A 28-year-old male presents to the cardiology clinic with a family history of sudden cardiac death in his father at age 35. Echocardiography reveals asymmetric septal hypertrophy with a left ventricular wall thickness of 16 mm and a dynamic left ventricular outflow tract (LVOT) gradient. Genetic testing identifies a heterozygous mutation in the MYH7 gene. The inheritance pattern marked **B** in the pedigree diagram is consistent with this finding. Which of the following best describes the inheritance pattern and genetic basis of this patient's condition?
A. X-linked dominant inheritance with male lethality; MYH7 mutations predominantly affect females
B. Mitochondrial inheritance with maternal transmission; mutations in oxidative phosphorylation genes cause HCM phenotype
C. Autosomal dominant inheritance with variable penetrance and expressivity; mutations in sarcomeric proteins (MYH7, MYBPC3) account for 60-70% of genotype-positive HCM cases
D. Autosomal recessive inheritance requiring two mutant alleles; MYBPC3 mutations are the most common cause of HCM
Explanation
Why Option 1 is correct
The structure marked B represents autosomal dominant inheritance with variable penetrance and expressivity—the hallmark inheritance pattern of hypertrophic cardiomyopathy (HCM). The ESC HCM Guideline 2023 and AHA/ACC 2024 consensus confirm that HCM is the most common inherited cardiac disorder (prevalence 1:500) and the most common cause of sudden cardiac death in young athletes and individuals <35 years. Mutations in >11 sarcomeric protein genes cause HCM; the two most common are MYBPC3 (cardiac myosin binding protein C—most common overall) and MYH7 (beta-myosin heavy chain—often associated with more severe phenotype). Together, these two genes account for 60–70% of genotype-positive HCM cases. This patient's MYH7 mutation, heterozygous state, and severe phenotype (asymmetric septal hypertrophy, LVOT obstruction, family history of SCD) exemplify autosomal dominant inheritance with variable expressivity.
Why each distractor is wrong
Option 2 (Autosomal recessive): HCM is autosomal dominant, not recessive. Autosomal recessive inheritance would require two mutant alleles and typically presents in consanguineous families; this patient is heterozygous with a single MYH7 mutation, inconsistent with recessive inheritance.
Option 3 (X-linked dominant): HCM is not X-linked. X-linked dominant inheritance would show affected males in every generation and no male-to-male transmission; this pedigree shows paternal transmission (father to son), which excludes X-linked inheritance.
Option 4 (Mitochondrial): HCM is not a mitochondrial disorder. Mitochondrial inheritance shows maternal-only transmission and affects all offspring of affected mothers; the autosomal dominant pattern with variable penetrance and the specific sarcomeric gene mutations (MYH7, MYBPC3) are incompatible with mitochondrial pathology.
High-YieldNEET PG
HCM is autosomal dominant with variable penetrance/expressivity; MYH7 and MYBPC3 mutations account for 60–70% of cases and are the two most common causes—essential for cascade screening and risk stratification in families.
ESC HCM Guideline 2023; AHA/ACC 2024
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