ESPE2023 Free Communications Fat, metabolism and obesity 1 (6 abstracts)
Frequency of Obesity-Related Gene Variants in a European Population With Early-Onset, Severe Obesity
Carel W. le Roux 1 , Jesus Dominguez-Riscart 2 , Maria Rosaria Licenziati 3 , Leandro Soriano-Guillén 4 , Belma Haliloglu 5 , Anjali Zalin 6 , Simona Filomena Madeo 7 , Patrick Sleiman 8 , Charles Savoie 8 , Liya Kerem 9 & Jesús Argente 10,11
1Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland. 2Instituto de Investigación e Innovación Biomédica de Cádiz, Hospital Universitario Puerta del Mar, Universidad de Cádiz, Cádiz, Andalusia, Spain. 3Neuro-Endocrine Diseases and Obesity Unit, Department of Neurosciences, Santobono-Pausilipon Children’s Hospital, Naples, Italy. 4Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain. 5Department of Pediatrics and Pediatric Endocrinology and Diabetes, Marmara University Medical School, Istanbul, Turkey. 6Barts Health NHS Trust, London, UK and Bedfordshire Hospitals NHS Foundation Trust, Bedford, United Kingdom. 7Pediatric Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena, Modena, Italy. 8Rhythm Pharmaceuticals, Inc., Boston, USA. 9Pediatric Endocrinology, Hadassah University Medical Center, Jerusalem, Israel. 10Department 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, Madrid, Spain. 11IMDEA Food Institute, Madrid, Spain
Background: Patients with genetic variants in the melanocortin-4 receptor (MC4R) pathway may present with early-onset, severe obesity and hyperphagia. Increasing awareness of genetic testing could improve diagnosis of rare genetic causes of obesity and identify patients who might benefit from targeted therapy; however, such testing has been limited. 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 genetic causes of obesity. Here, we used ROAD data to assess the frequency of selected rare variants in individuals with early-onset, severe obesity.
Methods: Individuals with early-onset, severe obesity were sequenced as part of the ROAD genetic testing program. The panel included 79 genes and 1 chromosomal region that have well-established associations with obesity and the MC4R pathway. Eligible individuals had severe obesity (defined as ≥97th percentile of body mass index [BMI] for age in those aged ≤18 years or BMI ≥40 kg/m2 in those aged ≥19 years), were an immediate family member of selected previously tested patients, or showed clinical symptoms that suggested Bardet-Biedl syndrome.
Results: Overall, 2,253 individuals were sequenced in Spain (n=1,020), Italy (n=508), Ireland (n=216), Turkey (n=178), Israel (n=189), the United Kingdom (n=138), and Germany (n=4), of whom 1,208 (54%) were aged <18 years. The mean (standard deviation [SD]) BMI Z score of individuals aged ≤18 years was 3.40 (0.93), the mean (SD) BMI of individuals aged >18 years was 44.2 kg/m2 (8.48), and the mean (SD) age of obesity onset for all individuals was 6.9 years (8.5). Genetic variants that have been indicated for treatment in Europe with the MC4R agonist setmelanotide or that are being investigated for setmelanotide efficacy in clinical trials were identified in 46 (2.0%) and 661 (29.3%) individuals, respectively. An additional 481 (21.3%) individuals had variants that might support a diagnosis of genetic obesity but are neither currently indicated for setmelanotide treatment nor being investigated for setmelanotide efficacy in clinical trials. Genetic variants were not identified in 1065 (47.3%) individuals.
Conclusions: In this cohort of individuals with early-onset, severe obesity, ~35% carried potentially actionable variants. Genetic testing of patients with early-onset, severe obesity may be an important component of understanding the etiology of these patients’ disease and could potentially affect the course of care for these patients.
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