A 35-year-old man presents to the genetics clinic with a family history of Huntington disease. His father was diagnosed at age 40 and died at age 65 with progressive chorea and dementia. The patient's paternal grandfather was unaffected. The pedigree shows the feature marked **A** — vertical transmission across generations with disease appearing in every generation without skipped generations. Which of the following best explains why this pattern is characteristic of autosomal dominant inheritance?

Explanation

## Why option 1 is right Autosomal dominant inheritance is defined by the presence of a mutant allele on an autosome (non-sex chromosome) that causes disease in heterozygotes. The vertical transmission pattern marked **A** — where the disease appears in every generation with no skipped generations — is the hallmark pedigree signature of AD inheritance. Each affected heterozygote has a 50% probability of passing the mutant allele to each offspring, regardless of the child's sex. This explains why both males and females are equally affected and why the disease does not skip generations in families with full penetrance. In Huntington disease (the clinical example here), the HTT gene mutation on chromosome 4 follows this exact pattern, with affected individuals having a 50% recurrence risk to offspring (Nelson Pediatrics 21e Ch 99; Harrison 21e Ch 460). ## Why each distractor is wrong - **Option 2**: X-linked inheritance would show affected males with unaffected sons (no male-to-male transmission), and affected heterozygous females would have a 50% chance of affected sons and 50% affected daughters. The vertical transmission pattern would be disrupted by the absence of male-to-male transmission, which is NOT seen in the pedigree marked **A**. - **Option 3**: Autosomal recessive inheritance requires two mutant alleles for disease expression. Affected individuals (homozygotes) mating with unaffected individuals (heterozygotes) would have all heterozygous (unaffected) children, not affected children. This does not produce vertical transmission across generations. - **Option 4**: While Huntington disease does show anticipation (earlier onset and increased severity in successive generations, particularly with paternal transmission), the vertical transmission pattern **A** is not explained by sex-specific penetrance. AD inheritance affects both sexes equally because the mutation is on an autosome, not because penetrance differs by sex. **High-Yield:** Vertical transmission in every generation (no skipped generations) + male-to-male transmission possible + 50% recurrence risk = **Autosomal Dominant**. Incomplete penetrance or variable expressivity may modify the pattern, but the fundamental mechanism is heterozygosity for an autosomal mutation. [cite: Nelson Pediatrics 21e Ch 99; Harrison 21e Ch 460]