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

Understanding the genetics of early onset obesity in a cohort of children from Qatar.

Monogenic obesity is a rare form of obesity due to pathogenic variants in genes implicated in the leptin-melanocortin signaling pathway and accounts for around 5% of severe early onset obesity. Mutations in the genes encoding the MC4R, leptin and leptin receptor are commonly reported in various populations to cause monogenic obesity. Determining the genetic cause has important clinical benefits as novel therapeutic interventions are now available for some forms of monogenic obesity. To unravel the genetic causes of early onset obesity in the population of Qatar. 243 patients with early-onset obesity (above the 95% percentile) and age of onset below 10 years were screened for monogenic obesity variants using a targeted gene panel, consisting of 52 obesity-related genes. Thirty rare variants potentially associated with obesity were identified in 36 of 243 (14.8%) probands, in 15 candidate genes (LEP, LEPR, POMC, MC3R, MC4R, MRAP2, SH2B1, BDNF, NTRK2, DYRK1B, SIM1, GNAS, , ADCY3, RAI1, and BBS2). Twenty-three of the variants identified were novel to this study and the rest, seven variants, were previously reported in literature. Variants in MC4R were the most common cause of obesity in our cohort (19%) and the c.485C > T p.T162I variant was the most frequent MC4R variant seen in five patients. We identified likely pathogenic/pathogenic variants that seem to explain the phenotype of around 14.8% of our cases. Variants in the MC4R gene are the commonest cause of early onset obesity in our population. Our study represents the largest monogenic obesity cohort in the Middle East which revealed novel obesity variants in this understudied population. Functional studies will be required to elucidate the molecular mechanism of their pathogenicity.This research was supported by the Qatar National Research Fund (QNRF-NPRP 10-6100017-AXX) and a research grant from Amryt awarded to Professor Khalid Hussain