MYL2 – Hypertrophic Cardiomyopathy

MYL2 encodes the ventricular myosin regulatory light chain, a key component of the sarcomere that modulates cross-bridge cycling and calcium sensitivity. Pathogenic variants in MYL2 are a recognized cause of hypertrophic cardiomyopathy (HCM), characterized by unexplained left ventricular hypertrophy, diastolic dysfunction, and risk of sudden death. The clinical validity of the MYL2–HCM association has been classified as Definitive based on multiple segregation studies and concordant functional data ([PMID:30681346]).

Inheritance of MYL2-related HCM is predominantly autosomal dominant with incomplete penetrance, but recessive loss-of-function alleles can underlie early infantile cases. Segregation analyses across families have identified at least 18 additional affected relatives carrying pathogenic MYL2 variants (12 with p.Gly162Glu ([PMID:29549657]) and 6 with p.Arg58Gln ([PMID:31104103])).

Case reports and cohort studies describe a spectrum of MYL2 variants, principally missense changes such as c.173G>A (p.Arg58Gln) and c.485G>A (p.Gly162Glu), as well as rare frameshift and splice site mutations. The variant c.173G>A (p.Arg58Gln) recurs in multiple pedigrees with concordant segregation and a malignant HCM phenotype.

Functional assessments indicate that MYL2 pathogenic variants disrupt myosin mechanics and regulatory interactions. Pseudo-phosphorylation at Ser-15 restores force generation and ATPase activity in R58Q mutant myosin ([PMID:24374283]; [PMID:30430732]). Conversely, the IVS6-1 splice-site variant (c.403-1G>C) reduces myosin ATPase and impairs acto-myosin kinetics in vitro ([PMID:27378946]).

Together, genetic and experimental findings delineate a mechanism of haploinsufficiency and perturbation of sarcomeric regulation in MYL2-mediated HCM. These data support robust diagnostic testing strategies and cascade screening in at-risk relatives.

Key Take-home: Pathogenic MYL2 variants cause autosomal dominant HCM with high clinical utility for genetic diagnosis, familial risk assessment, and tailored management.

References

• Circulation. Genomic and precision medicine • 2019 • Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes PMID:30681346
• Molecular diagnosis & therapy • 2018 • A Novel Missense Mutation p.Gly162Glu of the Gene MYL2 Involved in Hypertrophic Cardiomyopathy: A Pedigree Analysis of a Proband. PMID:29549657
• Molecular genetics and genomics : MGG • 2019 • The co-segregation of the MYL2 R58Q mutation in Chinese hypertrophic cardiomyopathy family and its pathological effect on cardiomyopathy disarray. PMID:31104103
• Archives of biochemistry and biophysics • 2014 • In vitro rescue study of a malignant familial hypertrophic cardiomyopathy phenotype by pseudo-phosphorylation of myosin regulatory light chain PMID:24374283
• Frontiers in physiology • 2016 • Molecular and Functional Effects of a Splice Site Mutation in the MYL2 Gene Associated with Cardioskeletal Myopathy and Early Cardiac Death in Infants. PMID:27378946
• The FEBS journal • 2019 • Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain PMID:30430732

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