Upregulation vs. loss of function of NTRK2 in 44 affected individuals leads to two distinct neurodevelopmental disorders

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

doi:10.1016/j.gim.2024.101326

Upregulation vs. loss of function of NTRK2 in 44 affected individuals leads to two distinct neurodevelopmental disorders

Genet Med. 2024 Nov 11:101326. doi: 10.1016/j.gim.2024.101326. Online ahead of print.

Authors

Eva Berger¹, Robin-Tobias Jauss¹, Judith D Ranells², Emir Zonic³, Lydia von Wintzingerode¹, Ashley Wilson⁴, Johannes Wagner⁵, Annabelle Tuttle⁶, Amanda Thomas-Wilson⁴, Björn Schulte⁷, Rachel Rabin⁸, John Pappas⁸, Jacqueline A Odgis⁹, Osama Muthaffar¹⁰, Alejandra Mendez-Fadol¹¹, Matthew Lynch¹², Jonathan Levy¹³, Daphné Lehalle¹³, Nicole J Lake¹⁴, Ilona Krey¹, Mariya Kozenko¹⁵, Ellen Knierim¹⁶, Guillaume Jouret¹⁷, Vaidehi Jobanputra¹⁸, Bertrand Isidor¹⁹, David Hunt²⁰, Tzung-Chien Hsieh²¹, Alexander M Holtz²², Tobias B Haack²³, Nina B Gold²⁴, Désirée Dunstheimer²⁵, Mylène Donge²⁶, Wallid Deb¹⁹, Katlin A De La Rosa Poueriet²⁷, Magdalena Danyel²⁸, John Christodoulou²⁹, Saurabh Chopra³⁰, Bert Callewaert³¹, Andreas Busche³², Lauren Brick¹⁵, Bary G Bigay²⁷, Marie Arlt⁵, Swathi S Anikar³, Mohammad N Almohammal³³, Deanna Almanza², Amal Alhashem³⁴, Aida Bertoli-Avella³, Heinrich Sticht³⁵, Rami Abou Jamra³⁶

Affiliations

¹ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
² Department of Pediatrics, Division of Genetics and Metabolism, University of South Florida, Tampa, USA.
³ CENTOGENE GmbH, Rostock, Germany.
⁴ Molecular Diagnostics, New York Genome Center, New York, USA.
⁵ Instititue of Human Genetics, University Clinic Carl Gustav Carus, Dresden, Germany.
⁶ Lead Genetic Counseling Assistant GeneDx, University of New England, New York, USA.
⁷ Diagnostics, Zentrum für Humangenetik Tübingen, Tübingen, Germany.
⁸ Department of Pediatrics, NYU Grossman School of Medicine, New York, USA.
⁹ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, USA.
¹⁰ Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
¹¹ Departamento de pediatría, Universidad de la Frontera, Temuco, Chile.
¹² Neurosceinces Unit, Queensland Children's Hospital, Brisbane, Australia.
¹³ Genetics Department, Robert Debré Hospital, APHP, Paris, France.
¹⁴ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
¹⁵ Genetics and Metabolics Clinic, McMaster University, Hamilton, Canada.
¹⁶ Department of Pediatric Neurology and Center for Chronically Sick Children, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁷ National Center of Genetics (NCG), Laboratoire National de Santé (LNS), Dudelange, Luxemburg.
¹⁸ Molecular Diagnostics, New York Genome Center, New York, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, USA.
¹⁹ Department of Genetics, Centre Hospitalier Universitaire de Nantes, Nantes, France.
²⁰ Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
²¹ Institute for Genome Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
²² Division of Genetics and Genomics, Boston Children's Hospital, Boston, USA.
²³ Institute of Medical Genetics and Applied Genomics, Universitätsklinikum Tübingen, Tübingen, Germany.
²⁴ Department of Pediatrics, Division of Medical Genetics and Metabolism, Massachusetts General Hospital, Boston, USA.
²⁵ Department of Pediatrics and Adolescent Medicine, University Hospital Augsburg, Augsburg, Germany.
²⁶ Pediatric neurology, Centre Hospitalier de Luxembourg, Luxembourg, Luxemburg.
²⁷ Department of Human Genetics Instituto ChromoMED, Santo Domingo, Dominican Republic.
²⁸ Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin/ Berlin Institute of Health (BIH), Berlin, Germany.
²⁹ Brain and Mitochondrial Research Group; Department of Paediatrics Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia.
³⁰ Senior Consultant Pediatric Neurologist Indraprastha Apollo Hospital, New Delhi, India.
³¹ Center for Medical Genetics / Department of Biomolecular Medicine, University Hospital Gent / Ghent University, Gent, Belgium.
³² Department of Medical Genetics, University Hospital Münster, Münster, Germany.
³³ Department of Pediatrics Maternity Children Hospital, Bisha, Saudi Arabia.
³⁴ Department of Pediatrics: Division of Medical Genetic and Metabolic Medicine, Prince Sultan Military Medical City,Riyadh,Saudi Arabia, College of Medicine, Alfaisal University, Riyad, Saudi Arabia.
³⁵ Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
³⁶ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany. Electronic address: [email protected].

PMID: 39540377
DOI: 10.1016/j.gim.2024.101326

Abstract

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 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.

Keywords: TRKB; blindness; obesity; transmembrane domain; tyrosine kinase domain.