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Autosomal dominant mutations in MYPN have been implicated in hypertrophic cardiomyopathy (Hypertrophic Cardiomyopathy) through genetic and functional studies that highlight disrupted sarcomeric and nuclear signaling at the Z-disc.
In a cohort of 900 patients with hypertrophic, dilated, or restrictive cardiomyopathy, targeted sequencing of MYPN identified 15 rare variants (2 nonsense, 13 missense) corresponding to a 1.66% prevalence (PMID:22286171). Variants were absent in 400 controls and affected conserved residues, supporting pathogenicity.
Notably, the missense variant c.59A>G (p.Tyr20Cys) was detected in unrelated HCM probands and shown to segregate with disease within a family (PMID:22286171). A second missense, c.3848G>A (p.Arg1283His), was identified in a father–daughter pair presenting with obstructive HCM, atrioventricular block, and early repolarization patterns on ECG (PMID:28427417).
Functional characterization of p.Tyr20Cys in neonatal rat cardiomyocytes revealed disrupted binding to cardiac ankyrin repeat protein (CARP) and failure of nuclear translocation. Cardiac‐restricted transgenic mice expressing p.Tyr20Cys developed left ventricular hypertrophy and intercalated disc abnormalities, phenocopying human HCM (PMID:22286171). These data support a dominant‐negative mechanism rather than haploinsufficiency.
No studies to date have refuted MYPN’s role in HCM, and no alternative gene–disease assignments overlap these variants. Together, the identification of multiple unrelated probands, familial segregation, and concordant in vitro and in vivo functional evidence justify a Moderate level of clinical validity for MYPN in HCM.
Key Take-home: Pathogenic MYPN variants such as c.59A>G (p.Tyr20Cys) cause autosomal dominant hypertrophic cardiomyopathy via disrupted Z-disc integrity and impaired nuclear signaling, supporting their use in genetic diagnosis and risk assessment.
Gene–Disease AssociationModerateAD MYPN variants identified in multiple unrelated HCM probands with segregation in one family and concordant functional data Genetic EvidenceModerateIdentified c.59A>G (p.Tyr20Cys) and c.3848G>A (p.Arg1283His) in HCM patients with absence in controls and familial segregation Functional EvidenceModerateTransgenic mice expressing p.Tyr20Cys develop HCM; in vitro studies show disrupted CARP binding and nuclear localization consistent with disease mechanism |