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Background TCF7L2 is a transcription factor and critical effector of the Wnt/β-catenin pathway, with pleiotropic roles across human biology and disease. Intronic SNPs in TCF7L2 have been linked to increased risk for type 2 diabetes, colon cancer, schizophrenia, and autism spectrum disorder (ASD). In 2021, a case series of pediatric patients with mono-allelic predicted loss-of-function (pLOF) variants in TCF7L2 were described as having similar features, including developmental delays and variable myopia, autism, and ADHD, among other features. Defining the genetic and phenotypic spectrum and natural history of this patient population – herein referred to as TCF7L2-related neurodevelopmental disorder (TRND) – is urgently required.
Methods We identified an international cohort of 76 patients with neurodevelopmental features and pLOF TCF7L2 variants from 2022-2024 using multiple recruitment strategies (GeneMatcher, DECIPHER, and clinician outreach following literature review and screening of public/private repositories). We phenotypically characterized these patients with a clinician-facing survey, extracting 81 enriched Human Phenotype Ontology (HPO) terms and 11 broader categories of phenotypic features. In parallel, we interrogated ~60,000 adult PennMedicine BioBank (PMBB) patients to identify a distinct group of 11 patients with pLOF TCF7L2 variants.
Results We identified 76 patients with truncating (n=10), out-of-frame indel (n=18), missense (n=33), splice site (n=10), in-frame indel (n=1), and CNV (n=4) variants in TCF7L2 meeting clinical and variant-specific criteria. Speech delay (95%), craniofacial dysmorphisms (73%), ophthalmologic conditions (65%), ASD (62%), and orthopedic abnormalities (53%) were most commonly observed, comprising the defining syndromic features of TRND. Ear morphology abnormalities (22%), hypertelorism (21%), down-slanted palpebral fissures (19%), and frontal bossing (16%) were the most frequent craniofacial features, co-occurring in a subset of patients. Phenotypic differences did not grossly cluster by variant type or genomic locus. Among PMBB patients, compared to an age/sex-matched PMBB control group, there was a nominal increased risk for type 2 diabetes with renal manifestations (nominal P=0.03), inviting neurodevelopmental follow-up to correlate with our cohort of pediatric patients and further functional investigation.
Conclusion We have assembled the most comprehensive characterization of the largest panel of patients to date with TRND, a new neurodevelopmental syndrome with hallmark speech, ophthalmologic, and orthopedic abnormalities. We launched a Simons Searchlight registry that is now accepting patients and the TRND Network, a coalition of TRND patients, researchers, physicians, and families. Alongside international patient recruitment, we plan to leverage this study tool to build a foundation for longitudinal investigation and generate clinical guidelines to improve patient care.
