Open Access

Eva Berger, Robin-Tobias Jauss, Judith D. Ranells, Emir Zonic, Lydia von Wintzingerode, Ashley Wilson, Johannes Wagner, Annabelle Tuttle, Amanda Thomas-Wilson, Björn Schulte, Rachel Rabin, John Pappas, Jacqueline A. Odgis, Osama Muthaffar, Alejandra Mendez-Fadol, Matthew Lynch, Jonathan Levy, Daphné Lehalle, Nicole J. Lake, Ilona Krey, Mariya Kozenko, Ellen Knierim, Guillaume Jouret, Vaidehi Jobanputra, Bertrand Isidor, David Hunt, Tzung-Chien Hsieh, Alexander M. Holtz, Tobias B. Haack, Nina B. Gold, Désirée Dunstheimer, Mylène Donge, Wallid Deb, Katlin A. De La Rosa Poueriet, Magdalena Danyel, John Christodoulou, Saurabh Chopra, Bert Callewaert, Andreas Busche, Lauren Brick, Bary G. Bigay, Marie Arlt, Swathi S. Anikar, Mohammad N. Almohammal, Deanna Almanza, Amal Alhashem, Aida Bertoli-Avella, Heinrich Sticht, Rami Abou Jamra

• Introduction Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation Methods We report extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported. Results Our analysis led to splitting the cohort into two entities. Discussion One group had variants in the cholesterol binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of TRKB activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variantsIntroduction Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation Methods We report extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported. Results Our analysis led to splitting the cohort into two entities. Discussion One group had variants in the cholesterol binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of TRKB activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity and hyperphagia.…