ECEESPE2025 Rapid Communications Rapid Communications 15: Metabolism, Nutrition and Obesity (6 abstracts)
Age of onset of hyperphagia and/or obesity as key predictors of a positive genetic test for POMC, PCSK1 or LEPR deficiency or BBS
Jesús Argente 1 , Giuseppina Umano 2 , Jesús Dominguez-Riscart 3 , Belma Haliloglu 4 , Maria Licenziati 5 , Patrick Sleiman 6 , Charles Savoie 6 , Orit Pinhas-Hamiel 7 , Melek Yildiz 8 , Carel le Roux 9 & Anthony Goldstone 10
1Department of Pediatrics & Pediatric Endocrinology, Universidad Autónoma de Madrid, University Hospital Niño Jesús, CIBER “Fisiopatología de la obesidad y nutrición” (CIBEROBN), Instituto de Salud Carlos III, IMDEA Institute, Madrid, Spain; 2University of Campania “Luigi Vanvitelli”, Department of Woman, Child and of General and Specialized Surgery, Naples, Italy; 3Instituto de Investigación e Innovación Biomédica de Cádiz, Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, Spain; 4Marmara University Medical School, Department of Pediatrics and Pediatric Endocrinology and Diabetes, Istanbul, Türkiye; 5Santobono-Pausilipon Children’s Hospital, Neuro-endocrine Diseases and Obesity Unit, Department of Neurosciences, Naples, Italy; 6Rhythm Pharmaceuticals, Inc, Boston, United States; 7Tel Aviv University, Pediatric Endocrinology and Diabetes Unit, Sheba Medical Center, Faculty of Medical & Health Sciences, Tel Aviv, Israel; 8Istanbul University Faculty of Medicine, Department of Pediatric Endocrinology, Istanbul, Türkiye; 9University College Dublin, Diabetes Complications Research Centre, Dublin, Ireland; 10Imperial College London, PsychoNeuroEndocrinology Research Group, Division of Psychiatry, Department of Brain Sciences, London, United Kingdom
JOINT2526
Introduction: The melanocortin-4 receptor (MC4R) pathway plays a crucial role in regulating hunger, caloric intake, and energy expenditure. Genetic variants in this pathway can lead to hyperphagia and early-onset obesity. Raising awareness about genetic testing can help diagnose and identify patients who might benefit from innovative precision therapies. To improve access to genetic testing for individuals with suspected rare MC4R pathway diseases, the Rare Obesity Advanced Diagnosis™ (ROAD) genetic testing program was created, using a gene panel including 79 genes and 1 chromosome region including the most frequently tested genes associated with obesity. Here, we analysed ROAD data to identify prognostic factors for a positive genetic test.
Methods: Genes from individuals with early-onset obesity were sequenced. Analysis focused on biallelic variants in POMC, PCSK1, or LEPR, or in BBS genes (BBS1-BBS22). Variants were categorized as pathogenic, likely pathogenic, or of uncertain significance (P/lP/VUS) based on the criteria established by the American College of Medical Genetics.
Results: Overall, 6,169 individuals (54.5% female) from Germany, Greece, Ireland, Israel, Italy, Spain, Türkiye, UK, and the United Arab Emirates were sequenced, who had a mean age of obesity onset of 5.2 (3.8) years. A total of 1,830 P/lP/VUS variants were found in 1,755 unique individuals (28.4%), including 17 biallelic variants in LEPR, 3 in POMC/PCSK1 and 112 in any of the tested BBS genes. Mean age of onset of hyperphagia and of obesity in individuals with any of these biallelic variants was 2.7 (2.7) and 4.0 (3.6) years, respectively. In individuals in whom no variant from the gene panel was found, the ages were 4.6 (4.3) and 5.4 (3.8) years, respectively. When assessing the correlation between a positive test for biallelic LEPR, POMC, PCSK1 or BBS and no identified variant, age of onset of hyperphagia (P=0.0001) and age at onset of obesity (P=0.0007) are key predictors for a positive genetic test, with BMI at time of testing (P=0.0232) and BMI z-score at time of testing (0.0661) showing potential predictive value.
Conclusions: A positive correlation was observed for individuals with biallelic variants in POMC, PCSK1, LEPR, or in any of the tested BBS genes, indicating that the age of onset of hyperphagia and obesity are key predictors for a positive test result for these genes. Hence, individuals presenting with early-onset hyperphagia and obesity are more likely to test positive for the disease, highlighting the importance of these factors as key predictors.
Volume 110
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Endocrine Abstracts
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