Disruption of the <i>TCF4</i> gene in a girl with mental retardation but without the classical Pitt–Hopkins syndrome

Kalscheuer, Vera M.; Feenstra, Ilse; Ravenswaaij-Arts, Conny M. A. van; Smeets, Dominique; Menzel, Corinna; Ullmann, Reinhard; Musante, Luciana; Ropers, Hans-Hilge r

doi:10.1002/ajmg.a.32419

Cited by 71 publications

(84 citation statements)

References 20 publications

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“…Previous studies have provided clues that TCF4 may be a candidate gene for intelligence. For example, it was found that haploinsufficiency of TCF4 may induce PittHopkins syndrome that is characterized by severe mental retardation (Flora et al, 2007), and that mutations in the TCF4 gene are linked to other types of mental retardation, such as Pitt-Hopkins and Angelman syndromes (Kalscheuer et al, 2008;Takano et al, 2010). Quednow et al (2011) also found a moderate effect of rs9960767 on years of education in patients (although not in controls).…”

Section: Discussionmentioning

confidence: 99%

Associations between TCF4 Gene Polymorphism and Cognitive Functions in Schizophrenia Patients and Healthy Controls

Zhu

Liu

et al. 2012

Neuropsychopharmacol

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The SNP rs2958182 was reported to be significantly associated with schizophrenia (SCZ) in Han Chinese. This study examined this SNP's associations with cognitive functions in 580 SCZ patients and 498 controls. Cognitive functions were assessed using the Wechsler Adult Intelligence Scale-Revised (WAIS-RC), the Attention Network Task (ANT), the Stroop task, the dot pattern expectancy (DPX), task and the N-back working memory task. Results showed significant or marginally significant interaction effects between genotype and diagnosis status on IQ (P ¼ 0.011) and attention-related tasks (ie, the forward digit span of WAIS-RC, P ¼ 0.005; the ANT conflict effect; P ¼ 0.020, and its ratios over mean reaction time (RT), P ¼ 0.036; the Stroop conflict effect, P ¼ 0.032, and its ratios over mean RT, P ¼ 0.062; and the DPX task's error rate under the BX condition, Po0.001, and the error rate of BX minus the error rate of AY (BX À AY), P ¼ 0.002). There were no such interaction effects on the measures of working memory (all P-values 40.05). Further analysis of the significant genotype-by-diagnosis interactions showed that the risk (T) allele was associated with better performance on cognitive tasks in patients but with worse performance in controls. These results seem to indicate that the association between this SNP and selected cognitive functions may be of an inverted U-shaped pattern. Future research is needed to replicate these results and to explore the biochemical mechanisms behind this association.

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Section: Discussionmentioning

confidence: 99%

Associations between TCF4 Gene Polymorphism and Cognitive Functions in Schizophrenia Patients and Healthy Controls

Zhu

Liu

et al. 2012

Neuropsychopharmacol

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“…c Other mutations include a frameshift mutation creating a longer protein and a balanced translocation disrupting TCF4 but with a fusion transcript. 4,6 Phenotypic features reported by de Pontual et al 10 and some phenotypic features reported by Giurgea et al 8 were not attributed to specific patients. d Based on a Fisher exact two-tailed test, comparing missense mutations to the subtotal of those likely resulting in haploinsufficiency (the first two columns).…”

Section: Patient Ascertainmentmentioning

confidence: 92%

“…[2][3][4][5][6][7][8][9][10] A summary of the clinical features of these individuals, categorized by the type of mutation or deletion, is listed in Table 1. Figure 2 shows the locations of all reported mutations in TCF4.…”

Section: Review Of Cases With Tcf4 Mutations or Deletions In The Litementioning

confidence: 99%

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

Rosenfeld

Leppig

Ballif

et al. 2009

Genetics in Medicine

101

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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...

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“…A translocation that contains exon four of the TCF4 gene was also found to be associated with milder mental retardation when compared with patients with Pitt-Hopkins syndrome (20).…”

Section: Genementioning

confidence: 97%

Transcription factor 4 gene rs9960767 polymorphism in bipolar disorder

2016

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Abstract. The transcription factor 4 (TCF4) gene encodes a helix-loop-helix transcription factor protein, which initiates neuronal differentiation and is primarily expressed during nervous system development. The aim of the present study is to investigate the association of the TCF4 rs9960767 polymorphism and bipolar disorder, which is highly heritable. DNA isolation was performed on 95 patients with bipolar disorder and 108 healthy control subjects to examine the TCF4 rs9960767 polymorphism. Genotypic and allelic frequencies were determined using the polymerase chain reaction-restriction fragment length polymorphism method designed in our laboratory. Statistical analysis was performed using χ 2 test within the 95% confidence interval. Odds ratios were calculated and Hardy-Weinberg equilibrium (HWE) was verified for all control subjects and patients. The A allele frequency was 95.8% in the patients and 94.4% in the control subjects, and 4.2% in the patients and 5.6% in the control subjects for the C allele. The genotype frequencies of the TCF4 gene rs9960767 variant were as follows: AA, 91.6% and AC, 8

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Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt–Hopkins syndrome

Cited by 71 publications

References 20 publications

Associations between TCF4 Gene Polymorphism and Cognitive Functions in Schizophrenia Patients and Healthy Controls

Associations between TCF4 Gene Polymorphism and Cognitive Functions in Schizophrenia Patients and Healthy Controls

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

Transcription factor 4 gene rs9960767 polymorphism in bipolar disorder

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