ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Obesity
Volume 16 - 2025 | doi: 10.3389/fendo.2025.1608398
This article is part of the Research TopicHyperphagia in Syndromic and Hypothalamic Obesity: Mechanisms, Consequences, and InterventionsView all articles
Monogenic etiologies in a cohort of early-onset obesity: a real-world experience from Belgium
Provisionally accepted
Julie Harvengt1,2*
Muriel Hannon2
Leonor Palmeira2Marie-Christine Lebrethon3
Vinciane Dideberg2
Vincent Bours2- 1University Hospital of Liège, Liège, Belgium
- 2Human Genetics Department, Liège, Liège, Belgium
- 3Department of Pediatrics, University Hospital of Liège, Liège, Liège, Belgium
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Obesity is a major global health issue with multifactorial etiologies. Among them, recent advances in the comprehension of eating and energy regulation showed that around 60 genes involved in the hypothalamic leptin/melanocortin pathway contribute to the development of rare monogenic or syndromic forms of obesity.Objective To better delineate the genetic diagnostic rate and the phenotype in a cohort of early-onset obesity and to integrate our results in guidance for genetic testing.In a diagnostic setting 223 patients with early-onset obesity were screened through a targeted panel including 44 genes for severe early-onset obesity. Genetic results and clinical description were reviewed for all the cohort.Results A diagnostic yield of 3.1% was established. Likely pathogenic or pathogenic variants were found in MRAP2, MC4R, BBS2, BBS4 and a 16p11.2 deletion was confirmed. Clinically, 23% of the cohort had early onset obesity at <1 year, 47% at 1-4 years and 30% at >4 years. No discriminative clinical feature appears to enhance the diagnostic yield. 36% of the cohort presented additional neurological complaints that lead to more extensive genetic investigations with a diagnosis rate of 1.8% in this subgroup.Our work found a diagnostic yield of 3.1% . Additionally, 19.7% % of heterozygous variants of unknown significance were found in genes related to autosomal conditions and 34.9% in genes related to recessive conditions These results highlight the need for accurate genotype-phenotype correlations. Genetic laboratory expertise in obesity is highly recommended, especially in the context of the availability of new targeted anti-obesity therapies that open the field for current and future perspectives of these targeted genetic investigations.
Keywords: Early-onset obesity, Monogenic obesity, mc4r, Bardet biedl syndrome, hypothalamic obesity
Received: 08 Apr 2025; Accepted: 02 Jun 2025.
Copyright: © 2025 Harvengt, Hannon, Palmeira, Lebrethon, Dideberg and Bours. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Julie Harvengt, University Hospital of Liège, Liège, Belgium
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