Authors
Sally Nijim, Mimi Kim, Melissa Denish, Michael V Gonzalez, Joseph Zinski, Claudine Rieubland, Dominique Braun, Elsebet Ostergaard, Amelle Shillington, Laurence Faivre, Julien Maraval, Aurore Garde, Christophe Philippe, Fréderic Tran-Mau-Them, Amy Crunk, UCI GREGoR Site, Megan Hawley, Bert Callewaert, Maria Iascone, Anna Cereda, Cecilia Daolio, Tova Hershkovitz, Jean-Marc Good, Katharina Steindl, Tanja Frey, Anita Rauch, Alexandra Afenjar, Cyril Mignot, Jean-Madeleine de Sainte Agathe, Nicolette den Hollander, Yvonne Hilhorst-Hofstee, Saskia Koene, Gijs Santen, Emilia K Bijlsma, Sara Berger, Lakshmi Mehta, Radka Stoeva, Clara Houdayer, Paul Gueguen, Helene Faust, Sabine Specht, Annick Klabunde-Cherwon, Melik Malek Khelifa, Anke Bergmann, Carol Saunders, Magdalena Krygier, Diana Carrasco, Kay Metcalfe, Stephan J Sanders, David Y Zhang, Renae Judy, Wes Nijim, David Exposito-Alonso, Christine X Deng, Jusung Kim, Jozef Gecz, Corrado Romano, Cindy Skinner, Angie Lichty, Ellen Linebaugh, Steven A Skinner, Maria Chahrour, Tianyun Wang, Kun Xia, Hui Guo, Sien Van Daele, Gert Van Goethem, Christina Fagerberg, Jesper Graakjaer, Susanne Anders, Heike Fink, D Isum Ward, Dorothy K Grange, Alanna Strong, Petra Zwijnenburg, Meghan Towne, René G Feichtinger, Jennifer Morrison, Aditi Dagli, Jonathan Levy, Yline Capri, Rebecca C Spillman, Sarah Hart, Vandana Shashi, Boris Keren, Tjitske Kleefstra, Rolph Pfundt, Christian Gilissen, Evan E Eichler, Melanie Brugger, Michael Zech, Wendy K Chung, Maria Fasolino, Holly C Dow, Daniel J Rader, Edward S Brodkin, Maja Bucan, Eric D Marsh, Caroline Dias, David C Fajgenbaum
Published in
Genetics in medicine : official journal of the American College of Medical Genetics. Pages 102642. Jul 07, 2026. Epub Jul 07, 2026.
Abstract
TCF7L2 (OMIM:602228; HGNC:11641) is a transcription factor and critical effector of the Wnt/β-Catenin pathway. In 2021, 11 pediatric patients with mono-allelic 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 (TRND) - is urgently needed.
We leveraged multiple methods (GeneMatcher, DECIPHER, literature review, 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 60,000+ PennMedicine BioBank (PMBB) patients.
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 most commonly observed. Phenotypic differences did not cluster by variant type or genomic locus. Among PMBB patients, an association of nominal significance with type 2 diabetes with renal manifestations (OR = 5.8; p-value = 0.03) was detected, warranting further investigation.
This represents the most comprehensive characterization to date of TRND, a novel neurodevelopmental disorder, defining its genotypic and phenotypic spectrum. We opened a Simons Searchlight natural history study (https://www.simonssearchlight.org/research/what-we-study/tcf7l2/) to enhance understanding of this condition.
PMID:
42417140
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.
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