MYH7 – Congenital Heart Disease

β-Myosin heavy chain, encoded by MYH7, is a core sarcomeric protein traditionally implicated in cardiomyopathies but increasingly recognized in congenital heart disease (CHD). Multiple independent cohorts report heterozygous MYH7 variants in patients with septal defects, Ebstein anomaly, and left ventricular noncompaction (LVNC) combined with CHD ([PMID:32183154]; [PMID:35491958]; [PMID:28864942]). This expanding phenotypic spectrum underscores the clinical relevance of MYH7 in developmental cardiac septation.

Genetic studies have identified at least 28 unrelated probands harboring eight distinct MYH7 missense or truncating variants in CHD cohorts ([PMID:32183154]). A Dutch founder mutation, c.5754C>G (p.Asn1918Lys), segregates with early-onset cardiomyopathy and CHD in 15 probands and 65 family members, seven of whom manifest septal defects ([PMID:28864942]). In a single-center series, three probands with complex CHD and LVNC carried novel heterozygous MYH7 variants with segregation in 12 affected relatives, including Ebstein anomaly and LVNC ([PMID:35491958]).

Inheritance is autosomal dominant, with segregation data supporting pathogenicity. The founder p.Asn1918Lys allele shows co-segregation in 65 carriers (57.5% with cardiomyopathy, 8.8% with CHD) ([PMID:28864942]), and familial clustering in three pedigrees accounts for 11 additional affected relatives ([PMID:35491958]). MYH7 CHD variants are rare in population databases, consistent with dominant Mendelian transmission.

The reported MYH7 variant spectrum in CHD comprises missense substitutions affecting critical motor domains (e.g., c.2134C>T (p.Arg712Cys) in LVNC + CHD; [PMID:32183154]) and a recurrent Dutch founder mutation. No other recurrent or deep-intronic alleles have been noted beyond p.Asn1918Lys.

Functional assays on MYH7 missense mutations—though primarily in hypertrophic cardiomyopathy—demonstrate impaired actin-activated ATPase activity, reduced in vitro motility, and altered crossbridge kinetics. The Arg403Gln mutation lowers Vmax by >3-fold and reduces motility ~5-fold ([PMID:8294404]), while Arg453Cys slows ATP hydrolysis 3-fold ([PMID:8981935]). These data support a dominant-negative mechanism disrupting sarcomere force generation.

Integrated genetic and experimental evidence fulfills a moderate level of clinical validity for MYH7 in CHD. Further comprehensive segregation analyses and in vivo modeling of CHD-associated alleles could elevate the evidence level. Key take-home: heterozygous MYH7 variants should be considered in genetic screening of familial CHD, informing diagnosis, risk stratification, and counseling.

References

• Journal of Clinical Medicine • 2020 • Left Ventricular Noncompaction and Congenital Heart Disease Increases the Risk of Congestive Heart Failure. PMID:32183154
• Netherlands Heart Journal • 2017 • A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects PMID:28864942
• American Journal of Medical Genetics Part A • 2022 • MYH7 variants cause complex congenital heart disease. PMID:35491958
• The Journal of Biological Chemistry • 1994 • Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. PMID:8294404
• The Journal of Clinical Investigation • 1996 • Functional analysis of the mutations in the human cardiac beta-myosin that are responsible for familial hypertrophic cardiomyopathy. Implication for the clinical outcome. PMID:8981935

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