MYH7 – Left Ventricular Noncompaction

Left ventricular noncompaction (LVNC) is a genetically heterogeneous cardiomyopathy characterized by prominent trabeculations and deep intertrabecular recesses of the left ventricle. MYH7 encodes the β-myosin heavy chain, a key sarcomeric motor protein expressed in cardiac muscle. Pathogenic variants in MYH7 disrupt sarcomere assembly and function, leading to autosomal dominant LVNC with variable expressivity and onset.

Genetic screening of large cohorts has identified MYH7 variants in 63 adult probands ([PMID:18506004]), 102 unrelated patients ([PMID:28855170]), and 33 fetal-onset cases ([PMID:33309763]). Familial segregation across at least 19 affected relatives in multiple kindreds confirms co-segregation of MYH7 variants with LVNC ([PMID:18506004]; [PMID:35209905]). Both de novo and inherited alleles, including low-frequency maternal somatic mosaicism (c.2729A>T (p.Lys910Ile)) ([PMID:37360367]), have been reported.

Over 80 unique MYH7 variants have been described, predominantly missense changes clustering in the motor and rod domains, with canonical splice-site (c.732+1G>A) and truncating alleles also observed. A representative variant is c.1625A>C (p.Lys542Thr) ([PMID:25547560]), identified in a fetus with cardiomegaly. MYH7 variants account for ~9% of adult LVNC cases ([PMID:30980206]) and >20% in pediatric cohorts ([PMID:28855170]). Recurrent alleles such as c.732+1G>A are found in independent families.

Functional studies reveal dominant-negative and haploinsufficiency mechanisms. The p.Arg403Gln mutation reduces actin-activated ATPase Vmax >3.5-fold and motility by ~5-fold in vitro ([PMID:8294404]), whereas R453C slows ATP binding and recovery stroke kinetics 3-fold ([PMID:24344137]). Transgenic mice expressing R403Q demonstrate isoform-specific kinetic defects in β- versus α-MHC backgrounds ([PMID:23580644]), mirroring human LVNC phenotypes.

Some MYH7 truncating and splice-site variants appear in population databases, and 18/60 previously reported LVNC-associated missense/nonsense alleles are present in ExAC/ESP, underscoring the need for comprehensive phenotype correlation ([PMID:27066506]). Enrichment of MYH7 truncating variants in LVNC versus other cardiomyopathies suggests both shared and distinct etiologies ([PMID:33500567]).

Clinical validity is Definitive based on replication in >250 probands, multi-family segregation, and concordant functional data. Genetic evidence is Strong: multiple AD cohorts, 19 segregations, and variant diversity reaching ClinGen caps. Functional evidence is Moderate: in vitro motility/ATPase assays and transgenic models demonstrate mechanistic plausibility.

MYH7 variant analysis is recommended in LVNC evaluation. Genetic diagnosis informs prognostic assessment, guides family screening, and aids surgical decision-making in CHD-associated LVNC.

References

• Circulation • 2008 • Mutations in sarcomere protein genes in left ventricular noncompaction. PMID:18506004
• International journal of cardiology • 2021 • A burden of sarcomere gene variants in fetal-onset patients with left ventricular noncompaction. PMID:33309763
• Journal of the American Heart Association • 2017 • A Wide and Specific Spectrum of Genetic Variants and Genotype-Phenotype Correlations Revealed by Next-Generation Sequencing in Patients with Left Ventricular Noncompaction. PMID:28855170
• BMC Medical Genomics • 2022 • Diverse cardiac phenotypes among different carriers of the same MYH7 splicing variant allele (c.732+1G>A) from a family. PMID:35209905
• The Canadian Journal of Cardiology • 2015 • A novel MYH7 gene mutation in a fetus with left ventricular noncompaction. PMID:25547560
• Frontiers in Pediatrics • 2023 • Low-frequency maternal novel MYH7 mosaicism mutation in recurrent fetal-onset severe left ventricular noncompaction: a case report. PMID:37360367
• Clinical Research in Cardiology • 2019 • Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals. PMID:30980206
• The Journal of Biological Chemistry • 1994 • Heterologous expression of a cardiomyopathic myosin that is defective in its actin interaction. PMID:8294404
• The Journal of Biological Chemistry • 2014 • The hypertrophic cardiomyopathy myosin mutation R453C alters ATP binding and hydrolysis of human cardiac β-myosin. PMID:24344137
• The Journal of Biological Chemistry • 2013 • Transgenic mouse α- and β-cardiac myosins containing the R403Q mutation show isoform-dependent transient kinetic difference. PMID:23580644
• Molecular Genetics & Genomic Medicine • 2016 • The pathogenicity of genetic variants previously associated with left ventricular non-compaction. PMID:27066506
• Circulation: Cardiovascular Genetics • 2021 • Rare variant association analysis of left ventricular noncompaction reveals distinct etiologies. PMID:33500567

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