ESPE Abstracts

Introduction: Genetic variants in the melanocortin-4 receptor (MC4R) pathway can lead to hyperphagia and early-onset obesity. Increasing awareness of genetic testing may aid in the diagnosis and identification of patients who could benefit from novel precision therapies. To enhance access to genetic testing for patients with suspected rare MC4R pathway diseases, the Rare Obesity Advanced Diagnosis ™ (ROAD) genetic testing program was established. Here, we used ROAD data to assess the frequency of selected rare non-syndromic diseases in individuals with early-onset obesity.

Methods: Genes from individuals with early-onset obesity were sequenced and analysis focused on rare non-syndromic diseases, which included SIM1, SEMA3 family (SEMA3A, SEMA3B, SEMA3C, SEMA3D, SEMA3E, SEMA3F, SEMA3G), PLXNA family (PLXNA1, PLXNA2, PLXNA3, PLXNA4), POMC, PCSK1, LEPR, SH2B1 and NCOA1. Variants were classified as pathogenic/likely pathogenic/variants of unknown significance (P/LP/VUS) according to American College of Medical Genetics criteria.

Results: Overall, 5,051 individuals from Germany, Greece, Ireland, Israel, Italy, Spain, Türkiye, and the UK were sequenced, 54.7% were female, and mean age of obesity onset for all individuals was 6.9 (8.5) years. A total of 1,263 P/LP/VUS variants were found in 1,138 unique individuals (22.53%), with 49 (0.97%) of individuals having one or more P/LP variant. Sixty-six (1.31%) carried a variant in SIM1, 371 (7.35%) a variant in SEMA3, 501 (9.92%) a variant in PLXNA, 2 (0.04%) a biallelic variant in POMC/PCSK1 (excluding PCSK1 p.(Asn221Asp)), 16 (0.32%) a biallelic variant in LEPR, 72 (1.43%) a heterozygous variant in POMC/PCSK1, 10 (0.20%) a heterozygous variant in LEPR, 125 (2.47%) a variant in SH2B1, and 100 (1.98%) a variant in NCOA1. In the overall population and in the variant-carrying population, mean (SD) BMI z-score was 3.6 (1.0) and 3.6 (1.1), respectively, for individuals <18 years, and mean BMI 43.7 (10.1) and 42.7 (10.2) kg/m², respectively, for individuals ≥18 years. Age of onset of obesity was 5.2 (3.8) years and age of hyperphagia onset 4.1 (4.0) years.

Conclusion: About a quarter of tested individuals with early-onset obesity carried a P/LP/VUS variant in ≥1 of the studied SIM1, SEMA3 family, PLXNA family, POMC, PCSK1, LEPR, SH2B1 and NCOA1 genes. This demonstrates the need to test patients with early-onset obesity for a genetic cause. Given the high rate of positive variants in this panel, Whole Exome Sequencing might be preferred over a gene panel.