MYH7 p.(Arg1712Gln) is pathogenic founder variant causing hypertrophic cardiomyopathy with overall relatively delayed onset.

Abstract

The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate apotential founder effect. We retrospectively collected clinical and genetic data of 22probands and 74family members from an international cohort. In total, 53individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8years (standard deviation:18.1; range: 8-74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68years, and afamily history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had agenerally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75years. Haplotypes were reconstructed for 35patients and showed afounder effect in asubset of patients. MYH7 p.(Arg1712Gln) is apathogenic founder variant with aconsistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30years.