TRND is a genetic disorder that causes developmental delay and intellectual disability, social communication deficits and other behavioral challenges, and may present certain physical characteristics.

Initial studies have hypothesized that variants in the TF7L2 gene are the plausible genetic cause. TCF7L2 encodes a transcription factor and is located on chromosome 10q25.2-q25.3. Transcription factors act as DNA-binding factors that regulate the expression of other genes; that is, they can ultimately control the abundance of specific proteins (encoded by other genes) in specific cells.

TCF7L2 is an important regulator of canonical Wnt signaling, a key molecular pathway involved in various developmental processes. Several research studies have shown that TCF7L2 can play an important role in processes of brain development such as cellular proliferation and myelination. However, how genetic variants in TCF7L2 may impact brain development, cognitive processes, and other behavioral functions remains poorly understood.

Genetic analyses have begun to characterize the spectrum of genetic variants associated with TRND. Most reported cases show de novo mutations, which are genetic variants that are not found in parents and therefore are not inherited–they are only present in the child. An important proportion of genetic variants target the “HMG box domain,” which is the part of the molecule that binds DNA. In addition, there are a few cases in which TCF7L2 mutations have been inherited from parent to child.

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