TRND results from heterozygous pathogenic variants in TCF7L2, which encodes a transcription factor of the TCF/LEF family. TCF7L2 is a key downstream effector of the canonical Wnt/β-catenin signaling pathway. It binds β-catenin upon pathway activation but can also regulate transcription independently of Wnt signaling. The protein binds DNA through a conserved high-mobility group (HMG) domain.
In the brain, two types of isoforms of TCF7L2 are expressed from alternative promoters. The longer isoforms contain the β-catenin–binding domain, whereas the shorter isoforms lack this region. In individuals with TRND, pathogenic variants occur within exons shared by both sets of isoforms, and therefore affect all brain-expressed transcripts. Identified variants include stop-gain (nonsense), splice-site and missense changes. Missense variants cluster predominantly within the HMG-coding region, consistent with disruption of DNA binding. Stop-gain variants are predicted to produce truncated proteins and result in loss of function.
To date, all reported pathogenic variants have arisen de novo. The disorder follows an autosomal dominant mechanism, with haploinsufficiency representing the primary pathogenic model. Reduced TCF7L2 activity is believed to impair transcriptional programs essential for early and postnatal brain development, leading to the observed neurodevelopmental phenotype. Studies in mice with brain-specific, developmentally timed TCF7L2 knockouts have shown broad dysregulation of genes involved in neurodevelopment and mature brain function, along with measurable behavioral changes.
TCF7L2