Endocrine Abstracts

JOINT1603

Introduction: Obesity due to variants in genes in the leptin-melanocortin-4 receptor (MC4R) pathway may benefit from personalised treatments. The aim of this study was to assess the frequency of selected rare genetic disorders in individuals presenting with early-onset obesity using data from the “Rare Obesity Advanced Diagnosis™”(ROAD) genetic diagnosis programme.

Methods: DNA was isolated from buccal swab samples of 72 patients with obesity onset before age 6 and body mass index (BMI) ≥ 2.5SD. Whole-exome sequencing (WES) targeted 80 obesity-related genes, including copy number variation (CNV) analysis. Variants were classified as pathogenic (P), likely pathogenic (LP), or of variants of uncertain significance (VUS) per the American College of Medical Genetics (ACMG) criteria.

Results: Of the patients from whom buccal swab samples were taken for DNA analysis, 52 (72.2%) with adequate DNA quality could be included in the study. Of the 52 cases included in the study, 63.5% (n = 33) were female and 36.5% (n = 19) were male, with a mean age of 11.63 years (1.71–19.5 years). Mean BMI was 34.60 (9.62) kg/m² and mean SD BMI Z-score was 3.34 (0.89). The mean age at onset of obesity was 2.9 (2.7) years. Genetic analysis identified disease-causing variants in obesity-related genes in 4 (7.7%) cases. According to ACMG criteria, two variants were classified as LP and two as P. One case harbored a homozygous c.1091C>A p.(Ala364Glu) variant in the BBS4, another a homozygous c.133_136dup p.(Tyr46*) variant in the LEPR, a third a heterozygous c.496G>A p.(Val166Ile) variant in the MC4R, and a fourth compound heterozygous variants c.3907C>T p.(Arg1303*), c.2462A>C p.(Lys821Thr) in the IFT172. The mean BMI of cases with pathogenic variants was 40.89 kg/m², with a BMI SD of 3.58. Additionally, heterozygous variants c.706C>G p.(Arg236Gly) in the POMC and c.1405G>A p.(Val469Ile) in the PCSK1 were identified in 2 (3.8%) cases, which were classified as carriers. Moreover, variants requiring further analysis to confirm clinical significance were identified in 5 (9.6%) cases, and variants in obesity-related genes not yet associated with disease were found in 9 (17.3%) cases.

Conclusion: In 38.4% of patients with early-onset obesity included in the study, VUS/l/lP variants were identified in at least one of the studied genes, including SIM1, SEMA3 family, PLXNA family, POMC, PCSK1, LEPR, SH2B1, NCOA1, BBS family, MC4R, MKS1, IFT172, NRP1, and DYRK1B. These findings highlight the diagnostic value of genetic testing in obesity and its potential to guide personalized treatment strategies.

Keywords Early onset obesity, WES, ROAD, MC4R