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

Mono-allelic loss-of-function TCF7L2 variants, effector of the Wnt/β-catenin pathway

TCF7L2, a Wnt/β-catenin transcription factor, was linked in 2021 to a syndromic phenotype in 11 patients. The authors characterize an international cohort of 76 patients with pLOF TCF7L2 variants and neurodevelopmental features (TRND) plus an independent cohort of 11 adults from the PennMedicine BioBank. Speech delay (95.3%), craniofacial dysmorphism, ophthalmologic conditions, autism and orthopedic abnormalities predominate, with no clustering by variant type or locus. A nominally significant association with type 2 diabetes with renal manifestations was detected in adults.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The most comprehensive characterization to date of an emerging NDD, useful for counseling and follow-up (a Simons Searchlight natural-history study is open). The lack of genotype-phenotype correlation simplifies interpretation but limits stratification. The target is already captured by WES/WGS: the challenge is recognizing this presentation when annotating pLOF TCF7L2 variants.

Analysis by Dr Thibaut Benquey