A 45-year-old man from North India presents with progressive fatigue, joint pain in the 2nd and 3rd metacarpophalangeal joints, and hepatomegaly. Serum ferritin is 850 ng/mL and transferrin saturation is 62% (fasting). HFE genotyping confirms homozygosity for the C282Y mutation. His parents are both clinically well but have not been genotyped. The inheritance pattern shown in the pedigree at **A** — with two affected siblings born to unaffected parents — is most consistent with which mode of inheritance?
A. Autosomal recessive inheritance with both parents obligate heterozygous carriers
B. Mitochondrial inheritance with maternal transmission
C. X-linked recessive inheritance with the mother as a carrier
Autosomal dominant inheritance with incomplete penetrance in the father
D.
Explanation
Why Autosomal recessive inheritance with both parents obligate heterozygous carriers is right
The pedigree pattern at A shows two affected siblings born to clinically unaffected parents. This is the hallmark of autosomal recessive inheritance. Hereditary hemochromatosis (HFE-HH, type 1) is caused by homozygosity for the C282Y missense mutation on chromosome 6p21.3. Both parents must be heterozygous carriers (C282Y/wild-type) to produce homozygous affected children. Heterozygous carriers are clinically silent because one functional HFE allele is sufficient to maintain near-normal hepcidin expression and iron homeostasis. The horizontal pattern of inheritance (siblings affected, parents unaffected) and the ~25% recurrence risk in subsequent siblings are diagnostic features of autosomal recessive disease. This inheritance pattern is distinct from the vertical transmission seen in autosomal dominant conditions (AASLD Hemochromatosis Practice Guideline 2024; Bacon et al).
Why each distractor is wrong
Autosomal dominant inheritance with incomplete penetrance in the father: Autosomal dominant disorders show vertical transmission across generations (affected parent → affected child). The father is unaffected, which contradicts this pattern. Incomplete penetrance cannot explain why both parents are clinically well yet have two affected children.
X-linked recessive inheritance with the mother as a carrier: X-linked recessive disorders affect males predominantly and show a characteristic pattern of affected males through carrier mothers, with no male-to-male transmission. The HFE gene is on chromosome 6 (autosomal), not the X chromosome. Furthermore, if this were X-linked, an affected male would pass the allele to all daughters (making them carriers or affected) but not to sons.
Mitochondrial inheritance with maternal transmission: Mitochondrial disorders show maternal-line transmission with all children of affected mothers being affected, regardless of sex. There is no paternal transmission. The pedigree pattern here (unaffected mother with affected children) does not fit mitochondrial inheritance. Additionally, HFE is a nuclear gene, not mitochondrial.
High-YieldNEET PG
Autosomal recessive disease = affected sibling clusters from unaffected carrier parents; C282Y homozygosity in HFE causes ~1 in 200 Northern Europeans to be at risk, but only 10–30% develop clinical iron overload.
AASLD Hemochromatosis Practice Guideline 2024; Bacon et al
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