Document Type
Article
Publication Date
10-1-2026
Abstract
PURPOSE: TCF7L2 (OMIM 602228; HGNC:11641) is a transcription factor and a critical effector of the Wnt/ β-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.
Recommended Citation
Nijim, Sally; Kim, Mimi; Denish, Melissa; Gonzalez, Michael V.; Zinski, Joseph; Rieubland, Claudine; Braun, Dominique; Ostergaard, Elsebet; Shillington, Amelle; Faivre, Laurence; Maraval, Julien; Garde, Aurore; Philippe, Christophe; Tran-Mau-Them, Fréderic; Crunk, Amy; Daber, Robert; Westheimer, Emily; O' Callaghan, William; Malni, Nirav; Chen, Ingrid; Scozarro, Kaylee; Barbosa, Michelle; Cohen, Andrew; Ko, Arthur; Delot, Emmanuele; Pitsava, Georgia; Berger, Seth; Auriga, Lightning; Cui, Ya; Xiao, Changrui; King, Charles Hadley; Vilian, Eric; Dios, Ivan de; LoTempio, Jonathan; Almalvez, Miguel; Fusaro, Vincent; Li, Wei; Fraser, Jamie; Delaney, Meghan; Boukas, Leandros; Losic, Bojan; Hsiao, Esther (Yun-Ha); Harting, John; Bluske, Kriste; Karam, Rachid; Belhadj, Sami; Hawley, Megan; Callewaert, Bert; Iascone, Maria; Cereda, Anna; Daolio, Cecilia; Hershkovitz, Tova; Good, Jean-Marc; Steindl, Katharina; Frey, Tanja; Rauch, Anita; Afenjar, Alexandra; Mignot, Cyril; Agathe, Jean-Madeleine de Sainte; Hollander, Nicolette den; Hilhorst-Hofstee, Yvonne; Koene, Saskia; Santen, Gijs; Bijlsma, Emilia K; Berger, Sara; Mehta, Lakshmi; Stoeva, Radka; Houdayer, Clara; Gueguen, Paul; Faust, Helene; Specht, Sabine; Klabunde-Cherwon, Annick; Khelifa, Melik Malek; Bergmann, Anke; Saunders, Carol; Krygier, Magdalena; Carrasco, Diana; Metcalfe, Kay; Sanders, Stephan J.; Zhang, David Y.; Judy, Renae; Nijim, Wes; Exposito-Alonso, David; Deng, Christine X.; Kim, Jusung; Gecz, Jozef; Romano, Corrado; Skinner, Cindy; Lichty, Angie; Linebaugh, Ellen; Skinner, Steven A.; Chahrour, Maria; Wang, Tianyun; Xia, Kun; Guo, Hui; Van Daele, Sien; Van Goethem, Gert; Fagerberg, Christina; Graakjaer, Jesper; Anders, Susanne; Fink, Heike; Isum, Ward D.; Grange, Dorothy K.; Strong, Alanna; Zwijnenburg, Petra; Towne, Meghan; Feichtinger, René G.; Morrison, Jennifer; Dagli, Aditi; Levy, Jonathan; Capri, Yline; Spillman, Rebecca C.; Hart, Sarah; Shashi, Vandana; Keren, Boris; Kleefstra, Tjitske; Pfundt, Rolph; Gilissen, Christian; Eichler, Evan E.; Brugger, Melanie; Zech, Michael; Chung, Wendy K.; Fasolino, Maria; Dow, Holly C.; Rader, Daniel J.; Brodkin, Edward S.; Bucan, Maja; Marsh, Eric D.; Dias, Caroline; and Fajgenbaum, David C., "Characterization of the Genotypic and Phenotypic Spectrum of TCF7l2-Related Neurodevelopmental Disorder (TRND)" (2026). SKMC Student Presentations and Publications. Paper 93.
https://jdc.jefferson.edu/skmcstudentworks/93
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Supplemental Table S1-S6.
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Language
English
Comments
This article is the author's final published version in Genetics in Medicine, Volume 28, Issue 10, Article Number 102642.
The published version is available at https://doi.org/10.1016/j.gim.2026.102642. Copyright © 2026 The Authors.