A 28-year-old man presents to the cardiology clinic with a family history of sudden cardiac death. His father died at age 35 from aortic dissection, and his paternal grandfather had a similar presentation. On examination, the patient is tall with arachnodactyly, pectus carinatum, and a systolic murmur. Echocardiography reveals aortic root dilatation at the sinuses of Valsalva with a Z-score of 2.8. Genetic testing confirms a heterozygous pathogenic mutation in the FBN1 gene on chromosome 15q21.1. The pedigree pattern shown in the diagram, marked as **A**, demonstrates affected individuals in every generation with male-to-male transmission. Which of the following best describes the inheritance pattern and its implications for this patient's siblings?
A. X-linked dominant inheritance with affected males unable to pass the condition to sons, making male siblings unaffected
B. Autosomal recessive inheritance with 25% recurrence risk, requiring genetic counselling only if both parents are carriers
C. Mitochondrial inheritance with maternal transmission only, meaning paternal transmission rules out this diagnosis
D. Autosomal dominant inheritance with 50% recurrence risk for each sibling regardless of sex, and need for screening echocardiography in all siblings
Explanation
Why Autosomal dominant inheritance with 50% recurrence risk for each sibling regardless of sex, and need for screening echocardiography in all siblings is right
Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene on chromosome 15q21.1 encoding fibrillin-1. The pedigree pattern marked A — showing affected individuals in every generation, male-to-male transmission, and equal distribution across both sexes — is the hallmark of autosomal dominant inheritance. Each child of an affected individual has a 50% probability of inheriting the mutant allele regardless of sex. The presence of paternal transmission (father to son) is pathognomonic for autosomal dominant inheritance and excludes X-linked patterns. All siblings of this patient have a 50% risk of carrying the same FBN1 mutation, and those who inherit it will develop Marfan syndrome with essentially complete penetrance by adulthood. Consequently, screening echocardiography is indicated in all siblings to detect aortic root dilatation early and guide prophylactic management (beta-blockers, ARBs, and aortic surveillance per the Revised Ghent Nosology 2010 and ACC/AHA guidelines).
Why each distractor is wrong
Autosomal recessive inheritance with 25% recurrence risk: Autosomal recessive conditions require two mutant alleles and typically present in siblings with unaffected parents. The presence of an affected father and vertical transmission across generations excludes recessive inheritance. Recurrence risk would be 25% only if both parents were carriers, which is not the case here.
X-linked dominant inheritance with affected males unable to pass the condition to sons: X-linked inheritance is excluded by the presence of male-to-male transmission (father to son). In X-linked dominant conditions, affected fathers cannot pass the condition to sons because sons receive the Y chromosome from their father, not the X. The pedigree clearly shows paternal transmission, which is incompatible with X-linked inheritance.
Mitochondrial inheritance with maternal transmission only: Mitochondrial disorders show maternal transmission exclusively — all children of affected mothers are affected, and affected fathers do not transmit the condition to any offspring. The presence of paternal transmission in this pedigree definitively excludes mitochondrial inheritance.
High-YieldNEET PG
Marfan syndrome is autosomal dominant (FBN1, chromosome 15q21.1); male-to-male transmission is the key finding that excludes X-linked and mitochondrial patterns. All siblings of an affected individual have 50% recurrence risk and require screening echocardiography.
Revised Ghent Nosology 2010; ACC/AHA Aortic Disease Guidelines; Loeys et al. J Med Genet. 2010
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