MYL3 – Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant inherited cardiomyopathy characterized by fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and risk of sudden cardiac death.

Rare variants in MYL3 have been identified in ARVC cohorts. In a study of 43 advanced cardiomyopathy patients (including 10 with ARVC), one ARVC proband carried a heterozygous missense variant c.461G>A (p.Arg154His) ([PMID:29253866]). In a separate cohort of 137 ARVC patients negative for desmosomal gene mutations, 6/137 (4%) probands harbored rare sarcomeric variants, including c.461G>A (p.Arg154His) in MYL3 ([PMID:29709087]).

The inheritance pattern is consistent with autosomal dominant transmission, although familial segregation data for MYL3 variants in ARVC families are lacking. No additional affected relatives with documented MYL3 variant segregation have been reported.

The variant spectrum in ARVC is currently limited to the missense change c.461G>A (p.Arg154His), predicted to be damaging, with no reports of loss-of-function or splice-altering alleles in this disease context.

Functional studies directly assessing MYL3 variants in ARVC are not available. Mechanistic work in hypertrophic cardiomyopathy and recessive cardiomyopathy contexts suggests that MYL3 missense and truncating variants impair myosin essential light chain function, but these findings have not been validated in ARVC models.

Overall, the clinical validity of MYL3 in ARVC is limited due to the small number of probands, absence of segregation evidence, and lack of functional validation in ARVC. Further studies, including family-based segregation and disease-relevant functional assays, are required.

Key Take-home: MYL3 missense variants have been observed in a minority of ARVC cases, but current evidence is insufficient for definitive diagnostic use and should be interpreted with caution pending corroborative studies.

References

• PloS One • 2017 • High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation. PMID:29253866
• Journal of cardiovascular electrophysiology • 2018 • Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). PMID:29709087

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