Two percent of patients suspected of having Angelman syndrome have TCF4 mutations

Abstract

The TCF4 gene encodes a basic helix-loop-helix (bHLH) transcription factor which belongs to the family of E-proteins. E-proteins form homo- and heterodimers with other members of the HLH family and bind to the common DNA sequence called E-box. Haploinsufficiency of the TCF4 gene has been found to be associated with the Pitt-Hopkins syndrome (PTHS). PTHS is characterized by severe mental retardation, a wide mouth plus other distinctive facial features (fleshy lips, beaked nose, broad nasal bridge) and breathing abnormalities. Because of some phenotypical overlap with Angelman syndrome (AS), it has been suggested that PTHS be considered in its differential diagnosis. To explore this possibility, we screened 86 patients who were suspected of having AS. All the patients were negative for UBE3A testing, and 53 were known to be negative for methylation analysis. We identified two TCF4 mutations in this cohort. The p.S384Tfsx7 mutation lacks the bHLH domain. The p.R582P mutation lies within the bHLH domain in which seven other missense mutations have been reported. Both mutations most likely affect the critical function of the bHLH domain of the TCF4 protein. In summary, we found two TCF4 mutations in 86 patients (2%) suspected to have AS. Screening for mutations in this gene should be considered in patients who present with findings of AS but who have been negative for methylation and UBE3A testing.

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

“…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).…”

“…TCF4 is critical for normal brain development (Flora et al, 2007). Human haploinsufficiency of TCF4 may result in severe cognitive deficiency (ie, mental retardation) in patients with Pitt-Hopkins syndrome (Pitt and Hopkins, 1978) or Angelman syndrome (Takano et al, 2010). However, the role of the TCF4 gene in cognitive deficiency in SCZ patients has seldom been studied (for exceptions, see Lennertz et al (2011); Quednow et al (2011)).…”

Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective

“…Heterozygous hypomorphic, null mutations or deletion (haploinsufficiency) of the TCF4 gene in humans causes the rare PTHS -an autosomal-dominant neurodevelopmental disorder characterized by severe mental, motor and language retardation, epilepsy, facial dysmorphisms, intermittent hyperventilation, and rarely also postnatal microcephaly -, pointing to the fact that TCF4 is critical also for normal development of the mammalian nervous system ( which displays a similar phenotype as PTHS and also have mutations in the TCF4 gene [136]. A recent study with 10 young PTHS patients revealed strong intellectual and motor disabilities together with a behavioral phenotype that overlaps with autism spectrum disorders [137].…”

Development, cognition, and behaviour in Pitt–Hopkins syndrome

“…Some of these behaviours may be consistent with the definition of an autism spectrum disorder (ASD). [11][12][13]15 To our knowledge there have been no investigations of cognition, behaviour, and autism in PTHS to date. Here we report an exploratory investigation of behaviour, adaptive, and cognitive functioning in 10 individuals with molecularly confirmed classic PTHS, with the specific aim of exploring the hypothesis that PTHS may be characterized by differing degrees of severity of ASD.…”

“…The dominant form of PTHS is caused by deletions ⁄ mutations in Transcription Factor 4 (TCF4) on chromosome 18 at 18q21. [6][7][8][9][10][11][12][13][14] Recessive forms of a PTHS-like disorder are caused by mutations in NeuReXiN1 (NRXN1) on chromosome 2 and CoNTactiN Associated Protein-like 2 (CNT-NAP2) on chromosome 7. 15,16 As studies of the syndrome have accumulated, it has become clear that not all individuals with molecularly confirmed alterations show intermittent overbreathing.…”