Decoding monogenic obesity: Genetics, diagnosis, and emerging therapies

Monogenic obesity is an uncommon but clinically actionable subset of childhood obesity, typically characterized by early-onset severe obesity and pathological hyperphagia. This narrative review summarizes clinical recognition, diagnostic evaluation, cytogenetic and molecular genetic testing, and variant interpretation in view of the evolving genetic spectrum, as well as emerging opportunities for precision therapy in monogenic non-syndromic obesity. The leptin melanocortin pathway, involving the leptin gene (LEP) , leptin receptor ( LEPR ), pro-opiomelanocortin (POMC) , proprotein convertase subtilisin/kexin type-1 (PCSK1) , and melanocortin-4 receptor ( MC4R ) genes, remains central to the pathogenesis of monogenic obesity, with additional contributions from genes including SH2B adaptor protein (SH2B1) 1, single-minded homolog 1, Kinase suppressor of Ras 2 (KSR2), and GNAS complex locus (GNAS) , as well as emerging genes such as prolyl 4-hydroxylase, transmembrane (P4HTM) and Bassoon presynaptic cytomatrix protein (BSN) . Genetic evaluation should be guided by obesity onset before the age of 5 years, marked hyperphagia, family history of consanguinity, and associated syndromic or endocrine features rather than by the severity of obesity alone. Recent exome-wide studies highlight the limitations of restricted gene panels and support broader genomic approaches when clinical suspicion remains high. Molecular diagnosis has important therapeutic implications—metreleptin provides hormone replacement in congenital LEP deficiency, whereas setmelanotide activates the downstream MC4R pathway in selected genetic forms of obesity. Rigorous variant interpretation and functional correlation remain essential, as the presence of a rare variant alone does not establish causality or therapeutic eligibility. Recognition of monogenic obesity is, therefore, increasingly important because a molecular diagnosis can guide prognosis, genetic counseling, family testing, and mechanism-based treatment. As the genetic and therapeutic landscape expands, monogenic obesity is evolving from a primarily diagnostic entity into an increasingly actionable group of disorders, amenable to therapy.