MYH7 – Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant cardiomyopathy characterized by ventricular arrhythmias, fibrofatty replacement of the right ventricle, and risk of sudden cardiac death. Although desmosomal gene mutations account for the majority of ARVC cases, rare sarcomeric gene variants have been identified in ARVC cohorts. In a series of 137 individuals meeting 2010 Task Force Criteria and negative for pathogenic desmosomal, TMEM43, SCN5A, and PLN variants, three probands (3/137, 2%) harbored rare MYH7 missense variants—c.4499G>A (p.Arg1500Gln), c.5536C>T (p.Arg1846Cys), and c.2167C>T (p.Arg723Cys)—absent or extremely rare in population databases and predicted deleterious (PMID:29709087).

Additional case reports include an 11-year-old male with de novo MYH7 and DES variants presenting with right heart failure due to ARVC (PMID:35579085), and a 51-year-old woman carrying MYH7 c.2770G>A (p.Glu924Lys) alongside a PKP2 frameshift, who exhibited hypertrophic cardiomyopathy without ARVC features (PMID:39691896). No evidence of multigenerational segregation or ARVC-specific functional assays for these MYH7 variants has been reported. Moreover, desmosomal-negative families with MYH7 variants show no consistent phenotype co-segregation.

Given only three unrelated ARVC probands with MYH7 missense variants and absence of segregation or mechanistic confirmation, the clinical validity of MYH7 in ARVC remains in the Limited range. Integration of larger ARVC cohorts, family segregation studies, and ARVC-focused functional models are required to clarify the role of MYH7 in ARVC pathogenesis.

Key Take-home: MYH7 missense variants have been observed in a small fraction of desmosome‐negative ARVC cases, but current evidence is insufficient to support routine MYH7 testing for ARVC without further segregation and functional validation.

References

• Journal of cardiovascular electrophysiology • 2018 • Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). PMID:29709087
• Cardiology in the young • 2023 • Arrhythmogenic right ventricular cardiomyopathy presenting as heart failure in a child. PMID:35579085
• JACC. Case reports • 2024 • Coinheritance of Hypertrophic and Arrhythmogenic Cardiomyopathy Variants in a Patient With Hypertrophic Cardiomyopathy PMID:39691896

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