ESPE Abstracts

The melanocortin-4 receptor (MC4R) pathway is critical for the regulation of hunger, energy balance, and weight regulation. Individuals who carry variants in MC4R pathway genes may present with early-onset severe obesity and hyperphagia. Historically, genetic testing in individuals with severe obesity has been limited. The Rare Obesity Advanced Diagnosis™ genetic testing program aims to enhance access to genetic testing for European individuals with suspected rare genetic causes of obesity. Genes from individuals with early-onset (<5 years of age) severe obesity (defined as ≥97th percentile of body mass index [BMI] for age in those ≤18 years old or BMI ≥40 kg/m2 in those >18 years old) were sequenced. We evaluated a subset of genes that encode proteins in the MC4R pathway (POMC, PCSK1, LEPR, NCOA1, SH2B1, MC4R, MC3R, CPE, LEP, KSR2, SIM1) and are associated with genetic obesity. Variants were classified as pathogenic/likely pathogenic/variants of unknown significance (P/LP/VUS) according to American College of Medical Genetics criteria. The VUS category was further divided into suspected pathogenic (SP), uncertain, or suspected benign (SB) based on available evidence. A non-rare variant (PCSK1 p.N221D) that has been suggested to predispose carriers to obesity was included and is therefore categorized as “risk.” Among 2,253 individuals, 6.0%, 20.7%, 26.9%, and 46.4% were aged <6, 6-12, 12-18, and >18 years, respectively, and the mean age of obesity onset was 6.9 years. Overall, 20.4% of individuals carried ≥1 variant in the 11 studied genes; 5.0% had a P/LP/VUS-SP variant and 15.4% had a VUS-uncertain/VUS-SB/risk variant. The variant frequency for genes with demonstrated responsiveness to the MC4R agonist setmelanotide (POMC, PCSK1, LEPR, NCOA1, SH2B1) was 15.7%, which included 7.3% of individuals with the PCSK1 p.N221D variant. When stratified by age, 30.4% (41/135), 20.1% (94/467), 19.5% (118/606), and 19.7% (206/1045) of individuals aged <6, 6-12, 12-18, and >18 years, respectively, carried ≥1 of the 11 studied MC4R pathway variants. In our large European-based cohort of individuals with early-onset severe obesity, 20.4% carried a variant in ≥1 of the 11 studied MC4R pathway-related genes. Ongoing clinical trials EMANATE (NCT05093634) and DAYBREAK (NCT04963231) are currently assessing the effect of setmelanotide in individuals with variants in a subset of these genes. Genetic testing of individuals with severe obesity may therefore be an important part of clinical care at any age to improve understanding of their disease etiology and identify those who may benefit from novel therapies.