Disruption and deletion of the proximal part of TCF4 are associated with mild intellectual disability: About three new patients

Eur J Med Genet. 2022 Apr;65(4):104458. doi: 10.1016/j.ejmg.2022.104458. Epub 2022 Feb 18.


TCF4 gene (18q21.1) encodes for a transcription factor with multiple isoforms playing a critical role during neurodevelopment. Molecular alterations of this gene are associated with Pitt-Hopkins syndrome, a severe condition characterized by intellectual disability, specific facial features and autonomic nervous system dysfunction. We report here three patients presenting with structural variations of the proximal part of TCF4 associated with a mild phenotype. The first patient is a six-years-old girl carrier of a pericentric inversion of chromosome 18, 46,XX,inv(18)(p11.2q21.1). Whole genome sequencing (WGS) characterized the breakpoint at the base-pair level at chr18:1262334_1262336 and chr18:53254747_53254751 (hg19). This latter breakpoint disrupted the proximal promotor region of TCF4 in the first intron of the gene. The second and third patients are a son and his mother, carrier of a 46 kb deletion characterized by high-resolution chromosomal micro-array and WGS (chr:18:53243454_53287927, hg19) encompassing the first three exon of TCF4 gene and including the proximal promotor region. Expression studies on blood lymphocytes in these patients showed a marked decrease of mRNA level for long isoforms of TCF4 and an increased level for shorter isoforms. The patients described here, together with previously reported patients with proximal structural alterations of TCF4, help to delineate a phenotype of mild ID with non-specific facial dysmorphism without characteristic features of PTHS. It also suggests a gradient of phenotypic severity inversely correlated with the number of intact TCF4 promotor regions, with expression of short isoforms compensating in part the loss of longer isoforms.

Keywords: Intellectual disability; Next generation sequencing; Pitt hopkins syndrome; TCF4.

MeSH terms

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Facies
  • Humans
  • Hyperventilation / genetics
  • Intellectual Disability* / genetics
  • Transcription Factor 4 / genetics
  • Transcription Factor 4 / metabolism


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • TCF4 protein, human
  • Transcription Factor 4