Six Years of Genetic Diagnosis of Severe Early-Onset Obesity in a French Cohort.

Objective: Obesity is a multifactorial disease with a strong genetic component. It is imperative to enhance the identification of genetic variations in their early and severe manifestations in order to facilitate the development of personalized therapeutic strategies, informed clinical care, and the facilitation of genetic counseling. The objective of the study was to provide a comprehensive description of rare variations identified by next generation sequencing of a panel of genes. Methods: From 2018 to 2023, a panel of 22 genes was genotyped in 1066 probands (499 children and 567 adults) with severe early-onset obesity. Results: The genetic study led to a molecular diagnosis in 34 probands (3.2%) and revealed variants of unknown significance (VUS) in 10.3% of cases. In the pediatric cohort, a genetic diagnosis was established in 19 probands (3.8%) and a VUS was identified in 67 (13.4%). A total of 152 rare single-nucleotides variants (SNVs) were identified, of which 34 were classified as pathogenic, predominantly within the MC4R gene. Furthermore, 110 participants were carriers of one or two rare variants of uncertain significance (VUS). A total of three copy number variations (CNVs) were identified in the genes that were analyzed. Conclusion: Early genetic screening in severe obesity provides valuable diagnostic insights and identifies candidates for personalized treatment. The integration of genetics into clinical practice is imperative for the enhancement of care pathways and the facilitation of targeted therapeutic strategies.