MYH7 – Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by left ventricular chamber enlargement and systolic dysfunction, leading to heart failure and sudden cardiac death (MONDO:0005021). MYH7 (HGNC:7577) encodes the β-cardiac myosin heavy chain, a key sarcomeric motor protein. Heterozygous missense variants in MYH7 have been implicated in DCM through multiple case reports and cohort studies.

Six unrelated DCM probands with rare MYH7 variants have been reported. In a Finnish cohort, two index patients harbored c.4498C>T (p.Arg1500Trp), one with a typical DCM phenotype (PMID:15556047). In a multigenerational family, c.2167C>T (p.Arg723Cys) segregated with mixed DCM and hypertrophic phenotypes in four mutation-positive members, including two with DCM diagnosis by echocardiography and autopsy (PMID:37509704). Additional screening of 46 young DCM patients identified MYH7 c.667G>A (p.Ala223Thr) and c.1925C>T (p.Ser642Leu) in two individuals (PMID:12379228).

Variants in MYH7 causing DCM are predominantly missense changes affecting conserved residues in the motor and converter domains. The recurrent p.Arg1500Trp allele has been observed in different populations. To date, no homozygous or truncating MYH7 variants have been linked to isolated DCM, consistent with a dominant mechanism.

MYH7-related DCM follows autosomal dominant inheritance, with evidence of co-segregation in two families providing an affected relatives count of 2. Variable expressivity is noted, with some carriers displaying hypertrophic features prior to dilation. Penetrance appears age-dependent, and no clear genotype-phenotype correlation has been established.

Functional assays in mouse models of point mutations equivalent to human DCM alleles (p.Ser532Pro and p.Phe764Leu) demonstrate dilated ventricular remodeling and depressed sarcomeric motor function, including reduced in vitro actin translocation velocity and decreased actin-activated ATPase activity (PMID:16983074). These findings underscore a loss-of-function mechanism leading to impaired contractile force.

Integration of genetic and experimental data supports that rare, dominant MYH7 missense variants cause DCM through impaired myosin motor activity, resulting in ventricular dilation and systolic failure. While additional modifiers likely influence penetrance and severity, current evidence reaches a moderate level of clinical validity.

Key Take-Home: MYH7 missense variants should be considered in familial and sporadic DCM; genetic testing informs prognosis and management.

References

• Biomedicines • 2023 • A Family with Myh7 Mutation and Different Forms of Cardiomyopathies PMID:37509704
• European journal of heart failure • 2004 • Two novel mutations in the beta-myosin heavy chain gene associated with dilated cardiomyopathy PMID:15556047
• Biochemical and biophysical research communications • 2002 • Novel mutations in sarcomeric protein genes in dilated cardiomyopathy PMID:12379228
• Proceedings of the National Academy of Sciences of the United States of America • 2006 • Cardiac myosin missense mutations cause dilated cardiomyopathy in mouse models and depress molecular motor function PMID:16983074

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