ArticleGenetics in medicine : official journal of the American College of Medical Genetics2026
Characterization of the genotypic and phenotypic spectrum of TCF7L2-related neurodevelopmental disorder (TRND).
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100 authors.
Sally NijimDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Mimi KimDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Melissa DenishDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
Michael V GonzalezDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Joseph ZinskiDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Claudine RieublandDepartment of Medical Genetics, Central Institute of the Hospitals, Hospital of the Valais, Sion, Valais, Switzerland.
Dominique BraunDepartment of Human Genetics, Inselspital Bern, University of Bern, Bern, Switzerland.
Elsebet OstergaardDepartment of Genetics, Copenhagen University Hospital Rigshospitalet Blegdamsvej, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Amelle ShillingtonDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Division of Human Genetics, Cincinnati, OH.
Laurence FaivreCentre de génétique, Centre de référence Anomalies du Développement et Syndromes Malformatifs, Université Bourgogne Europe, CHU Dijon Bourgogne, Inserm, CTM UMR1231, équipe GAD, FHU TRANSLAD, Dijon, France.
Julien MaravalCentre de référence GénoPsy, Université Bourgogne Europe, CHU Dijon Bourgogne, Inserm, CTM UMR1231, équipe GAD, FHU TRANSLAD, Dijon, France.
Aurore GardeCentre de génétique, Centre de référence Déficiences Intellectuelles de Causes Rares, Université Bourgogne Europe, CHU Dijon Bourgogne, Inserm, CTM UMR1231, équipe GAD, FHU TRANSLAD, Dijon, France.
Christophe PhilippeService de Génomique Médicale, Université Bourgogne Europe, CHU Dijon Bourgogne, Inserm, CTM UMR1231, équipe GAD, FHU TRANSLAD, Dijon, France.
Fréderic Tran-Mau-ThemService de Génomique Médicale, Université Bourgogne Europe, CHU Dijon Bourgogne, Inserm, CTM UMR1231, équipe GAD, FHU TRANSLAD, Dijon, France.
Amy CrunkGeneDx, LLC., Gaithersburg, MD.
UCI GREGoR Site
Megan HawleyLabcorp Genetics Inc, Burlington, NC.
Bert CallewaertCenter for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Maria IasconeLaboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.
Anna CeredaDepartment of Pediatrics Papa Giovanni XXIII Hospital, Bergamo, Italy.
Cecilia DaolioDepartment of Pediatrics Papa Giovanni XXIII Hospital, Bergamo, Italy.
Tova HershkovitzInstitute of Human Genetics, Galilee Medical Center, Nahariya, Israel.
Jean-Marc GoodDivision of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Katharina SteindlInstitut für Medizinische Genetik, Universität Zürich, Schlieren, Switzerland.
Tanja FreyInstitut für Medizinische Genetik, Universität Zürich, Schlieren, Switzerland.
Anita RauchInstitut für Medizinische Genetik, Universität Zürich, Schlieren, Switzerland.
Alexandra AfenjarDépartement de Génétique, GH Pitié-Salpêtrière et Hôpital Trousseau, & Centre de Référence Déficiences Intellectuelles de Causes Rares, APHP.Sorbonne Université, Paris, France.
Cyril MignotDépartement de Génétique, GH Pitié-Salpêtrière et Hôpital Trousseau, & Centre de Référence Déficiences Intellectuelles de Causes Rares, APHP.Sorbonne Université, Paris, France.
Jean-Madeleine de Sainte AgatheDépartement de Génétique, GH Pitié-Salpêtrière et Hôpital Trousseau, & Centre de Référence Déficiences Intellectuelles de Causes Rares, APHP.Sorbonne Université, Paris, France; Laboratoire de Biologie Médicale Seqoia, Paris, France.
Nicolette den HollanderLeiden University Medical Center, Leiden, The Netherlands.
Yvonne Hilhorst-HofsteeLeiden University Medical Center, Leiden, The Netherlands.
