Various haploinsufficiency mechanisms in Pitt-Hopkins syndrome

Eur J Med Genet. 2020 Dec;63(12):104088. doi: 10.1016/j.ejmg.2020.104088. Epub 2020 Oct 15.

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.

Keywords: Functional analysis; Haploinsufficiency; PTHS; Pitt-hopkins syndrome; Splicing; TCF4.

Publication types

  • Case Reports

MeSH terms

  • Child, Preschool
  • Chromosome Deletion
  • Chromosomes, Human, Pair 18 / genetics
  • Codon, Nonsense
  • Facies
  • Female
  • HEK293 Cells
  • Haploinsufficiency*
  • Humans
  • Hyperventilation / genetics*
  • Hyperventilation / pathology
  • Infant
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Transcription Factor 4 / genetics*
  • Transcription Factor 4 / metabolism

Substances

  • Codon, Nonsense
  • TCF4 protein, human
  • Transcription Factor 4

Supplementary concepts

  • Pitt-Hopkins syndrome