Courbage S, Poitou C, Le Beyec - Le Bihan J, et al. - Researchers conducted this retrospective study for describing the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. Genotyping was conducted on at least one of the LEP, LEPR, POMC, and PCSK1 genes in 1,486 probands with severe obesity (600 children, 886 adults). The phenotypes of 60 individuals with heterozygous variants and 16 individuals with homozygous variants were collected. Data reported that the frequency of individuals with homozygous variants was 1.7% and 6.7% with heterozygous variants. There were no significant differences in the age of onset of obesity and BMI in children. Heterozygous LEP, LEPR, POMC, and PCSK1 variants are common in severe obesity and are sometimes associated with a phenotype similar to homozygotes. These findings point to a systematic search for variants in severe early-onset obesity in order to discuss potential therapies that target this key pathway.