Saskia KoeneLeiden University Medical Center, Leiden, The Netherlands.
Gijs SantenLeiden University Medical Center, Leiden, The Netherlands.
Emilia K BijlsmaLeiden University Medical Center, Leiden, The Netherlands.
Sara BergerDivision of Clinical Genetics, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.
Lakshmi MehtaDivision of Clinical Genetics, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY.
Radka StoevaDepartment of Medical Genetics, Le Mans Hospital, Le Mans, France.
Clara HoudayerService de Génétique Médicale, CHU d'Angers, Angers, France.
Paul GueguenService de Génétique, CHRU de Tours, Tours, France; INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253, Université de Tours, Tours, France.
Helene FaustInstitute of Human Genetics, University Hospital Leipzig, Leipzig, Germany; Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany.
Sabine SpechtDivision of Pediatric Neurology and Metabolic Medicine, Department I, Center for Pediatric and Adolescent Medicine, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
Annick Klabunde-CherwonDivision of Pediatric Epileptology, Department I, Center for Pediatric and Adolescent Medicine, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
Melik Malek KhelifaDepartment of Human Genetics, Hannover Medical School, Hannover, Germany.
Anke BergmannInstitute of Human Genetics, Hannover Medical School, Hannover, Germany; Clinical Genetics and Genomic Medicine, University Hospital Würzburg, Würzburg, Germany.
Carol SaundersDepartment of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO; School of Medicine, University of Missouri Kansas City, Kansas City, MO.
Magdalena KrygierDepartment of Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland.
Diana CarrascoClinical Genetics, Cook Children's Medical Center, Fort Worth, TX.
Kay MetcalfeManchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, England, United Kingdom.
Stephan J SandersDepartment of Pediatrics, Institute of Developmental and Regenerative Medicine, University of Oxford, Oxford, England, United Kingdom; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA.
David Y ZhangUniversity of Pennsylvania, Philadelphia, PA.
Renae JudyUniversity of Pennsylvania, Philadelphia, PA.
Wes NijimDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; The University of Illinois at Chicago, Chicago, IL.
David Exposito-AlonsoDivision of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA.
Christine X DengDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Drexel University School of Medicine, Philadelphia, PA.
Jusung KimDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Jozef GeczAdelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
Corrado RomanoDepartment of Biomedical and Biotechnological Sciences, Section of Clinical Biochemistry and Medical Genetics, University of Catania, Catania, Italy; Research Unit of Rare Diseases and Neurodevelopmental Disorders-IRCCS, Oasi Research Institute, Troina, Italy.
Cindy SkinnerJC Self Research Institute, Greenwood, SC.
Angie LichtyJC Self Research Institute, Greenwood, SC.
Ellen LinebaughJC Self Research Institute, Greenwood, SC.
Steven A SkinnerJC Self Research Institute, Greenwood, SC.
Maria ChahrourUniversity of Texas Southwestern Medical Center, Dallas, TX.
Tianyun WangDepartment of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China; Neuroscience Research Institute, Peking University and Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Beijing, China; Autism Research Center, Peking University Health Science Center, Beijing, China.
Kun XiaHunan Key Laboratory of Medical Genetics and MOE Key Laboratory of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China.
Hui GuoHunan Key Laboratory of Medical Genetics and MOE Key Laboratory of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China.
Sien Van DaeleDepartment of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
Gert Van GoethemUniversity of Antwerp, Department of Neurology, Antwerpen, Belgium.
Christina FagerbergHospital of Lillebaelt, Vejle Hospital, Clinical Genetics, Vejle, Denmark.
Jesper GraakjaerHospital of Lillebaelt, Vejle Hospital, Clinical Genetics, Vejle, Denmark.
Susanne AndersMVZ Mitteldeutscher Praxisverbund Humangenetik, Dresden, Germany.
Heike FinkMVZ Mitteldeutscher Praxisverbund Humangenetik, Dresden, Germany.
