ESPE2024 Poster Category 1 Fat, Metabolism and Obesity 4 (9 abstracts)
Prevalence of variants in the Leptin Melanocortin 4 receptor (MC4R) pathway in an Israeli cohort of children with severe obesity and their clinical and laboratory characteristics
Michal Ben Ami 1 , Hanna Ludar 2 , Ilana Koren 2 , Tal Keidar 1 , Eve Stern 1 , Zohar Landau 3 , Avivit Brener 4,5 , Yael Lebenthal 4,5 , Avigail Wittenberg 6 , Marianna Rachmiel 5,6 , Dikla Pivko-Levy 7,5 , Tal Ben-Ari 7,5 , Elinor Mauda 1 , Noah Levek 1 , Noy Eli 1 , Neria Levran 1 , Adi Uretzky 4 , Noah Gruber 1,5 & Orit Pinhas-Hamiel 1,5
1Pediatric Endocrine and Diabetes Unit, Edmond and Lily Safra Childrens Hospital, Sheba Medica Center, Ramat Gan, Israel. 2Pediatric Endocrinology Unit, Carmel Medical Center, Clalit Health Servicesl, Haifa, Israel. 3Faculty of Health Sciences, Ben-Gurion University of the Negev, Ber Sheva, Israel. 4The Institute of Pediatric Endocrinology, and Diabetes Unitand Metabolism, Dana-Dwek Children's Hospital, Sourasky Medical Center, Tel Aviv, Israel. 5Faculty of Medical and Heaith Sciences, Tel Aviv University, Tel Aviv, Israel. 6Pediatric Endocrinology and Diabetes Institute, Shamir (Assaf Harofeh) Medical Center, Zerifin, Israel. 7Pediatric Endocrinology and Diabetes Unit, Wolfson Medical Center, Holon, Israel
Background: Monogenic obesity is a rare form of obesity caused by pathogenic variants in genes implicated in the leptin–melanocortin receptor (MC4R) signaling pathway. The MC4R pathway plays a crucial role in the regulation of satiety, energy balance, and body weight. Abnormalities in the leptin–melanocortin pathway are characterized by early weight gain, hyperphagia, and severe obesity.
Objective: To investigate the genetic causes of early-onset obesity in children and adolescents living with severe obesity
Methods: The study group comprised a nationally representative sample of 292 children living with severe obesity. A targeted gene panel, consisting of 80 obesity-related genes, was used for screening as part of the genetic testing program of Rhythm Pharmaceuticals, Inc.
Results: Among the cohort, 160 (55%) children exhibited a total of 232 gene variants. Of these, 102 children carried one variant, 41 children carried two variants, 12 children had three different gene variants and 3 children carried four different gene variants. The variants were classified as follows: 33% were suspected benign, 33% were of uncertain significance, and 34% were pathogenic, likely pathogenic or suspected pathogenic. The most common variants among the 77 genes classified as pathogenic likely pathogenic or suspected pathogenic were in the PCSK1 (23%), MC4R (12%), PLAXNA1-4 (12%), MRAP2 and POMC (8% each). No significant differences were found between children with pathogenic or suspected pathogenic variants and those with negative are likely benign results in terms of BMI-zscore or metabolic comorbidities, including the prevalence of abnormal blood pressure, glucose, HBA1c, liver enzymes, HDL and triglycerides levels.
Conclusions: Approximately 25% of our cohort exhibited pathogenic/likely pathogenic/suspected pathogenic variants that appear to account for their phenotype. Implementing genetic testing into the clinical care of individuals with severe obesity is crucial, especially when considering innovative treatments targeting the MC4R pathway. This approach is important as obesity class and clinical characteristics alone may not reliably indicate underlying genetic etiologies.
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