Abstract
This study reports on a Chinese Han cardiomyopathy family line carrying the MYH7 c.2770G > A (p.Glu924Lys) mutation. This mutation has been shown to result in cross-generational phenotypic heterogeneity between hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM). The proband was a 17-year-old male diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) due to post-exercise syncope, which resolved after septal septectomy. Family lineage analysis revealed that the mother (RCM, NYHA class III) and uncle (RCM, NYHA class IV) of the proband presented with bi-atrial enlargement and reduced systolic function (LVEF 45%), whereas aunts and cousins (n = 3) had asymptomatic hypertrophic non-obstructive cardiomyopathy (HNCM). Whole exome sequencing identified six family members carrying the MYH7 c.2770G > A heterozygous mutation with an ACMG rating of probable pathogenic (PM2 + PP3 + PP5). The subjects carrying the mutation exhibited three distinct phenotypes: HOCM (1 case), HNCM (3 cases), and RCM (2 cases). However, the mutation locus did not fully co-segregate with the observed phenotypes. The study hypothesises that the MYH7 c.2770G > A mutation can lead to transgenerational and multisubtype cardiomyopathy phenotypic heterogeneity, and that the mechanism may be related to transcriptional regulation and epigenetic modifications. It is imperative that early genetic screening and clinical intervention are implemented to enhance the prognosis of affected families.