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

Abstract

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.

• Authors: 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
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 11 Issue 11 Pg. 797-805 (Nov 2009) ISSN: 1530-0366 [Electronic] United States
• PMID: 19938247 (Publication Type: Journal Article)

Chemical References

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

Topics

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics)
• Child
• Female
• Genotype
• Humans
• Intellectual Disability (genetics, physiopathology)
• Male
• Mutation, Missense
• Phenotype
• Seizures (genetics, physiopathology)
• Sequence Deletion
• Syndrome
• Transcription Factor 4
• Transcription Factors (genetics)