Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.
Genet Med
; 11(11): 797-805, 2009 Nov.
Article
in En
| MEDLINE
| ID: mdl-19938247
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Seizures
/
Transcription Factors
/
Mutation, Missense
/
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
/
Intellectual Disability
Type of study:
Prognostic_studies
Limits:
Child
/
Female
/
Humans
/
Male
Language:
En
Journal:
Genet Med
Journal subject:
GENETICA MEDICA
Year:
2009
Document type:
Article
Affiliation country:
Estados Unidos