Document Type

Article

Publication Date

10-2026

Identifier

DOI: 10.1016/j.gim.2026.102642; PMCID: PMC13693294

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.

Journal Title

Genetics in medicine : official journal of the American College of Medical Genetics

Volume

28

Issue

10

First Page

102642

Last Page

102642

MeSH Keywords

Humans; Transcription Factor 7-Like 2 Protein; Neurodevelopmental Disorders; Phenotype; Female; Genotype; Child; Male; Child, Preschool; Adult; Adolescent; Retrospective Studies; Loss of Function Mutation

PubMed ID

42417140

Keywords

Neurodevelopmental syndrome; Speech delay; TCF7L2; TCF7L2-related neurodevelopmental disorder (TRND)

Comments

Grants and funding

This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://www.gimjournal.org/article/S1098-3600(26)00960-3/fulltext

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