Identifying mutations causing sarcomeric hypertrophic cardiomyopathy in the Maltese population

Abstract

Hypertrophic Cardiomyopathy (HCM) is characterized by the presence of increased left ventricular (LV) wall thickness, which cannot be explained by abnormal loading conditions such as systemic hypertension and aortic stenosis. This condition is known to be a familial disease with an increased risk for sudden cardiac death and progression to heart failure. HCM is the commonest genetic cardiac condition with a prevalence of 1:500. Therefore in Malta, it is estimated that approximately 900 people are affected. Since the first disease-causing mutation was found in 1990, many advances have been made in the genetics of this condition. No study has yet been conducted on Maltese patients to assess the disease-causing variants found in this population. This project makes use of applied next generation sequencing (NGS), to identify the disease-causing variants in sarcomeric HCM in the Maltese population. In this study a total of 12 missense variants were found in a cohort of 9 families. The variants found were located in sarcomeric genes, in the Z-disc or M band of the sarcomere, as well as in genes coding for desmosomal and mitochondrial proteins. Only one known pathogenic/likely pathogenic variant was found in the MYH7 gene. In total four pathogenic/likely pathogenic and 8 variants of unknown significance were found. This study has shown that the genetics in Maltese HCM subjects is unique to the Maltese population. High throughput sequencing (HTS) in HCM subjects, was found to be a valid approach at identifying functional variants and the study should be expanded allowing for targeted clinical screening and shedding light on the genotype-phenotype association of HCM in the Maltese Islands.