Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum

Hum Mutat. 2012 Jan;33(1):64-72. doi: 10.1002/humu.21639. Epub 2011 Nov 23.


Pitt-Hopkins syndrome (PTHS), characterized by severe intellectual disability and typical facial gestalt, is part of the clinical spectrum of Rett-like syndromes. TCF4, encoding a basic helix-loop-helix (bHLH) transcription factor, was identified as the disease-causing gene with de novo molecular defects. While PTHS appears to be a recognizable clinical entity, it seems to remain underdiagnosed, especially when facial gestalt is less typical. With the aim to facilitate the diagnosis of PTHS and to increase its rate and specificity, we have investigated 33 novel patients and defined a Clinical Diagnosis Score. Analysis of 112 individuals (79 previously reported and 33 novel patients) allowed us to delineate the TCF4 mutational spectrum, with 40% point mutations, 30% small deletions/insertions, and 30% deletions. Most of these were private mutations and generated premature stop codons. Missense mutations were localized in the bHLH domain, which is a mutational hotspot. No obvious difference was observed between patients harboring truncating, missense mutations, or deletions, further supporting TCF4 haploinsufficiency as the molecular mechanism underlying PTHS. In this study, we have summarized the current knowledge of TCF4 molecular pathology, reported all the mutations in the TCF4 database (, and present a novel and comprehensive diagnostic strategy for PTHS.

MeSH terms

  • Adolescent
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 18 / chemistry
  • Chromosomes, Human, Pair 18 / genetics*
  • Databases, Genetic
  • Facies
  • Female
  • Genetic Association Studies
  • Genetic Variation
  • Genotype
  • Haploinsufficiency
  • Haplotypes
  • Humans
  • Hyperventilation / diagnosis*
  • Hyperventilation / genetics
  • Infant
  • Intellectual Disability / diagnosis*
  • Intellectual Disability / genetics
  • Male
  • Mutation, Missense
  • Phenotype
  • Protein Structure, Tertiary
  • Sequence Deletion
  • Sequence Inversion
  • Severity of Illness Index
  • Transcription Factor 4
  • Transcription Factors / genetics*


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

Supplementary concepts

  • Pitt-Hopkins syndrome