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Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder characterized by unexplained left ventricular hypertrophy, myocyte disarray, and interstitial fibrosis. MYH6 encodes the α-cardiac myosin heavy chain, a sarcomeric motor protein critical for myocardial contractility. Although MYH6 variants were historically considered secondary to MYH7 mutations in HCM, accumulating case and cohort data implicate MYH6 as an autosomal dominant cause of HCM (PMID:11273720).
Multiple unrelated probands with HCM harbor heterozygous MYH6 variants: a frameshift c.1091_1092insTGAA (p.Lys364fsTer) co-segregated with HCM in a Japanese family with four affected members (PMID:35911064); missense variants c.611G>A (p.Arg204His) in a patient-derived iPSC line (PMID:39154416); c.3195G>T (p.Gln1065His) in 1/21 elderly-onset HCM families (PMID:15998695); c.2384G>A (p.Arg795Gln) in late-onset cohorts (PMID:11815426); and c.2425C>T (p.Arg809Cys) identified by next-generation sequencing in early-onset HCM (PMID:27483260). In total, six probands with five distinct missense and one frameshift variant support pathogenicity in HCM.
Inheritance is autosomal dominant, with segregation documented in one multiplex pedigree (three additional affected relatives) carrying p.Lys364fsTer (PMID:35911064). Variant spectrum includes missense substitutions within the motor domain and a truncating frameshift, consistent with haploinsufficiency or dominant-negative mechanisms.
Functional studies corroborate pathogenicity: expression of human α-myosin motor domains bearing Arg249Gln, Arg403Gln, and Val606Met—homologous to reported MYH6 variants—revealed graded reductions in actin-activated MgATPase activity and sliding velocity that correlate with clinical severity (PMID:9826622). In Drosophila models, R249Q expression decreased muscle power and force production, demonstrating impaired contractility rather than hypercontractile gain of function (PMID:30950055).
The convergence of genetic and experimental data indicates that MYH6 variants disrupt sarcomeric motor function, triggering compensatory myocardial hypertrophy. No studies have refuted the association or identified benign variants at equivalent residues, and phenotypes remain specific to HCM without conflicting overlap.
Overall, there is moderate clinical validity for MYH6 in autosomal dominant HCM, supported by six probands, one multiplex segregation, and concordant functional assays. Further large-scale segregation studies and quantitative in vivo models could strengthen the evidence towards a definitive classification.
Key Take-Home: Heterozygous MYH6 missense and truncating variants cause autosomal dominant hypertrophic cardiomyopathy via impaired myosin motor activity, warranting inclusion in diagnostic sarcomeric gene panels.
Gene–Disease AssociationModerate6 unrelated probands with segregating variants and concordant functional data Genetic EvidenceModerate5 missense and 1 frameshift variants in 6 probands, autosomal dominant inheritance, segregation in one multiplex family Functional EvidenceModerateBiochemical assays and model organism studies show reduced ATPase activity and force production for HCM-associated variants |