The Necessity of POMC and MC3R Analysis in the First-Level Diagnosis of Monogenic Obesity: The Experience of Two Italian Centers

BACKGROUND/OBJECTIVES: often fail to identify a causative variant, leaving a significant diagnostic gap. This study aimed to assess the prevalence of variants in other critical genes of the melanocortin pathway to improve diagnostic yield. METHODS: genes. In silico bioinformatic tools were used to predict the functional consequences of identified variants on protein structure and splicing. RESULTS: , specifically within the regions coding for alpha-, beta-, and gamma-MSH peptides. A bioinformatic analysis suggests that these variants disrupt the melanocortin signaling pathway, likely contributing to an intermediate susceptibility phenotype in our adult cohort. Additionally, a clinical follow-up of a patient carrying the rare BDNF p.Thr2Ile variant revealed a suboptimal response to high-dose tirzepatide treatment (9% weight loss over 72 weeks), notably inferior to the average response observed in clinical trials. CONCLUSIONS: is essential to maximize diagnostic yield and improve clinical management.