Exploring Autosomal Dominant Non-Syndromic Monogenic Obesity: From Genes to Therapy

Genetic factors are key determinants in the pathophysiology of obesity, regulating energy homeostasis. Monogenic non-syndromic obesity accounts for 2-3% of obesity in both children and adults and is most often attributable to mutations in genes encoding components of the leptin-melanocortin pathway. Genetic testing is indicated in children with severe obesity before age 5, hyperphagia, a family history of obesity, and neurodevelopmental delay or organ dysfunction. Mutations associated with monogenic obesity follow autosomal recessive (<i>LEP</i>, <i>LEPR</i>, <i>POMC</i>, and <i>PCSK1</i>) or autosomal dominant (<i>MC4R</i>, <i>SH2B1</i>, <i>SIM1</i>, <i>GNAS</i>) modes of inheritance. Other gene mutations in heterozygous states (<i>MRAP2</i>, <i>MC3R</i>, <i>SRC1</i>, <i>KSR2</i>) are associated with obesity and may exhibit autosomal dominant inheritance; however, the clinical phenotype depends on the degree of genetic penetrance and interactions with other genetic and/or environmental factors. No approved targeted pharmacotherapies are currently available for autosomal dominant monogenic obesity, and the frequent detection of variants of uncertain significance often hinders timely diagnostic confirmation. The review provides a comprehensive appraisal of autosomal dominant forms of monogenic non-syndromic obesity, analyzing genetic and molecular features, clinical presentations, and therapeutic strategies.