Genotype-phenotype correlation and allele dating analysis of a novel variant in hypertrophic cardiomyopathy: p.Arg652Lys in MYH7

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is a genetic disease characterised by increased left ventricle (LV) wall thickness caused by mutations in sarcomeric genes. Finding a causal mutation can help to better assess the proband's risk, as it allows the presence of the mutation to be evaluated in relatives and the follow-up to be focused on carriers. Purpose The objectives of the present study are to assess the genotype-phenotype correlation of a novel variant found in patients with HCM and explore the possibility of a founder effect in the Balearic Islands, Spain. Methods We performed an observational study with phenotype description and genotype correlation of patients with HCM in whom we found a novel variant in the MYH7 gene (NM_000257.4:c.1955G>A) which putatively causes a p.Arg652Lys missense protein change. We did IBD/coalescent-based allele dating analysis of this novel variant. Results This previously non-described variant was found in twelve families with HCM. Out of those, 59 patients corresponding to 8 families were clinically characterized with a median follow-up of 63 months. Among them, 39 (66%) carry the variant. Twenty-five (64%) of carriers developed HCM. A median maximum LV wall thickness of 16.5 mm was described. The LV hypertrophy was asymmetric septal in 75% of cases, with LV outflow tract obstruction in 28%. The incidence of a composite of serious adverse cardiovascular events (sudden death, aborted sudden death, appropriate implantable cardiac defibrillator dis-charge, an embolic event, or admission for heart failure) was observed in five (20%) patients. This p.Arg652Lys variant was classified as likely pathogenic (LP) and associated with the development of HCM for the following reasons: 1) It is found in patients with HCM, but not in controls, 2) There is evident segregation with HCM on the 8 families described, and 3) It is located in an active site of the protein where a variant in the same amino acid has already been clearly established as pathogenic (p.Arg652Gly). Interestingly, the exclusive presence of the variant in our region could correspond to a founder effect in the Balearic Islands, Spain, which we have further investigated. IBD/coalescent-based allele dating analysis reveals that the origin of this allele is 96 generations away which would correspond to 1900–2400 years ago, when the Balearic Islands were already populated. Conclusions We can define the p.Arg652Lys variant in MYH7 as LP in HCM and a founder effect is in the Balearic Islands is highly probable due to the exclusive presence at the region and the dating analysis of it. Funding Acknowledgement Type of funding sources: None.