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, splicesite mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the PittHopkins 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 PittHopkins 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. itt-Hopkins syndrome (PTHS, OMIM 610954) was first described in 1978 1 in two individuals and is characterized by specific dysmorphic features (deep-set eyes, broad-beaked nose, wide mouth with bow-shaped upper lip, and widely spaced teeth), childhood-onset hyperventilation episodes, childhood-onset seizures, microcephaly, and severe psychomotor retardation with a happy disposition. 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. Further screening of individuals with PTHS or phenotypic overlap with PTHS found individuals with de novo missense and nonsense mutations in TCF4. 3,5 Subsequently, more individuals have been published with disruptions, deletions, and mutations in TCF4, most with typical PTHS features. 4,6 -10 TCF4 is a transcription factor that belongs to the class I basic helix-loop-helix (bHLH) protein family, also known as the "E-protein" family. These proteins form homo-and heterodimers with other heli...

Development, cognition, and behaviour in Pitt–Hopkins syndrome

“…Behaviour will also be influenced by interactions within social and learning environments and by reactions from that environment to the individual's tempera- [6][7][8][9][10][11]13,14,[30][31][32][33][34][35] Published cases with proven TCF4 mutations [6][7][8][9][10][11]13,14,[30][31][32][33][34][35] Present study ment, external features, and neuropsychological deficits. Studying phenotypes of rare and ultra-rare genetic syndromes associated with severe intellectual disability has made it clear that, although individual outcomes may arise from genetic differences, the expression of genes affecting structure, development and function of the brain is also influenced by the interplay between genes, learning, and social context, and too much emphasis on biological determinants should be avoided.…”

Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients

“…In their genome scan metaanalysis of linkage studies on schizophrenia, Lewis et al [13] found the 18q21.1-qter 'bin' ranked around fifteenth in the genome. The TCF4 gene is involved in normal brain development [14] and has been associated with the Pitt-Hopkins syndrome, a severe encephalopathy with autonomic dysfunctions like intermittent hyperventilation [15][16][17][18] . Recently, Kalscheuer et al [19] reported a de novo translocation disrupting exon 4 of TCF4 in a girl with mental retardation, thus suggesting that there are also milder phenotypic expressions of TCF4 variability compared to the Pitt-Hopkins syndrome.…”

Impact of TCF4 on the genetics of schizophrenia

“…In this study, an interaction of TCF4 and MATH1, a proneural protein, on different neural progenitor populations was investigated and disrupted pontine nucleus development was found in TCF4 knock out mice. Second, several studies showed that TCF4 haploinsufficiency contributes to severe neurodevelopmental disorders such as the Pitt-Hopkins syndrome [1,4,9,33,40]. This autosomal dominant encephalopathy is characterized by severe mental retardation, microcephaly, disrupted motor development, and hyperventilation, as described above [25].…”

“…Pitt-Hopkins syndrome was described in 1978 as a syndrome of mental retardation, microcephaly, facial dysmorphisms, and intermittent hyperventilation [25]. Seizures also frequently occur in the syndrome [33]. In 2008, it was shown that a mutation of TCF4 may also cause mental retardation without the associated features of Pitt-Hopkins syndrome, i.e.…”