ESPE Abstracts

Background: The central melanocortin system is highly involved in the control of energy metabolism, receiving and integrating numerous metabolic signals, such as leptin, and biallelic mutations in several genes of the pathway have been reported in severe obesity. However, whether and how heterozygous rare sequence variants (hetRSVs) in genes of this satiety pathway contribute to the development of obesity is poorly explored.

Objective: Our aim was to define whether hetRSVs in 13 genes involved in the leptin-melanocortin pathway contribute to early obesity by comparing their prevalence in 1066 children and adolescents with obesity and a country-matched control population.

Patients and methods: A transversal study of 1066 patients below 18 years with obesity (BMI >+2 SDS, OB: 48.6% females; 54.4% prepubertal; 71.7% Caucasians; age: 10.37±3.44 years, BMI: +4.38±1.77 SDS) was carried-out with next generation sequencing (NGS) analysis of ADCY3, CPE, LEP, LEPR, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1, SIM1 and TBX3 performed. Rare (population frequency <0.01) heterozygous variants with a combined Annotation Dependent Depletion (CADD) score of “deleteriousness” >20 and >25 in each gene were considered and their relative frequency compared with that in a control population (C, n = 1012).

Results: A total of 199 patients of the OB group (18.8%) and 81 controls (8.0%) carried heterozygous RSVs in the 13 selected genes (OR=2.64, 95%CI=2.00-3.47, P < 0.0001), 101 patients vs. 45 controls when considering RSVs with CADD>25 (9.47% vs. 4.44%, OR=2.25, 95%CI=1.56-3.23, P < 0.0001). No significant differences in the prevalence of hetRSVs in ADCY3, LEP, LEPR, or TBX3 were observed between OB and C. In contrast, OB showed a significantly higher prevalence of hetRSVs with CADD>20 in CPE, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1 and SIM1. These intergroup differences were particularly relevant for POMC, PCSK1, MC4R and NCOA1.

Conclusions: The burden of heterozygous rare variants in leptin-melanocortin pathway genes, particularly in POMC, PCSK1, MC4R and NCOA1, in childhood obesity is higher than in general population, so they likely contribute to the early development of obesity in these patients.