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Nijim, S.* ; Kim, M.* ; Denish, M.* ; Gonzalez, M.* ; Zinski, J.* ; Rieubland, C.* ; Braun, D.* ; Ostergaard, E.* ; Shillington, A.* ; Faivre, L.* ; Maraval, J.* ; Garde, A.* ; Philippe, C.* ; Tran-Mau-Them, F.* ; Crunk, A.* ; Hawley, M.* ; Callewaert, B.* ; Iascone, M.* ; Cereda, A.* ; Daolio, C.* ; Hershkovitz, T.* ; Good, J.* ; Steindl, K.* ; Frey, T.* ; Rauch, A.* ; Afenjar, A.* ; Mignot, C.* ; Agathe, J.d.S.* ; den Hollander, N.* ; Hilhorst-Hofstee, Y.* ; Koene, S.* ; Santen, G.* ; Bijlsma, E.K.* ; Berger, S.* ; Mehta, L.* ; Stoeva, R.* ; Houdayer, C.* ; Gueguen, P.* ; Faust, H.* ; Specht, S.* ; Klabunde-Cherwon, A.* ; Khelifa, M.M.* ; Bergmann, A.* ; Saunders, C.* ; Krygier, M.* ; Carrasco, D.* ; Metcalfe, K.* ; Sanders, S.J.* ; Zhang, D.Y.* ; Judy, R.* ; Nijim, W.* ; Exposito-Alonso, D.* ; Deng, C.X.* ; Kim, J.* ; Gecz, J.* ; Romano, C.* ; Skinner, C.* ; Lichty, A.* ; Linebaugh, E.* ; Skinner, S.A.* ; Chahrour, M.* ; Wang, T.* ; Xia, K.* ; Guo, H.* ; Van Daele, S.* ; Van Goethem, G.* ; Fagerberg, C.* ; Graakjaer, J.* ; Anders, S.* ; Fink, H.* ; Ward, D.I.* ; Grange, D.K.* ; Strong, A.* ; Zwijnenburg, P.* ; Towne, M.* ; Feichtinger, R.G.* ; Morrison, J.* ; Dagli, A.* ; Levy, J.* ; Capri, Y.* ; Spillman, R.C.* ; Hart, S.* ; Shashi, V.* ; Keren, B.* ; Kleefstra, T.* ; Pfundt, R.* ; Gilissen, C.* ; Eichler, E.E.* ; Brugger, M.* ; Zech, M. ; Chung, W.K.* ; Fasolino, M.* ; Dow, H.C.* ; Rader, D.J.* ; Brodkin, E.S.* ; Bucan, M.* ; Marsh, E.D.* ; Dias, C.* ; Fajgenbaum, D.C.*

Characterization of the genotypic and phenotypic spectrum of TCF7L2-related neurodevelopmental disorder (TRND).

Genet. Med. 28:102642 (2026)
Verlagsversion DOI
Open Access Hybrid
Creative Commons Lizenzvertrag
Purpose: TCF7L2 (OMIM 602228; HGNC:11641) is a transcription factor and a critical effector of the Wnt/ beta-Catenin pathway. In 2021, 11 pediatric patients with monoallelic predicted loss-of-function (pLOF) TCF7L2 variants and syndromic features were observed. Characterization of patients with pLOF TCF7L2 variants and neurodevelopmental features-herein referred to as TCF7L2-related neurodevelopmental disorder-is urgently needed. Methods: We leveraged multiple methods (eg, GeneMatcher, DECIPHER, literature review, and public/private repositories) to identify an international cohort of 76 patients with pLOF TCF7L2 variants and neurodevelopmental features and phenotypically characterized them. We also retrospectively searched for an independent cohort of adults with pLOF TCF7L2 variants (n = 11) from more than 60,000 PennMedicine BioBank patients. Results: Among 76 patients with pLOF TCF7L2 variants, speech delay (95.3%), craniofacial dysmorphisms (73.3%), ophthalmologic conditions (65.5%), autism (62.1%), and orthopedic abnormalities (52.6%) were the most commonly observed. Phenotypic differences did not cluster by variant type or genomic locus. Among PennMedicine BioBank patients, an association of nominal significance with type 2 diabetes with renal manifestations (odds ratio = 5.8; P = .03) was detected, warranting further investigation. Conclusion: This study represents the most comprehensive characterization of TCF7L2-related neurodevelopmental disorder to date, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectra. We opened a Simons Searchlight natural history study that is now available for patient enrollment to enhance the understanding of this condition. (c) 2026 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Neurodevelopmental syndrome; Speech delay; Pathway Effector Tcf7l2; Genes
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 28, Heft: 10, Seiten: , Artikelnummer: 102642 Supplement: ,
Verlag Elsevier
Verlagsort Baltimore, Md.
Begutachtungsstatus Peer reviewed
Institut(e) Institiute of Neurogenomics (ING)
Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
Förderungen Health Data Research UK QQ2 Molecules to Health Records Driver Programme
Federal Ministry of Education and Research