ESPE Abstracts

Introduction: The melanocortin-4 receptor (MC4R) pathway is critical for hunger regulation, energy balance, and weight regulation. In patients with Bardet–Biedl syndrome (BBS), a rare, genetically heterogeneous, and highly pleiotropic disease, the immotile primary cilia are dysfunctional, leading to MC4R pathway impairment. Patients suffer from symptoms including early vision loss, learning difficulties, and renal dysfunction, next to hyperphagia and early-onset obesity. The Rare Obesity Advanced Diagnosis (ROAD) ™ genetic testing program aims to enhance genetic testing access for European and Middle Eastern individuals with suspected rare MC4R pathway diseases. Here, we assessed BBS gene variant frequency using ROAD data.

Methods: Genes from individuals with early-onset obesity were sequenced. This analysis focuses on BBS genes (BBS1-BBS22). Variants were classified as pathogenic/likely pathogenic/variants of unknown significance (P/LP/VUS) according to American College of Medical Genetics criteria. The VUS category was further divided into suspected pathogenic (SP), uncertain, or suspected benign (SB) based on available evidence.

Results: Among 5,051 individuals, 7.1%, 24.6%, 28.4%, and 39.8% were aged <6, 6-<12, 12-<18, and ≥18 years at the time of testing, respectively, and the mean age (standard deviation, SD) of obesity onset was 8.0 (3.9) years. Overall, 16 individuals caried a P/LP biallelic variant and 72 a VUS biallelic variant, with variants in BBS14 (n = 22), BBS20 (n = 11) and BBS9 (n = 9) most frequently reported. In this cohort, for individuals <18 years mean BMI z-score was 3.8 (1.2) and for individuals ≥18 BMI was 41.6 (9.5) kg/m². Age of onset of obesity was 4.8 (3.7) years and of hyperphagia 3.1 (2.8) years. Individuals with P/LP/VUS variants in BBS genes were from Türkiye (n = 38, 5.82% of tested individuals), Spain (n = 20, 1.09%), Italy (n = 14, 1.08%), UK (n = 10, 2.25%), Israel (n = 3, 0.60%), Ireland (n = 2. 0.80%), and Germany (n = 1, 1.32%). Of these patients, only 25 (28%) had a suspicion of BBS at the time of testing.

Conclusion: Among individuals tested, 1.74% with early-onset obesity caried a biallelic variant in 1 of 22 tested BBS genes, with a higher frequency of BBS14 and BBS20 variants versus literature, and a high frequency in Türkiye because of high consanguinity rates. At diagnosis, not all patients had a clear BBS phenotype. This indicates that all BBS genes should be included in panels testing for early-onset obesity, not just those investigating suspected syndromic disease, to help improve disease etiology understanding, and allow early diagnosis of patients who may benefit from novel treatments.