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.

The genetic elucidation of monogenic obesity in the Arab world: a systematic review.

BACKGROUND: Investigation of monogenic obesity (MO), a rare condition caused by a single gene variant(s), especially in consanguineous populations, is a powerful approach for obtaining novel insights into the genetic alterations involved. Here, we present a systematic review of the genetics of MO in the 22 Arab countries and apply protein modeling in silico to the missense variants reported. METHODS: We searched four literature databases (PubMed, Web of Science, Science Direct and Scopus) from the time of their first creation until December 2020, utilizing broad search terms to capture all genetic studies related to MO in the Arab countries. Only articles published in peer-reviewed journals involving subjects from at least one of the 22 Arab countries and dealing with genetic variants related to MO were included. Protein modelling of the variants identified was performed using PyMOL. RESULTS: The 30 cases with severe early-onset obesity identified in 13 studies carried 14 variants in five genes (LEP, LEPR, POMC, MC4R and CPE). All of these variants were pathogenic, homozygous and carried by members of consanguineous families. CONCLUSION: Despite the elevated presence of consanguinity in the Arab countries, the genetic origins of MO remain largely unexplained and require additional studies, both of a genetic and functional character.

The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar.

INTRODUCTION: Monogenic obesity (MO) is a rare genetic disease characterized by severe early-onset obesity in affected individuals. Previous genetic studies revealed 8 definitive genes for monogenic non-syndromic obesity; many were discovered in consanguineous populations. Here, we examined MO in the Qatari population, whose population is largely consanguineous (54%) and characterized by extensive obesity (45%). METHODS: Whole genome sequencing data of Qatar Biobank samples from 250 subjects with obesity and 250 subjects with normal weight, obtained in association with the Qatar Genome Programme, were searched for genetic variants in the genes known to be associated with MO (i.e., LEP, LEPR, POMC, PCSK1, MC3R, MC4R, MRAP2, and ADCY3). The impact of the variants identified was investigated utilizing in silico tools for prediction in combination with protein visualization by PyMOL. RESULTS: We identified potential MO variants in more than 5% of the cases in our cohort. We revealed 11 rare variants in 6 of the genes targeted, including two disease-causing variants in MC4R and MRAP2, all of which were heterozygous. Moreover, enrichment of a heterozygous ADCY3 variant (c.1658C>T; p.A553V) appeared to cause severe obesity in an autosomal dominant manner. CONCLUSION: These findings highlight the importance of implementing routine testing for genetic variants that predispose for MO in Qatar. Clearly, additional studies of this nature on populations not yet examined are required. At the same time, functional investigations, both in vitro and in vivo, are necessary in order to better understand the role of the variants identified in the pathogenesis of obesity.

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.