Diagnostic Approach to Genetic Obesity in Children: From Pathophysiology to Precision Medicine—A Narrative Review

Abstract

Childhood obesity is a major global health concern with a strong heritable component. While most cases are polygenic and environmentally driven, a subset of children present with rare genetic forms of obesity, including syndromic and monogenic disorders. Over the past three decades, advances in gene discovery—from candidate gene studies to genome-wide association studies (GWAS) and next-generation sequencing (NGS)—have significantly improved our understanding of the biological pathways regulating appetite and energy balance, particularly the leptin–melanocortin pathway. Early identification of genetic obesity is clinically relevant, as it allows for tailored management, targeted pharmacological interventions, genetic counseling, and a reduction in psychosocial stigma. However, distinguishing rare genetic obesity from common polygenic obesity remains challenging in clinical practice. This narrative review summarizes the current knowledge on the genetic architecture of pediatric obesity, explores the transition from gene discovery to precision medicine, discusses available diagnostic algorithms and genetic testing strategies, and proposes an updated diagnostic flowchart. In a more clinically useful model, genetic obesity is not defined solely by the presence or absence of a pathogenic variant, but as a continuum in which phenotype, genetic variants, age, and environmental exposure interact and define risk prediction and therapeutic strategies, especially in the pediatric population.