Genetic causes of severe childhood obesity: a remarkably high prevalence (≥49%) in an inbred population of Pakistan
figureposted on 29.04.2020 by Ada Admin, Sadia Saeed, Muhammad Arslan, Jaida Manzoor, Sadia M. Din, Qasim M. Janjua, Hina Ayesha, Qura-tul Ain, Laraib Inam, Stephane Lobbens, Emmanuel Vaillant, Emmanuelle Durand, Mehdi Derhourhi, Souhila Amanzougarene, Alaa Badreddine, Lionel Berberian, Stefan Gaget, Waqas I. Khan, Taeed A. Butt, Amélie Bonnefond, Philippe Froguel
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Monogenic forms of obesity have been identified in ≤10% of severely obese European patients. However, the overall spectrum of deleterious variants (point mutations and structural variants) responsible for childhood severe obesity remains elusive. In this study, we genetically screened 225 severely obese children from consanguineous Pakistani families through a combination of techniques including an in-house developed augmented whole-exome sequencing (CoDE-seq) enabling simultaneous detection of whole exome copy number variations (CNVs) and of point mutations in coding regions. We identified 110 probands (49%) carrying 55 different pathogenic point mutations and CNVs in 13 genes/loci responsible for non-syndromic and syndromic monofactorial obesity. CoDE-seq also identified 28 rare or novel CNVs associated with intellectual disability in 22 additional obese subjects (10%). Additionally, we highlight variants in candidate genes for obesity warranting further investigation. Altogether, 59% of the studied cohort are likely to have a discrete genetic cause with 13% of these due to CNVs demonstrating a remarkably higher prevalence of monofactorial obesity than hitherto reported and a plausible over lapping of obesity and intellectual disabilities in several cases. Finally, inbred populations with high prevalence of obesity, provide a unique genetically enriched material in quest of new genes/variants influencing energy balance.