A 52-year-old North Indian man presents with progressive fatigue, joint pain in the index and middle fingers, and recent-onset diabetes mellitus. Serum ferritin is 1200 ng/mL and transferrin saturation is 68%. HFE genotyping confirms C282Y homozygosity. His 28-year-old son is asymptomatic but screening reveals ferritin 180 ng/mL and transferrin saturation 52%; genetic testing shows he is also C282Y homozygous. The pedigree pattern marked **A** in the diagram shows what appears to be vertical transmission of the disease across generations, mimicking autosomal dominant inheritance. However, the underlying mode of inheritance is autosomal recessive. Which of the following BEST explains why this autosomal recessive disorder appears to follow a dominant pattern in this pedigree?

Explanation

## Why "High carrier frequency in the population (pseudodominance)" is right Pseudodominance is the phenomenon in which an autosomal recessive disease appears to follow an autosomal dominant pattern when the carrier frequency in the population is sufficiently high. In hereditary hemochromatosis (HH), the HFE C282Y mutation has a carrier frequency of approximately 10% in Northern European populations (and is also common in North Indian populations with European ancestry). This high carrier frequency means that an affected homozygote (C282Y/C282Y) has a substantial probability of marrying a carrier (C282Y/+), and such unions produce 50% affected homozygous offspring and 50% heterozygous carriers. When this occurs across multiple generations, the pedigree appears to show vertical transmission typical of autosomal dominant inheritance, even though the underlying mode is strictly recessive. The key diagnostic feature is that genotyping reveals all affected individuals are homozygotes (or compound heterozygotes), not heterozygotes as would be expected in true autosomal dominant disease. This is the classic teaching example from Harrison 21e Chapter 412 and is the defining mechanism of the pattern marked **A** in the diagram. ## Why each distractor is wrong - **Incomplete penetrance of the C282Y allele**: Incomplete penetrance refers to some genotype carriers not expressing the phenotype. This does not explain vertical transmission or why heterozygotes would appear affected. HFE heterozygotes are typically asymptomatic carriers, not affected individuals, so penetrance is not the mechanism here. - **X-linked inheritance with male lethality**: HFE is located on chromosome 6 (autosomal), not the X chromosome. This option is factually incorrect and does not apply to hereditary hemochromatosis. Additionally, male lethality would reduce affected males, not create vertical transmission. - **Genomic imprinting of the HFE gene**: There is no evidence that the HFE gene is subject to genomic imprinting. Imprinting would cause parent-of-origin-dependent expression, not the pattern seen here. The disease manifests equally regardless of which parent carries the mutation, ruling out imprinting as the mechanism. **High-Yield:** Pseudodominance = AR disease with high carrier frequency mimicking AD; HH C282Y is the classic example; genotyping (not pedigree alone) confirms the recessive mode. [cite: Harrison 21e Ch 412; Adams Neurology references]