Endocrine Abstracts

The leptin/melanocortin pathway plays a critical role in hypothalamic control of food intake. Variants in the genes involved in this pathway, such as leptin (LEP), its receptor (LEPR), proopiomelanocortin (POMC) or proconvertase 1 (PCSK1) are associated with early-onset severe obesity and endocrine abnormalities especially in case of homozygosity. Heterozygous variants in the melanocortin-4 receptor (MC4R) gene are associated with an increased risk of severe obesity. The aim is to describe the frequency of variants in the genes of the leptin/melanocortin pathway in obese children and adults consulting in a reference center. The coding eons of the LEP, LEPR, POMC, PCSK1 et MC4R genes were sequenced by Sanger. The 6100 patients included had severe obesity (BMI >35 kg/m² for adults and BMI Zscore >+2.5 S.D. for children). MC4R was sequenced in 5815 subjects, LEPR in 1180 patients, LEP in 800 patients, POMC in 556 patients and PCSK1 in 288 patients. The frequency of homozygous variants was ≤1% with 13 (1.02%) variants in LEPR (p.C604G, p.L786P, p.H800_N831del, p.Y422H p.T711N, p.535-1G>A, p.P166CfsX7, p.Met1X), 3 (0.4%) variants in LEP (p.Q55X, p.R105W, p.V94M), 1 variant in PCSK1 (0.4%) (c.286-2A>G), 3 variants in POMC (0.6%) (p.R75Profs*44; p.E214G; p.D53G) et 7 variants in MC4R (0.12%) (p.R165Q, p.S127L, p.C277X, p.V166I, p.C271R, p.I170V). Homozygous patients developed severe early-onset obesity (before the age of 3y) with major hyperplasia and associated endocrine phenotypes. The frequency of heterozygous variants was 2–3% for POMC, MC4R and LEPR whereas it was less than 2% for PCSK1 (1.4%) and LEP (0.5%). The presence of one heterozygous variant with functional consequence in these genes was always associated with early-onset obesity (before the age of 10y) without endocrine abnormalities. Four patients had heterozygous combined variants on two genes in the pathway suggesting a cumulative effect. Our work confirms the implication of variants in genes of the leptin/melanocortin pathway in early-onset severe obesity (2-3% of patients with severe obesity) and is currently expanded to other genes modulating this pathway. This screening is critical because now effective therapeutic options by MC4R agonist (setmelanotide) exist and can restore the melanocortin signal despite its interruption in case of variants. Development of clinical tools helping for diagnosis and NGS molecular tests extended to other genes involved in the pathway will help to diagnose patients candidates for this novel therapeutic.