Novel frameshift variant in < i > MYL2 < /i > reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy

by Sathiya N. Manivannan, Sihem Darouich, Aida Masmoudi, David Gordon, Gloria Zender, Zhe Han, Sara Fitzgerald-Butt, Peter White, Kim L. McBride, Maher Kharrat, Vidu Garg Hypertrophic cardiomyopathy (HCM) is characterized by the thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral val ve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant inMyosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominantMYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control.In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research