D Isum WardSanford Children's Specialty Clinic, Sioux Falls, SD.
Dorothy K GrangeWashington University School of Medicine, St Louis, MO.
Alanna StrongDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
Petra ZwijnenburgAmsterdam University Medical Center, Amsterdam, The Netherlands.
Meghan TowneAmbry Genetics Corporation, Aliso Viejo, CA.
René G FeichtingerUniversity Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
Jennifer MorrisonArnold Palmer Hospital for Children, Orlando, FL.
Aditi DagliArnold Palmer Hospital for Children, Orlando, FL.
Jonathan LevyHôpital Universitaire Robert-Debré, AP-HP. Nord - Université de Paris, Paris, France.
Yline CapriHôpital Universitaire Robert-Debré, AP-HP. Nord - Université de Paris, Paris, France.
Rebecca C SpillmanDuke University Medical Center, Durham, NC.
Sarah HartDuke University Medical Center, Durham, NC.
Vandana ShashiDuke University Medical Center, Durham, NC.
Boris KerenHôpital de la Pitié-Salpêtrière, AP-HP Sorbonne Université, Paris, France.
Tjitske KleefstraHôpital de la Pitié-Salpêtrière, AP-HP Sorbonne Université, Paris, France.
Rolph PfundtHôpital de la Pitié-Salpêtrière, AP-HP Sorbonne Université, Paris, France.
Christian GilissenHôpital de la Pitié-Salpêtrière, AP-HP Sorbonne Université, Paris, France.
Evan E EichlerDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA; Howard Hughes Medical Institute, University of Washington, Seattle, WA.
Melanie BruggerInstitute of Human Genetics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Michael ZechInstitute of Human Genetics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Institute of Neurogenomics, Helmholtz Munich, Munich, Germany; Institute for Advanced Study, Technical University of Munich, Munich, Germany.
Wendy K ChungBoston Children's Hospital, Harvard Medical School, Boston, MA.
Maria FasolinoAutism Spectrum Program of Excellence, University of Pennsylvania, Philadelphia, PA.
Holly C DowAutism Spectrum Program of Excellence, University of Pennsylvania, Philadelphia, PA.
Daniel J RaderAutism Spectrum Program of Excellence, University of Pennsylvania, Philadelphia, PA.
Edward S BrodkinAutism Spectrum Program of Excellence, University of Pennsylvania, Philadelphia, PA.
Maja BucanAutism Spectrum Program of Excellence, University of Pennsylvania, Philadelphia, PA.
Eric D MarshChildren's Hospital of Philadelphia, Philadelphia, PA.
Caroline DiasUniversity of Colorado Anschutz Medical Campus, Aurora, CO.
David C FajgenbaumDivision of Translational Medicine & Human Genetics, Center for Cytokine Storm Treatment & Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address: davidfa@pennmedicine.upenn.edu.
Funding
Pediatric Mendelian Genomics Research CenterU01HG011745 · NHGRI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Eric J. Vilain · 2021 to 2026
$13.3MSporadic Mutations and Autism Spectrum DisordersR01MH101221 · NIMH · UNIVERSITY OF WASHINGTON · PI EICHLER, EVAN · 2013 to 2025
$9.2M4/4 - The Autism Sequencing Consortium: Discovering autism risk genes and how they impact core features of the disorderR01MH129751 · NIMH · UNIVERSITY OF OXFORD · PI Stephan Sanders · 2022 to 2026
$1.4MHoward Hughes Medical InstituteNHGRI NIH HHS U01 HG011745NIMH NIH HHS R01 MH101221NIMH NIH HHS R01 MH129751
Abstract
purposeTCF7L2 (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.
methodsWe 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.
resultsAmong 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.
conclusionThis 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.
Indexed as
Neurodevelopmental syndromeSpeech delayTCF7L2TCF7L2-related neurodevelopmental disorder (TRND)
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