent does not carry the variant in every germ cell

• Assuming 100% penetrance: Always ask about penetrance for AD conditions
• Ignoring de novo rate: If both parents are unaffected and genetically tested negative, recurrence risk is low (but not zero due to gonadal mosaicism)
• Confusing penetrance with expressivity: Penetrance = whether the condition manifests at all; expressivity = severity/features when it does manifest