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Characterization of the genotypic and phenotypic spectrum of TCF7L2-related neurodevelopmental disorder (TRND)
Journal article   Open access   Peer reviewed

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

Sally Nijim, Mimi Kim, Melissa Denish, Michael V Gonzalez, Joseph Zinski, Claudine Rieubland, Dominique Braun, Elsebet Ostergaard, Amelle Shillington, Laurence Faivre, …
Genetics in medicine, 102642
07 Jul 2026
DOI: https://doi.org/10.1016/j.gim.2026.102642
PMID: 42417140
url
https://doi.org/10.1016/j.gim.2026.102642View
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Abstract

speech delay TCF7L2 TCF7L2-related neurodevelopmental disorder (TRND) neurodevelopmental syndrome
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.

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