Genetic Basis of Hypertrophic and Dilated Cardiomyopathy in Qatar

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are serious and genetically heterogenous inherited heart disorders. Here, we established the DOHA Registry and Biobank for cardiomyopathies in Qatar, followed by an initial targeted sequencing (TS) of 174 genes on 51 HCM and 53 DCM patients, and 31 relatives. Also, we used whole genome sequencing (WGS) to investigate the genetics of HCM in a consanguineous family (n=6) with two affected siblings for which the initial TS was negative. Segregation analysis of WGS data was performed assuming autosomal recessive inheritance. For the TS, 45% of HCM cases had pathogenic variants for cardiomyopathy, with MYBPC3 and MYH7 gene variants overshadowed in 23% of the cases, while 10% of HCM cases remained unexplained with no pathogenic or putative pathogenic variants identified. On the other hand, in DCM, 35% of cases had pathogenic variants, with TTN variants being most common (13% of cases), though 16% of DCM cases remained unexplained. Also, we identified or replicated at least five recurrent variants among patients, which could be founder disease mutations in the Arab population, including a frameshift variant (c.1371_1381dupTATCCAGTTAT) in the FKTN gene, which seems to cause DCM in homozygosity, and HCM in heterozygosity. For WGS analysis, two rare missense homozygous variants, p.Arg276Cys in UQCRC1 and p.Gly191Asp in ETFDH, were identified in the two affected siblings. Both UQCRC1 and ETFDH genes are highly expressed in the left ventricle and are involved in mitochondrial bioenergetic pathways. A synergistic effect of both variants toward the noticed severe disease phenotype is suggested. In conclusion, functional assessment is needed to confirm the pathogenicity of the identified variants and to understand the underlying mechanisms leading to diseases.