SaeedS_Supplemental_Material_Clean_F.docx (946.14 kB)
Genetic causes of severe childhood obesity: a remarkably high prevalence (≥49%) in an inbred population of Pakistan
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posted on 2020-04-29, 21:00 authored by Ada AdminAda 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 FroguelMonogenic 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.