Various haploinsufficiency mechanisms in Pitt-Hopkins syndrome.

Various haploinsufficiency mechanisms in Pitt-Hopkins syndrome. Eur J Med Genet. 2020 Oct 15;:104088 Authors: Sparber P, Filatova A, Anisimova I, Markova T, Voinova V, Chuhrova A, Tabakov V, Skoblov M Abstract Pitt-Hopkins syndrome is a rare neurodevelopment disorder caused by haploinsufficiency of the transcription factor 4 (TCF4). The main clinical symptoms of Pitt-Hopkins syndrome are severe development delay, intellectual disability, characteristic facial phenotype and breathing abnormalities, including episodic hyperventilation. Different pathogenic variants can lead to Pitt-Hopkins syndrome. The most common are large deletions at 18q21 encompassing the TCF4 gene and frameshifting/nonsense single nucleotide variants. However, variants in noncoding regions can also lead to Pitt-Hopkins syndrome by disrupting the normal pre-mRNA splicing machinery. Here we describe three patients with Pitt-Hopkins syndrome caused by a large deletion in chromosome 18, a nonsense variant and a novel variant located in intron 11 of TCF4 c.922+5G>A . Using RT-PCR analysis and minigene splicing assay we showed that this intronic variant leads to exon 11 skipping resulting in a formation of a premature stop-codon. To our knowledge, this is the first functional annotation of a splicing variant in Pitt-Hopkins syndrome. PMID: 33069932 [PubMed - as supplied by publisher]
Source: European Journal of Medical Genetics - Category: Genetics & Stem Cells Authors: Tags: Eur J Med Genet Source Type: research