Loss-of-function variants of the TCF4 gene cause the rare intellectual disability known as Pitt-Hopkins syndrome (PHS). PHS is characterized by specific dysmorphic facial features, periodic hyperventilation, early-onset seizures, microcephaly, and severe developmental delay. Sequence variants causing a loss of function include nonsense, frameshift, splice, and missense variants, and deletions affecting the TCF4 gene have also been reported. Phenotype is generally independent of variant type. TCF4 is a transcription factor believed to regulate central nervous system development. Mouse models of TCF4 haploinsufficiency support the neurological phenotypes of PHS (Zhuang 1996, Flora 2007, Kennedy 2016, Thaxton 2018). In summary, TCF4 is definitively associated with PHS in an autosomal dominant manner. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More information can be found at GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK100240/)
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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