MYH6 – Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and systolic dysfunction leading to heart failure (HP:0001635). While truncating variants in TTN predominate genetic DCM, heterozygous missense variants in MYH6, encoding the α-myosin heavy chain, have been reported in multiple independent cohorts of DCM patients.

In an initial screen of 434 subjects (374 in 69 DCM families), three heterozygous MYH6 missense variants (p.Pro830Leu, p.Ala1004Ser, p.Glu1457Lys) were identified in DCM probands (4.3% of probands) and were absent in ≥300 control chromosomes ([PMID:15998695]). In a subsequent resequencing study of 312 DCM probands, eight unique MYH6 rare variants were found in ten unrelated probands (3.2%), all absent in 246 control subjects, with evidence of familial cosegregation ([PMID:20215591]). A pediatric DCM cohort (n=41) yielded two additional MYH6 missense variants (p.Ile275Asn; p.Arg1502Gln) in affected children presenting before age 18 ([PMID:21483645]).

These MYH6 variants cluster in conserved motor and coiled-coil domains; c.3010G>T (p.Ala1004Ser) is observed in adult DCM cohorts and affects a residue critical for myosin head–tail interactions. All reported variants are heterozygous and fit an autosomal dominant inheritance pattern with incomplete penetrance. Segregation data are limited but consistent with familial transmission and absence in large control populations.

Functional studies specifically in DCM models are lacking; pathogenicity is supported by highly conserved amino acids, in silico structural predictions, and absence from control databases. No direct in vivo or cellular assays have yet demonstrated altered contractile function of MYH6 variants in DCM myocardium.

Despite limited functional work, the recurrent identification of heterozygous MYH6 missense variants in ~3–4% of DCM probands across three cohorts, their absence in controls, and familial cosegregation support a moderate clinical validity for MYH6 in autosomal dominant DCM (ClinGen). Additional mechanistic studies would strengthen causality.

Key Take-home: MYH6 heterozygous missense variants are a moderately validated cause of autosomal dominant dilated cardiomyopathy and should be considered in genetic testing panels for DCM.

References

• Circulation • 2005 • Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy. PMID:15998695
• Circulation. Cardiovascular genetics • 2010 • Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. PMID:20215591
• Progress in pediatric cardiology • 2011 • Rare variant mutations identified in pediatric patients with dilated cardiomyopathy. PMID:21483645

Evidence Based Scoring (AI generated)