Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium
IntroductionObesity 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...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Endocrinology |
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| author | Julie Harvengt Julie Harvengt Muriel Hannon Leonor Palmeira Leonor Palmeira Marie-Christine Lebrethon Vinciane Dideberg Vincent Bours Vincent Bours |
| author_facet | Julie Harvengt Julie Harvengt Muriel Hannon Leonor Palmeira Leonor Palmeira Marie-Christine Lebrethon Vinciane Dideberg Vincent Bours Vincent Bours |
| author_sort | Julie Harvengt |
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| description | IntroductionObesity 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.ObjectiveTo 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.MethodsIn 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 descriptions were reviewed for the entire cohort.ResultsA diagnostic yield of 3.1% was established. Likely pathogenic or pathogenic variants were found in MRAP2, MC4R, BBS2, and 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. Thirty-six percent of the cohort presented additional neurological complaints that led to more extensive genetic investigations with a diagnosis rate of 1.8% in this subgroup.ConclusionOur 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. |
| format | Article |
| id | doaj-art-07cfba37530a45369840b063ed2a0d61 |
| institution | Kabale University |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj-art-07cfba37530a45369840b063ed2a0d612025-08-20T03:58:14ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-08-011610.3389/fendo.2025.16083981608398Monogenic etiologies in a cohort of early onset obesity: a real-world experience from BelgiumJulie Harvengt0Julie Harvengt1Muriel Hannon2Leonor Palmeira3Leonor Palmeira4Marie-Christine Lebrethon5Vinciane Dideberg6Vincent Bours7Vincent Bours8Human Genetics Department, CHU of Liège, Liège, BelgiumGIGA Research, University of Liège, Liège, BelgiumHuman Genetics Department, CHU of Liège, Liège, BelgiumHuman Genetics Department, CHU of Liège, Liège, BelgiumGIGA Research, University of Liège, Liège, BelgiumPediatric Endocrinology, Pediatric Department, CHU of Liège, Liège, BelgiumHuman Genetics Department, CHU of Liège, Liège, BelgiumHuman Genetics Department, CHU of Liège, Liège, BelgiumGIGA Research, University of Liège, Liège, BelgiumIntroductionObesity 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.ObjectiveTo 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.MethodsIn 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 descriptions were reviewed for the entire cohort.ResultsA diagnostic yield of 3.1% was established. Likely pathogenic or pathogenic variants were found in MRAP2, MC4R, BBS2, and 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. Thirty-six percent of the cohort presented additional neurological complaints that led to more extensive genetic investigations with a diagnosis rate of 1.8% in this subgroup.ConclusionOur 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.https://www.frontiersin.org/articles/10.3389/fendo.2025.1608398/fullearly-onset obesitymonogenic obesityMC4RBardet–Biedl syndromehypothalamic obesity |
| spellingShingle | Julie Harvengt Julie Harvengt Muriel Hannon Leonor Palmeira Leonor Palmeira Marie-Christine Lebrethon Vinciane Dideberg Vincent Bours Vincent Bours Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium Frontiers in Endocrinology early-onset obesity monogenic obesity MC4R Bardet–Biedl syndrome hypothalamic obesity |
| title | Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium |
| title_full | Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium |
| title_fullStr | Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium |
| title_full_unstemmed | Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium |
| title_short | Monogenic etiologies in a cohort of early onset obesity: a real-world experience from Belgium |
| title_sort | monogenic etiologies in a cohort of early onset obesity a real world experience from belgium |
| topic | early-onset obesity monogenic obesity MC4R Bardet–Biedl syndrome hypothalamic obesity |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2025.1608398/full |
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