Upregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders

Berger E, Jauss RT, Ranells JD, Zonic E, von Wintzingerode L, Wilson A, Wagner J, Tuttle A, Thomas-Wilson A, Schulte B, Rabin R, Pappas J, Odgis JA, Muthaffar O, Mendez-Fadol A, Lynch M, Levy J, Lehalle D, Lake NJ, Krey I, Kozenko M, Knierim E, Jouret G, Jobanputra V, Isidor B, Hunt D, Hsieh TC, Holtz AM, Haack TB, Gold NB, Dunstheimer D, Donge M, Deb W, De La Rosa Poueriet KA, Danyel M, Christodoulou J, Chopra S, Callewaert B, Busche A, Brick L, Bigay BG, Arlt M, Anikar SS, Almohammal MN, Almanza D, Alhashem A, Bertoli-Avella A, Sticht H, Abou Jamra R (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Article Number: 101326

DOI: 10.1016/j.gim.2024.101326

Abstract

Purpose: 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 reported an 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 2 entities. Conclusion: 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 tropomyosin receptor kinase B 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.

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Additional Organisation(s)

Involved external institutions

Universität Leipzig Germany (DE) Morsani College of Medicine United States (USA) (US) Centogene GmbH Germany (DE) New York Genome Center (NYGC) United States (USA) (US) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) University of New England (USA) United States (USA) (US) New York University (NYU) United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز Saudi Arabia (SA) University of the Frontier / Universidad de La Frontera (UFRO) Chile (CL) Hôpital Universitaire Robert-Debré France (FR) Yale University United States (USA) (US) McMaster University Canada (CA) Charité - Universitätsmedizin Berlin Germany (DE) Laboratoire National de Santé (LNS) Luxembourg (LU) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) France (FR) Princess Anne Hospital United Kingdom (GB) Universitätsklinikum Bonn Germany (DE) Boston Children's Hospital United States (USA) (US) Universitätsklinikum Tübingen Germany (DE) Massachusetts General Hospital United States (USA) (US) Universitätsklinikum Augsburg Germany (DE) Luxembourg Hospital Center / Centre Hospitalier de Luxembourg (CHL) Luxembourg (LU) Berliner Institut für Gesundheitsforschung (BIH) Germany (DE) The University of Melbourne Australia (AU) Apollo Hospitals India (IN) University Hospital Ghent Belgium (BE) Universitätsklinikum Münster Germany (DE) Alfaisal University Saudi Arabia (SA) Children’s Health Queensland Hospital and Health Service Australia (AU)

How to cite

APA:

Berger, E., Jauss, R.T., Ranells, J.D., Zonic, E., von Wintzingerode, L., Wilson, A.,... Abou Jamra, R. (2025). Upregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders. Genetics in Medicine. https://doi.org/10.1016/j.gim.2024.101326

MLA:

Berger, Eva, et al. "Upregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders." Genetics in Medicine (2025).

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