ESPE Abstracts

Introduction: Patients with genetic variants in the melanocortin-4 receptor (MC4R) pathway may present with hyperphagia and early-onset obesity. Increasing awareness of genetic testing could improve diagnosis and identification of patients who might benefit from novel precision therapies. Moreover, the frequency of specific genetic variants in this population is currently unknown. The Rare Obesity Advanced Diagnosis ™ (ROAD) genetic testing program aims to enhance access to genetic testing for patients with suspected rare MC4R pathway diseases. Here, we used ROAD data to assess the frequency of selected rare syndromic diseases in individuals with early-onset obesity.

Methods: Genes from individuals with early-onset obesity were sequenced and analysis focused on rare syndromic diseases, which included TBX3 (ulnar-mammary syndrome), PHIP (Chung-Jansen syndrome), MAGEL2 (Prader-Willi syndrome), AS (Alström Syndrome), BBS (Bardet-Biedl syndrome – BBS1-BBS22 genes only). Classification of variants as pathogenic/likely pathogenic/variants of unknown significance (P/LP/VUS) was according to American College of Medical Genetics criteria.

Results: Overall, 5,051 individuals were sequenced in Spain (n = 1,834), Italy (n = 1,291), Türkiye (n = 653), Israel (n = 501), United Kingdom (n = 445), Ireland (n = 250), Germany (n = 76), and Greece (n = 1) of whom 3,040 (60.2%) were aged <18 years. A total of 269 variants were found in 246 unique individuals (4.87%); 88 (1.74%) carried a P/LP/VUS biallelic variant in one of the BBS genes, 41 (0.81%) a P/LP/VUS biallelic variant in AS, 53 (1.05%) a heterozygous variant in TBX3, 67 (1.33%) a heterozygous variant in PHIP, and 20 (0.40%) a heterozygous variant in MAGEL2 (though given maternal imprinting of MAGEL2 gene it is unknown if variant is on paternal allele). For the 161 individuals who were <18 years mean (SD) BMI z-score was 3.5 (1.1) and for the 85 individuals who were ≥18 BMI was 41.4 (10.6) kg/m². Age of onset of obesity was 4.7 (3.7) years and age of hyperphagia onset 3.8 (2.4) years.

Conclusion: Almost 5% of tested individuals carried a biallelic or heterozygous P/LP/VUS variant in ≥1 of the studied TBX3, PHIP, MAGEL2, AS or BBS genes. By testing patients with early-onset obesity with selected gene panels, or even with Whole Exome Sequencing, a genetic cause might be identified, allowing improved disease awareness and disease management.