Implication of Heterozygous Variants in Genes of the Leptin-Melanocortin Pathway in Severe Obesity

Abstract

Context: Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established. Objective: To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. Methods: In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. Results: The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P =. 015), an earlier onset of obesity (0.4 vs 5.4 years, P