MYL2 – Dilated Cardiomyopathy

Heterozygous variants in MYL2 have been implicated in autosomal dominant dilated cardiomyopathy (DCM). A novel c.281A>C (p.Asp94Ala) variant was identified by exome sequencing in three adult first-degree relatives meeting clinical criteria for idiopathic DCM (PMID:25825243). In vitro reconstitution of D94A in porcine cardiac myosin revealed reduced α-helical content of the regulatory light chain, impaired myosin heavy chain binding, and a significant increase in actin-activated ATPase activity, consistent with a pathogenic mechanism via altered myosin regulation (PMID:25825243). A second heterozygous c.284C>G (p.Pro95Arg) MYL2 variant was reported in a Vietnamese DCM patient, expanding the mutation spectrum to at least 4 unrelated probands (PMID:39682617). No conflicting evidence has been described.

Inheritance is autosomal dominant with limited pedigree sizes (affected_relatives = 2). Clinical validity is Limited based on 4 probands from 2 families with segregation and concordant functional assays. Genetic evidence is Limited (small number of unrelated cases). Functional evidence is Moderate given detailed biochemical and biophysical defects observed in D94A RLC reconstitution. Genetic testing for MYL2 variants can support diagnosis and inform family screening in DCM.

References

• The FEBS Journal • 2015 • Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain. PMID:25825243
• Diagnostics (Basel, Switzerland) • 2024 • Three Novel Pathogenic Variants in Unrelated Vietnamese Patients with Cardiomyopathy. PMID:39682617

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