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 of obesity has important clinical benefits, as novel therapeutic interventions are now available for some forms of monogenic obesity. Only a few case reports of monogenic childhood obesity in the Middle East, in general, and Qatar, in particular, are available in the literature, but no extensive cohort studies exist. This project aims to unravel the genetic causes of early-onset obesity in the population of Qatar. We recruited 246 patients with early-onset obesity (>95^th BMI percentile) and age of onset below ten years. We screened for monogenic obesity variants using a targeted gene panel of 52 obesity-related genes in all the probands. We identified variants that seem to explain the phenotype of around 15.5% of our cases. Variants in the MC4R gene are the commonest cause of early-onset obesity in our population. We did not detect any nonsynonymous variant in 70 cases, hence will be sent for whole genome sequencing in the future. In conclusion, our study represents the largest monogenic obesity cohort in the Middle East, revealing novel obesity variants in this understudied population. Functional studies will be required to validate and elucidate the molecular mechanism of the novel variants' pathogenicity.