TCF4, Schizophrenia, and Pitt-Hopkins Syndrome

Blake, Derek J.; Forrest, Marc P.; Chapman, Ria M.; Tinsley, Caroline L.; O’Donovan, Michael; Owen, Michael John

doi:10.1093/schbul/sbq035

Cited by 66 publications

(66 citation statements)

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“…Such analyses will also allow the identification of polymorphisms and their cumulative or epistatic interactions in neurological disease. In fact, such interactions are already being revealed, guided by the analysis of genes that have been initially associated with Mendelian ID (19) or in large phenomics studies (113).…”

Section: Intellectual Disability Autism and A Range Of Other Cognitmentioning

confidence: 99%

Genetic and Epigenetic Networks in Intellectual Disabilities

2011

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Mutations in more than 450 different genes have been associated with intellectual disability (ID) and related cognitive disorders (CDs), such as autism. It is to be expected that this number will increase three to fourfold in the next years due to the rapid implementation of innovative high-throughput sequencing technology in genetics labs. Numerous functional relationships have been identified between the products of individual ID genes, and common molecular and cellular pathways onto which these networks converge are beginning to emerge. Prominent examples are genes involved in synaptic plasticity, Ras and Rho GTPase signaling, and epigenetic genes that encode modifiers of the chromatin structure. It thus seems that there might be common pathological patterns in ID, despite its bewildering genetic heterogeneity. These common pathways provide attractive opportunities for knowledge-based therapeutic interventions.

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Section: Intellectual Disability Autism and A Range Of Other Cognitmentioning

confidence: 99%

Genetic and Epigenetic Networks in Intellectual Disabilities

2011

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“…A de novo translocation disrupted its exon 4, and the patient had mild to moderate mental retardation without any of the other PTHS characteristics [Kalscheuer et al, 2008]. In addition, genome-wide association studies for schizophrenia risk factors have pinpointed all PTHS-, PTHSL1-and PTHSL2-causing genes to be linked to the disease [Blake et al, 2010]. In particular, allele C of TCF4 has been of interest suggesting schizophrenia to be another TCF4 -related phenotype.…”

Section: Mutation Spectrum and Genotype-phenotype Correlationmentioning

confidence: 99%

Pitt-Hopkins Syndrome

Peippo

Ignatius

2011

Mol Syndromol

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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. Copyright © 2011 S. Karger AG, Basel History of the SyndromeIn 1978, pediatrician David Pitt and pediatric neurologist Ian Hopkins at the Royal Children's Hospital in Melbourne described 2 unrelated children with severe intellectual disability who while awake had spells of rapid overbreathing followed by holding of breath until cyanosis [Pitt and Hopkins, 1978]. Both patients had almost identical facial features with a wide mouth and palate, thick fleshy lips and a broad beaked nose with flared nostrils, and both also had clubbing of fingers and toes. The patients had been ascertained as a part of an etiological survey of 782 intellectually disabled individuals [Pitt and Roboz, 1965]. Over the next 28 years, only 4 sporadic patients [Singh 1993;Van Balkom et al., 1998;Peippo et al., 2006] and 1 pair of sibs [Orrico et al., 2001] supposed to have the same syndrome were published.In 2007, 2 independent groups using molecular karyotyping identified a microdeletion at 18q21.2 in 2 PittHopkins syndrome (PTHS) patients and subsequently haploinsufficiency of the TCF4 gene was found to cause the syndrome [Amiel et al., 2007;Zweier et al., 2007]. The original patients of Pitt and Hopkins [1978] and the one described by Singh [1993] were no longer available for Key WordsApnea ؒ Constipation ؒ Deletion of 18q ؒ Epilepsy ؒ Happy disposition ؒ Hyperpnea ؒ Myopia ؒ Pitt-Hopkins syndrome ؒ Stereotypic movements ؒ TCF4 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,

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“…[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. Most studies of individuals with PTHS have reported severe developmental delay and intellectual disability, motor abnormalities (late or absent walking, repetitive movements of hands and head), and behavioural traits such as autistic symptoms; a quiet, friendly disposition in most cases, and in other cases sudden aggression towards others in association with sudden changes in daily routine.…”

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confidence: 99%

Development, cognition, and behaviour in Pitt–Hopkins syndrome

Balkom

Vuijk²,

Franssens

et al. 2012

Develop Med Child Neuro

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ABBREVIATIONSASD Autism spectrum disorder PTHS Pitt-Hopkins syndrome AIM The aim of the study was to collect detailed data on behavioural, adaptive, and psychological functioning in 10 individuals with Pitt-Hopkins syndrome (PTHS), with specific attention to manifestations of autism spectrum disorder (ASD).METHOD The participants (four females, six males), residing in the Netherlands and Belgium, were ascertained through the Dutch national PTHS support group. Median age of participants was 10 years, the age range was between 32 and 289 months. They underwent psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery. Additionally, parental information was gathered through standardized interviews and questionnaires. Findings were compared with those from the literature.RESULTS All participants showed profound intellectual disability, amiable demeanour with minimal maladaptive behaviours, severe impairments of communication and language, and intense, frequent motor stereotypies. Impairments in all participants were beyond what would be expected for cognitive abilities, fitting a classification of ASD.INTERPRETATION Patients with PTHS are characterized not only by specific physical and genetic manifestations but also by specific behavioural and cognitive characteristics. Studying behaviour and cognition may improve diagnosis and prognosis, allows recognition of comorbidities, and contributes to adequate counselling of families.Pitt-Hopkins syndrome (PTHS) is characterized by intellectual disability, distinctive facial characteristics, breathing abnormalities, and repetitive behaviours. It is caused by genetic deletions ⁄ mutations resulting in TCF4 haploinsufficiency. To date, some 66 patients with confirmed TCF4 changes have been studied worldwide, mainly investigating somatic and genetic aspects.Early descriptions of PTHS in individuals with intellectual disability emphasized an abnormal breathing pattern, distinctive facial features, and postnatal microcephaly. Further definition of the PTHS phenotype in later publications included severe developmental delays in motor and speech ⁄ language development, episodic diurnal hyperventilation with apnoea, and frequent epilepsy.1-5 Three causes of PTHS have been identified. 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. Most studies of individuals with PTHS have reported severe developmental delay and intellectual disability, motor abnormalities (late or absent walking, repetitive movements of hands and head), and behavioural traits such as autistic symptoms; a quiet, friendly disposition in ...

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TCF4, Schizophrenia, and Pitt-Hopkins Syndrome

Cited by 66 publications

References 40 publications

Genetic and Epigenetic Networks in Intellectual Disabilities

Genetic and Epigenetic Networks in Intellectual Disabilities

Pitt-Hopkins Syndrome

Development, cognition, and behaviour in Pitt–Hopkins syndrome

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