Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients

Abstract

This study provides further evidence of the mutational and clinical spectrum of PTHS and confirms its important role in the differential diagnosis of severe mental retardation.

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

“…7 All but three of the missense mutations so far described have been in the bHLH region of TCF4. [3][4][5]8 To date, the only genotype-phenotype correlation observed has been limited flexion and an absent flexion crease on the thumb in some patients with deletions.We report seven individuals with TCF4 microdeletions detected by aCGH. We also show a genotype-phenotype analysis of these and all other TCF4 mutations in the literature, which revealed an increased incidence of seizures among individuals with missense mutations.…”

“…It is an autosomal dominant condition caused by haploinsufficiency for TCF4 (transcription factor 4, OMIM 602272) on 18q21.2. [2][3][4] The etiology of PTHS was determined when two groups concurrently screened individuals with PTHS for chromosomal deletions using microarray technology, one with arraybased comparative genomic hybridization (aCGH) 5 and the other with single-nucleotide polymorphism-based molecular karyotyping. 3 Each group described a patient with a de novo deletion involving this gene.…”

“…11,12 Missense, nonsense, frameshift, and splice-site mutations and larger deletions encompassing all or part of TCF4 have been found in patients with PTHS. [3][4][5][7][8][9][10] Whole-gene and large intragenic deletions represent 15% of molecularly confirmed TCF4 alterations in the literature, with the smallest deletion described to date a 0.5-Mb deletion that results in a deletion of the 5Ј half of TCF4. 7 All but three of the missense mutations so far described have been in the bHLH region of TCF4.…”

Association of Transcription Factor 4 (TCF4) variants with schizophrenia and intellectual disability

“…Furthermore, a de novo truncating mutation in TCF4 exon 7 (R157X), again only affecting TCF4-B isoforms, was found in another patient with non-syndromic ID [70]. Although the same mutation has been described in a PTHS patient, these studies demonstrate the variable phenotypes associated with TCF4 mutations [65,70].…”

“…Although epilepsy may be more common in PTHS patients with missense mutations, the disease phenotype seems remarkably similar across the mutational spectrum [24,[64][65][66]. Almost of all the TCF4 mutations that cause PTHS are predicted to disrupt transcripts encoding TCF4-A and TCF4-B.…”