IMPE Abstracts

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

Objectives: To explore the prevalence of hetRSVs in 13 genes involved in the leptin-melanocortin pathway in 1066 children and adolescents with obesity and to compare their clinical features with those of patients lacking variants.

Patients and methods: A transversal study of 1066 patients below 18 years of age with obesity (BMI >+2 SDS, 48.6% females; 54.4% prepubertal; 71.5% Caucasians; age: 10.38±3.44 years, BMI: +4.38±1.77 SDS) was carried-out using next generation sequencing (NGS) to analyze ADCY3, CPE, LEP, LEPR, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1, SIM1 and TBX3. 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. Newborn anthropometry, age at obesity onset and at first evaluation, height-SDS, BMI-SDS, glucose and lipid metabolic parameters were compared between patients with and without hetRSVs.

Results: A total of 199 patients (18.8%) carried hetRSVs with CADD>20 in the 13 genes, 101 patients (9.5%) carried hetRSVs with CADD>25. No significant differences in the studied parameters were observed between patients with obesity without variants and those harboring hetRSVs with CADD>20. When comparing exclusively for hetRSVs with CADD>25, the only significant difference was that these patients had was a higher newborn weight compared to patients without hetRSVs (0.74±1.90 vs. 0.28±1.37; P<0.05). No significant differences in the studied parameters were observed between patients carrying hetRSVs when compared by affected gene, neither when all hetRSVs with CADD>20 were considered nor when exclusively analyzing hetRSVs with CADD>25.

Conclusions: 1) The prevalence of hetRSVs in leptin-melanocortin pathway genes, particularly in POMC, MC4R and NCOA1, in childhood obesity is high. 2) These patients do not exhibit distinctive phenotypical features compared to patients without hetRSVs.