ESPE Yearbook of Paediatric Endocrinology

p.froguel@imperial.ac.uk Diabetes 2022;71:694–705https://doi.org/10.2337/db21-0373

Brief Summary: In this observational cross-sectional study in 128 randomly selected young obese adults (BMI 37.2±0.3 kg/m²; age 18.4±0.3 years) from the Severe Obesity in Pakistani Population (SOPP), screening by whole-exome analysis found 3% had (likely) pathogenic variants in the leptin-melanocortin pathway and a further 4 had a CNV and 11 had rare, homozygous non-synonymous variants in 15 different genes of interest.

Pakistan is known both for a high degree of consanguineous marriages [1] and high prevalence of obesity [2]. Thus, this country presents a unique opportunity to study autosomal recessive forms of obesity. Accordingly these authors had previously identified in their SOPP Children cohort loss of function in ADCY3 as a new form of monogenic obesity [3]. Here, they present further analysis of this interesting cohort with advanced molecular-genetic methods. The data are of high importance for the research community especially in terms of the need of a critical assessment of new genes potentially involved in weight regulation

Nevertheless, the identified variants display all the difficulties of identifying new pathogenic genes: For only two of the genes, mice knock-out models with increased obesity exist (ASNSD1 and IFI16) [4,5]. Though in the other genes, polymorphisms have been associated with obesity in GWAS, for only one gene (ABTB1), heterozygous LoF variants were associated with an increased risk for obesity in the UK Biobank population. And only 2 variants (B4GALNT3 and DNAJC27) were predicted by both SIFT analysis and Mutation Taster to be deleterious/disease causing. Thus, it remains to be proven if any of the here identified genes truly are the cause of obesity in these patients.

A further surprising finding is the low rate of only 3% of (likely) pathogenic variants in the leptin-melanocortin pathway in this cohort – in contrast to 30%–40% in the SOPP – Children cohort [6,7]. A lower yield of monogenic obesity in adult versus childhood cohorts has already been described by others [8]. One reason might be the additional selection criteria in the childhood cohort (parents had to be non-obese and consanguineous) [7]. The authors also argue that a high early mortality rate and/or severe disabilities of affected children prevent them to enter mainstream young adult populations.

References: 1. Hussain R, Bittles AH. The prevalence and demographic characteristics of consanguineous marriages in Pakistan. J Biosoc Sci. 1998;30(2):261–75. 2. Pigeyre M, Saqlain M, Turcotte M, Raja GK, Meyre D. Obesity genetics: insights from the Pakistani population. Obes Rev. 2018;19(3):364–80. 3. Saeed S, Bonnefond A, Tamanini F, Mirza MU, Manzoor J, Janjua QM, Din SM, Gaitan J, Milochau A, Durand E, Vaillant E, Haseeb A, De Graeve F, Rabearivelo I, Sand O, Queniat G, Boutry R, Schott DA, Ayesha H, Ali M, Khan WI, Butt TA, Rinne T, Stumpel C, Abderrahmani A, Lang J, Arslan M, Froguel P. Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nat Genet. 2018;50(2):175–9. 4. Vogel P, Ding ZM, Read R, DaCosta CM, Hansard M, Small DL, Ye GL, Hansen G, Brommage R, Powell DR. Progressive Degenerative Myopathy and Myosteatosis in ASNSD1-Deficient Mice. Vet Pathol. 2020;57(5):723–35. 5. Stadion M, Schwerbel K, Graja A, Baumeier C, Rödiger M, Jonas W, Wolfrum C, Staiger H, Fritsche A, Häring HU, Klöting N, Blüher M, Fischer-Posovszky P, Schulz TJ, Joost HG, Vogel H, Schürmann A. Increased Ifi202b/IFI16 expression stimulates adipogenesis in mice and humans. Diabetologia. 2018;61(5):1167–79. 6. Saeed S, Bonnefond A, Manzoor J, Shabbir F, Ayesha H, Philippe J, Durand E, Crouch H, Sand O, Ali M, Butt T, Rathore AW, Falchi M, Arslan M, Froguel P. Genetic variants in LEP, LEPR, and MC4R explain 30% of severe obesity in children from a consanguineous population. Obesity (Silver Spring). 2015;23(8):1687–95. 7. Saeed S, Arslan M, Manzoor J, Din SM, Janjua QM, Ayesha H, Ain QT, Inam L, Lobbens S, Vaillant E, Durand E, Derhourhi M, Amanzougarene S, Badreddine A, Berberian L, Gaget S, Khan WI, Butt TA, Bonnefond A, Froguel P. Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan. Diabetes. 2020;69(7):1424–38. 8. Kleinendorst L, Massink MPG, Cooiman MI, Savas M, van der Baan-Slootweg OH, Roelants RJ, Janssen ICM, Meijers-Heijboer HJ, Knoers N, Ploos van Amstel HK, van Rossum EFC, van den Akker ELT, van Haaften G, van der Zwaag B, van Haelst MM. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet. 2018;55(9):578–86.