Significance of α-Myosin Heavy Chain (MYH6) Variants in Hypoplastic Left Heart Syndrome and Related Cardiovascular Diseases

Abstract

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with complex genetic inheritance. HLHS segregates with other left ventricular outflow tract (LVOT) malformations in families, and can present as either an isolated phenotype or as a feature of a larger genetic disorder. The multifactorial etiology of HLHS makes it difficult to interpret the clinical significance of genetic variants. Specific genes have been implicated in HLHS, including rare, predicted damaging MYH6 variants that are present in >10% of HLHS patients, and which have been shown to be associated with decreased transplant-free survival in our previous studies. MYH6 (α-myosin heavy chain, α-MHC) variants have been reported in HLHS and numerous other CHDs, including LVOT malformations, and may provide a genetic link to these disorders. In this paper, we outline the MYH6 variants that have been identified, discuss how bioinformatic and functional studies can inform clinical decision making, and highlight the importance of genetic testing in HLHS.

Keywords: cardiac myosin heavy chain; congenital heart disease; hypoplastic left heart syndrome; rare variant analysis.

Figure 1

Event-free survival analysis comparing 36 HLHS patients. A total of 12 patients had rare, predicting damaging MYH6 variants. p-value = 0.074, log-rank test.

Figure 2

(A) Location of rare, predicted damaging MYH6 coding sequence variants by residue. Variants were considered rare if allele frequency was <1 × 10⁻³ in both the Genome Aggregation Database (gnomAD) Genomes dataset v3.1.2 and the Allele Frequency Aggregator (ALFA) dataset (release version 20201027095038). Single nucleotide variants were considered predicted damaging if the scaled Combined Annotation Dependent Depletion (CADD) score was >22.0 (GRCh37, v1.6) [60], or if the variant was predicted “damaging” or “probably damaging” by SIFT [61] and PolyPhen2 [62]. Deletions are not shown as CADD scores cannot be calculated. (B) Schematic of α—MHC domains. ELC, essential light chain; RLC, regulatory light chain; MyBP—C, myosin binding protein C; ACD, assembly competent domain.