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

Max Planck Institute for Molecular Genetics, Berlin, Germany.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 08/2008; 146A(16):2053-9. DOI: 10.1002/ajmg.a.32419
Source: PubMed


We have characterized a de novo balanced translocation t(18;20)(q21.1;q11.2) in a female patient with mild to moderate mental retardation (MR) and minor facial anomalies. Breakpoint-mapping by fluorescence in situ hybridization indicated that on chromosome 18, the basic helix-loop-helix transcription factor TCF4 gene is disrupted by the breakpoint. TCF4 plays a role in cell fate determination and differentiation. Only recently, mutations in this gene have been shown to result in Pitt-Hopkins syndrome (PHS), defined by severe MR, epilepsy, mild growth retardation, microcephaly, daily bouts of hyperventilation starting in infancy, and distinctive facial features with deep-set eyes, broad nasal bridge, and wide mouth with widely spaced teeth. Breakpoint mapping on the derivative chromosome 20 indicated that here the rearrangement disrupted the chromodomain helicase DNA binding protein 6 (CHD6) gene. To date, there is no indication that CHD6 is involved in disease. Our study indicates that TCF4 gene mutations are not always associated with classical PHS but can give rise to a much milder clinical phenotype. Thus, the possibility exists that more patients with a less severe encephalopathy carry a mutation in this gene.

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    • "Haploinsufficiency of the TCF4 gene may cause syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome/PHS) (Pitt and Hopkins, 1978; Zweier et al., 2007) and the TCF4 mutations were detected in some patients suspected of having Angelman syndrome (Takano et al., 2010). Additionally, the TCF4 gene mutations were also found to be associated with milder cognitive deficits without classical PHS (Kalscheuer et al., 2008). Genome wide association study (GWAS), a power tool for identifying schizophrenia risk loci, has found the TCF4 gene as one of the most consistent and significant susceptibility genes in schizophrenia (Stefansson et al., 2009; Steinberg et al., 2011; Ripke et al., 2011, 2014). "
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    ABSTRACT: Background: Cognitive deficits have been identified as an important core feature of schizophrenia. Single nucleotide polymorphisms in the transcription factor 4 (TCF4) gene have been reported to be involved in the susceptibility to schizophrenia and be significantly related to cognitive deficits of schizophrenia and controls. This study examines whether the TCF4 rs2958182 polymorphism influences cognitive functions in chronic schizophrenia and controls. Methods: The presence of the TCF4 rs2958182 was determined in 976 patients and 420 controls using a case-control design. We assessed all the patients' psychopathology using the Positive and Negative Syndrome Scale (PANSS). Cognition was assessed in 777 patients and 399 controls by using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results: There were marginally significant differences in the TCF4 rs2958182 allelic and genotypic distributions between patients and controls (χ(2) = 3.48, p = 0.062 and χ(2) = 0.036, p = 0.036, respectively). Cognitive test scores were significantly lower in patients than in controls on all scales (all p < 0.001) except for the visuospatial/constructional index (p > 0.05). There were significant genotype effects on delayed memory score (p = 0.013), the RBANS total score (p = 0.028) and language score (p = 0.034). Further analysis showed that the language score significantly differed according to the genotypic groups (A/A+T/A group versus T/T group) (p = 0.007) in patients but not in controls (p > 0.05), and the delayed memory score also significantly differed according to the genotypic groups (A/A+T/A group versus T/T group) (p = 0.021) in controls but not in patients (p > 0.05). Conclusions: This study found that the A allele of the TCF4 rs2958182 polymorphism was the risk allele of schizophrenia, and was associated with lower cognitive performance in language in schizophrenia and delayed memory in controls. In contrast, the T allele of this polymorphism was found to be the schizophrenia risk allele in another study in Han Chinese people.
    Journal of Psychiatric Research 09/2015; 69:95-101. DOI:10.1016/j.jpsychires.2015.07.022 · 3.96 Impact Factor
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    • "Hyperventilation can be followed by apnea, but apnea can also occur independent from hyperventilation.22, 24, 29, 38 However, one very recent report identified a bona fide case of Pitt–Hopkins Syndrome, confirmed by genetic diagnostics, of a 12-year-old boy presenting with psychomotor retardation, recurrent respiratory tract infections and typical dysmorphic features but with absence of hyperventilation or other breathing abnormalities. This case suggests that breathing anomalies will not be universally associated with PTHS. "
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    ABSTRACT: TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt-Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.
    05/2013; 45(5):e21. DOI:10.1038/emm.2013.32
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    • "In the first case, the patient had a de novo t(18; 20)(q21.1;q11.2) which disrupted exon 4 of TCF4 . This did not, however, cause PTHS, but instead a considerably milder clinical phenotype [Kalscheuer et al., 2008]. In another case, a de novo t(14; 18)(q13.1;q22.2) disrupted TCF4 and caused a full PTHS phenotype [Marangi et al., 2011]. "
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    ABSTRACT: Pitt-Hopkins syndrome (PTHS, MIM #610954) is characterized by severe intellectual disability, typical facial features and tendency to epilepsy, panting-and-holding breathing anomaly, stereotypic movements, constipation, and high myopia. Growth is normal or only mildly retarded, but half of the patients have postnatal microcephaly. Remarkably, congenital malformations are practically nonexistent. The cause of PTHS is de novo haploinsufficiency of the TCF4 gene (MIM *602272) at 18q21.2. Altogether 78 PTHS patients with abnormalities of the TCF4 gene have been published since 2007 when the etiology of PTHS was revealed. In addition, 27 patients with 18q deletion encompassing the TCF4 gene but without given PTHS diagnosis have been published, and thus, the number of reported patients with a TCF4 abnormality exceeds 100. The mutational spectrum includes large chromosomal deletions encompassing the whole TCF4 gene, partial gene deletions, frameshift (including premature stop codon), nonsense, splice site, and missense mutations. So far, almost all patients have a private mutation and only 2 recurrent mutations are known. There is no evident genotype-phenotype correlation. No familial cases have been reported. Diagnosis of PTHS is based on the molecular confirmation of the characteristic clinical features. Recently, a Pitt-Hopkins-like phenotype has been assigned to autosomal recessive mutations of the CNTNAP2 gene at 7q33q36 and the NRXN1 gene at 2p16.3.
    Molecular syndromology 04/2012; 2(3-5):171-180. DOI:10.1159/000335287
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