Investigation of Genetic Causes in Patients with Congenital Heart Disease in Qatar: Findings from the Sidra Cardiac Registry.

Congenital heart disease (CHD) is one of the most common forms of birth defects worldwide, with a prevalence of 1-2% in newborns. CHD is a multifactorial disease partially caused by genetic defects, including chromosomal abnormalities and single gene mutations. Here, we describe the Sidra Cardiac Registry, which includes 52 families and a total of 178 individuals, and investigate the genetic etiology of CHD in Qatar. We reviewed the results of genetic tests conducted in patients as part of their clinical evaluation, including chromosomal testing. We also performed whole exome sequencing (WES) to identify potential causative variants. Sixteen patients with CHD had chromosomal abnormalities that explained their complex CHD phenotype, including six patients with trisomy 21. Moreover, using exome analysis, we identified potential CHD variants in 24 patients, revealing 65 potential variants in 56 genes. Four variants were classified as pathogenic/likely pathogenic based on the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) classification; these variants were detected in four patients. This study sheds light on several potential genetic variants contributing to the development of CHD. Additional functional studies are needed to better understand the role of the identified variants in the pathogenesis of CHD.

Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are serious inherited heart diseases with various causative mutations identified. The full spectrum of causative mutations remains to be discovered, especially in understudied populations. METHODS: Here, we established the DOHA Registry and Biobank for cardiomyopathies in Qatar, followed by sequencing of 174 genes on 51 HCM and 53 DCM patients, and 31 relatives. RESULTS: In HCM, the analysis of 25 HCM-associated genes showed that 20% of HCM cases had putative pathogenic variants for cardiomyopathy, mainly in sarcomere genes. Additional 49% of HCM cases had variants of uncertain significance, while 31% of HCM cases had likely benign variant(s) or had no variants identified within the analyzed HCM genes. In DCM, 56 putative DCM genes were analyzed. Eight percent of DCM cases had putative pathogenic variants for DCM, in the TTN gene while 70% of cases had variants of uncertain significance, in the analyzed DCM genes, that will need further pathogenicity assessment. Moreover, 22% of DCM cases remain unexplained, by having likely benign variant(s) or having no variants detected in any of the analyzed DCM genes. CONCLUSION: We identified or replicated at least four recurrent variants among cardiomyopathy patients, which could be founder disease mutations in the Arabic population, including a frameshift variant (c.1371_1381dupTATCCAGTTAT) of unknown significance in the FKTN gene which seems to cause DCM in homozygosity, and HCM in heterozygosity. In vivo and/or in vitro functional validation need to be pursued in order to assess the pathogenicity of the identified variants.