Investigation of the genetic etiology of monogenic obesity cases

Objective: Early-onset severe obesity is associated with monogenic obesity, a rare form that can develop due to pathogenic variants in a single gene. It is often associated with hyperphagia, metabolic disorders, and neurodevelopmental findings. In this study, we aimed to identify rare variants that could cause monogenic obesity in individuals with a history of early-onset obesity and hyperphagia using WES and to evaluate the potential biological effects of these variants at the molecular level. Materials and Methods: The study included 24 individuals with a history of hyperphagia and obesity onset between 3 months and 10 years of age who underwent detailed phenotyping. Clinical data were comprehensively collected, whole-exome sequencing was performed, and variants were classified according to ACMG criteria. Molecular effects were supported by protein-protein interaction and biological pathway analyses. Results: Rare variants associated with early-onset obesity were identified in 13 (54%) of the cases; 47% of these were novel and previously unreported. Variants are frequently located in genes involved in energy homeostasis, such as LEPR, MC4R, and NUCB2; some syndromic cases carry variants in epigenetic regulatory genes such as SETD1A and NSD1. Most individuals without identified variants have VUSs associated with hypothalamic or metabolic functions. Conclusion: The findings suggest that early-onset obesity is shaped by complex genetic interactions involving not only monogenic but also epigenetic and neurodevelopmental mechanisms. WES is an important tool for diagnosis, but the biological effects of variants must be confirmed by functional studies. Keywords: Monogenic obesity, hyperphagia, leptin-melanocortin pathway, WES.