Genetic variants of the leptin–melanocortin pathway in a clinically selected Greek cohort with severe early-onset obesity and hyperphagia: implications for precision obesity medicine

Abstract

Background Rare genetic forms of obesity are characterized by severe, early-onset obesity and hyperphagia, often involving the leptin–melanocortin pathway. Although advances in genetic testing have improved the recognition of monogenic obesity, data from Southern European populations remain limited. We investigated the genetic landscape and associated clinical characteristics of Greek patients with severe early-onset obesity and hyperphagia. Methods This retrospective, single-center, observational study included 67 children and adults with severe obesity and hyperphagia, consecutively recruited at the University Hospital of Patras, Greece, between September 2019 and November 2020. Targeted next-generation sequencing, supplemented by Sanger sequencing, evaluated 101 genes associated with monogenic obesity. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results Among 67 participants, 37 (55.2%) carried obesity-associated variants, with 51 variant findings identified across 24 genes, predominantly involving PCSK1,ALMS1, and BBS20. Several variants occurred in more than one participant. Variant classification identified one benign, five likely benign, two variants of uncertain significance (VUS)-favoring benign, 37 VUS, one likely pathogenic, and five pathogenic variants. Nearly half of variant-positive participants (45.9%) carried variants in more than one obesity-associated gene, suggesting potentially oligogenic contributions. Conclusion Genetic variants affecting the leptin–melanocortin pathway were frequently identified in this cohort of patients, highlighting the marked genetic heterogeneity of rare obesity. From a clinical perspective, these findings support phenotype-driven genetic evaluation in patients with severe early-onset obesity and marked hyperphagia, particularly when syndromic, endocrine, developmental, or behavioral features are present. Genetic results may help establish an etiologic diagnosis, inform genetic counselling and family evaluation, and identify selected patients who may be candidates for mechanism-based therapies. Because most detected variants were VUS, results should be interpreted by clinicians with expertise in obesity and genetics and should not be used to guide treatment on the basis of a VUS alone.