Variants in MYH7 and MYH6 cosegregate with hypertrophic cardiomyopathy, with MYH6 potentially acting as a genetic modifier worsening disease severity.
The identification of cosegregating MYH7 and MYH6 variants in HCM families suggests a synergistic effect that may worsen disease severity, emphasizing the need for comprehensive genetic testing.
Absolute Event Rate: 0% vs 0%
Abstract Hypertrophic cardiomyopathy (HCM) is primarily characterized by unexplained left ventricular hypertrophy and affects approximately 1 in 500 individuals. Genetic variants in sarcomeric proteins play a key role in HCM pathogenesis, with the MYH7 gene being a major contributor. The role of MYH6, located adjacent to MYH7 on chromosome 14, remains less understood but has been implicated in cardiac phenotypes. This study aimed to investigate the impact of heterozygous variants in MYH7 and MYH6 on HCM phenotypic variability. Whole-exome sequencing was performed on probands from four unrelated families, identifying two variants: c.788TC in MYH7 and c.5072GA in MYH6. These variants cosegregated with the disease in affected family members, suggesting they may be in linkage disequilibrium. Additionally, the severity of disease phenotypes suggests a potential synergistic effect between MYH7 and MYH6, indicating that MYH6 could act as a genetic modifier. The c.788TC variant in MYH7 has been previously reported in six studies involving patients with similar phenotypes. It is located in the myosin head domain, a critical region essential for protein function and muscle contraction. The c.5072GA (p.Arg1691His) variant in MYH6 has been observed in individuals diagnosed with HCM; however, current evidence is insufficient to definitively determine its pathogenic role. It has been reported that carrying multiple sarcomeric variants, particularly in MYH7 and MYBPC3, may lead to an earlier disease onset. Moreover, a recently described family with double heterozygous variants in MYH7 and MYH6 also exhibited a more severe HCM phenotype, suggesting a possible genetic modifier effect. Our findings highlight the importance of analyzing multiple sarcomeric genes in genetic testing for HCM. They also suggest that MYH6, in conjunction with MYH7, may play a more significant role in HCM pathogenesis than previously recognized. Further research is necessary to elucidate the functional implications of MYH7–MYH6 interactions and their contribution to the clinical spectrum of hypertrophic cardiomyopathy.
Streitenberger et al. (Sat,) reported a other. Variants in MYH7 and MYH6 cosegregate with hypertrophic cardiomyopathy, with MYH6 potentially acting as a genetic modifier worsening disease severity.
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