RT Journal Article
SR Electronic
T1 Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 1424
OP 1438
DO 10.2337/db19-1238
VO 69
IS 7
A1 Saeed, Sadia
A1 Arslan, Muhammad
A1 Manzoor, Jaida
A1 Din, Sadia M.
A1 Janjua, Qasim M.
A1 Ayesha, Hina
A1 Ain, Qura-tul
A1 Inam, Laraib
A1 Lobbens, Stephane
A1 Vaillant, Emmanuel
A1 Durand, Emmanuelle
A1 Derhourhi, Mehdi
A1 Amanzougarene, Souhila
A1 Badreddine, Alaa
A1 Berberian, Lionel
A1 Gaget, Stefan
A1 Khan, Waqas I.
A1 Butt, Taeed A.
A1 Bonnefond, Amélie
A1 Froguel, Philippe
YR 2020
UL http://diabetes.diabetesjournals.org/content/69/7/1424.abstract
AB 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 method (CoDE-seq) that enables simultaneous detection of whole-exome copy number variations (CNVs) and point mutations in coding regions. We identified 110 (49%) probands carrying 55 different pathogenic point mutations and CNVs in 13 genes/loci responsible for nonsyndromic 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 cases in the studied cohort are likely to have a discrete genetic cause, with 13% of these as a result of CNVs, demonstrating a remarkably higher prevalence of monofactorial obesity than hitherto reported and a plausible overlapping of obesity and intellectual disabilities in several cases. Finally, inbred populations with a high prevalence of obesity provide unique, genetically enriched material in the quest of new genes/variants influencing energy balance.