Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome)

Am J Hum Genet. 2007 May;80(5):994-1001. doi: 10.1086/515583. Epub 2007 Mar 23.


Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by mental retardation, wide mouth, and intermittent hyperventilation. By molecular karyotyping with GeneChip Human Mapping 100K SNP arrays, we detected a 1.2-Mb deletion on 18q21.2 in one patient. Sequencing of the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with significant phenotypic overlap revealed heterozygous stop, splice, and missense mutations in five further patients with severe mental retardation and remarkable facial resemblance. Thus, we establish the Pitt-Hopkins syndrome as a distinct but probably heterogeneous entity caused by autosomal dominant de novo mutations in TCF4. Because of its phenotypic overlap, Pitt-Hopkins syndrome evolves as an important differential diagnosis to Angelman and Rett syndromes. Both null and missense mutations impaired the interaction of TCF4 with ASCL1 from the PHOX-RET pathway in transactivating an E box-containing reporter construct; therefore, hyperventilation and Hirschsprung disease in patients with Pitt-Hopkins syndrome might be explained by altered development of noradrenergic derivatives.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cell Line
  • Child
  • Chromosome Deletion
  • Chromosomes, Human, Pair 18 / genetics
  • DNA-Binding Proteins
  • Face / abnormalities
  • Female
  • Genes, Dominant
  • Haplotypes
  • Humans
  • Hyperventilation / complications*
  • Hyperventilation / genetics*
  • In Situ Hybridization, Fluorescence
  • Intellectual Disability / complications*
  • Intellectual Disability / genetics*
  • Male
  • Mutation*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Syndrome
  • TCF Transcription Factors / genetics*
  • Transcription Factor 4
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors
  • Transfection


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • TCF Transcription Factors
  • TCF4 protein, human
  • TCF7L2 protein, human
  • Transcription Factor 4
  • Transcription Factor 7-Like 2 Protein
  • Transcription Factors

Associated data

  • RefSeq/NM_003199
  • RefSeq/NT_025028