Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations

Jill A. Rosenfeld, Kathleen Leppig, Blake C. Ballif, Heidi Thiese, Christine Erdie-Lalena, Erwati Bawle, Sujatha Sastry, J. Edward Spence, Anne Bandholz, Urvashi Surti, Jonathan Zonana, Kory Keller, Wendy Meschino, Bassem A. Bejjani, Beth S. Torchia, Lisa G. Shaffer

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


PURPOSE: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splice-site mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the Pitt-Hopkins syndrome phenotype is independent of mutation or deletion type. METHODS: We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. RESULTS: We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with Pitt-Hopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. CONCLUSIONS: On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations.

Original languageEnglish (US)
Pages (from-to)797-805
Number of pages9
JournalGenetics in Medicine
Issue number11
StatePublished - Nov 2009


  • Array CGH
  • Deletion
  • Genotype-phenotype
  • Pitt-Hopkins syndrome
  • Seizures
  • TCF4

ASJC Scopus subject areas

  • Genetics(clinical)


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