TCF4Transcription factor 4
Autism Reports / Total Reports
11 / 57Rare Variants / Common Variants
51 / 3Aliases
TCF4, E2-2, ITF-2, ITF2, PTHS, SEF-2, SEF2, SEF2-1, SEF2-1A, SEF2-1B, SEF2-1D, TCF-4, bHLHb19Associated Syndromes
Pitt-Hopkins syndrome, Pitt-Hopkins syndrome, ID, schizophreniaChromosome Band
18q21.2Associated Disorders
DD/NDD, EPS, ASD, ADHDGenetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, FunctionalRelevance to Autism
Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012).
Molecular Function
This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor that binds to the immunoglobulin enchancer Mu-E5/KE5-motif and is involved in the initiation of neuronal differentiation. Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954], a syndrome characterized by mental retardation, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea.
Reports related to TCF4 (57 Reports)
# | Type | Title | Author, Year | Autism Report | Associated Disorders |
---|---|---|---|---|---|
1 | Support | Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction | Amiel J , et al. (2007) | No | - |
2 | Support | Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome) | Zweier C , et al. (2007) | No | - |
3 | Support | Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome | Kalscheuer VM , et al. (2008) | No | - |
4 | Support | TCF4 deletions in Pitt-Hopkins Syndrome | Giurgea I , et al. (2008) | No | - |
5 | Positive Association | Common variants conferring risk of schizophrenia | Stefansson H , et al. (2009) | No | - |
6 | Positive Association | Common variants at VRK2 and TCF4 conferring risk of schizophrenia | Steinberg S , et al. (2011) | No | - |
7 | Support | Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations | O'Roak BJ , et al. (2012) | Yes | - |
8 | Support | Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries | Talkowski ME , et al. (2012) | No | - |
9 | Support | Pitt-Hopkins Syndrome | Peippo M and Ignatius J (2012) | No | - |
10 | Support | Parent-child exome sequencing identifies a de novo truncating mutation in TCF4 in non-syndromic intellectual disability | Hamdan FF , et al. (2012) | No | - |
11 | Primary | Development, cognition, and behaviour in Pitt-Hopkins syndrome | Van Balkom ID , et al. (2012) | No | ASD |
12 | Support | Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases | Pham J , et al. (2014) | No | - |
13 | Support | Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing | Redin C , et al. (2014) | No | - |
14 | Support | De novo mutations in moderate or severe intellectual disability | Hamdan FF , et al. (2014) | No | Absent speech, hypotonia |
15 | Support | Synaptic, transcriptional and chromatin genes disrupted in autism | De Rubeis S , et al. (2014) | Yes | - |
16 | Support | Large-scale discovery of novel genetic causes of developmental disorders | Deciphering Developmental Disorders Study (2014) | No | Microcephaly |
17 | Recent Recommendation | Low load for disruptive mutations in autism genes and their biased transmission | Iossifov I , et al. (2015) | Yes | - |
18 | Support | Next-generation sequencing using a pre-designed gene panel for the molecular diagnosis of congenital disorders in pediatric patients | Lim EC , et al. (2015) | No | Microcephaly, absent speech |
19 | Recent Recommendation | Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease | Johnson MR , et al. (2015) | No | - |
20 | Recent Recommendation | A common molecular signature in ASD gene expression: following Root 66 to autism | Diaz-Beltran L , et al. (2016) | No | - |
21 | Recent Recommendation | De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia | Takata A , et al. (2016) | No | - |
22 | Recent Recommendation | Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1 | Rannals MD , et al. (2016) | No | - |
23 | Support | Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability | Maduro V , et al. (2016) | No | - |
24 | Support | Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability | Lelieveld SH et al. (2016) | No | - |
25 | Support | Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex | Hill MJ , et al. (2016) | No | - |
26 | Support | De novo genic mutations among a Chinese autism spectrum disorder cohort | Wang T , et al. (2016) | Yes | - |
27 | Support | The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies | Redin C , et al. (2016) | No | - |
28 | Support | Neurodevelopmental models of transcription factor 4 deficiency converge on a common ion channel as a potential therapeutic target for Pitt Hopkins syndrome | Rannals MD , et al. (2016) | No | - |
29 | Support | Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases | Stessman HA , et al. (2017) | No | - |
30 | Recent Recommendation | The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons in an activity-dependent manner | Page SC , et al. (2017) | No | - |
31 | Support | Genomic diagnosis for children with intellectual disability and/or developmental delay | Bowling KM , et al. (2017) | No | - |
32 | Support | Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients | Chrot E , et al. (2017) | No | - |
33 | Support | Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders | Li J , et al. (2017) | Yes | - |
34 | Support | Exome Pool-Seq in neurodevelopmental disorders | Popp B , et al. (2017) | No | Hypotonia |
35 | Support | The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectual Disability | Forrest MP , et al. (2017) | No | - |
36 | Positive Association | Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection | Pardias AF , et al. (2018) | No | - |
37 | Recent Recommendation | Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a role in development and plasticity of cortical and hippocampal neurons | Jung M , et al. (2018) | No | - |
38 | Support | Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis | Mary L , et al. (2018) | No | Stereotypic behavior |
39 | Support | Tcf4 regulates dendritic spine density and morphology in the adult brain | Crux S , et al. (2018) | No | - |
40 | Support | Pitt-Hopkins Syndrome: A Unique Case Study | Tan A , et al. (2018) | No | ASD, ADHD |
41 | Support | Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes | Guo H , et al. (2018) | Yes | - |
42 | Support | Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model | Guo H , et al. (2018) | Yes | - |
43 | Support | Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders | Gao C , et al. (2019) | No | - |
44 | Support | Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks | Ruzzo EK , et al. (2019) | Yes | - |
45 | Support | Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism | Satterstrom FK et al. (2020) | Yes | - |
46 | Support | The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing | Wang J et al. (2020) | No | - |
47 | Support | Tcf4 is required for correct brain development during embryogenesis | Mesman S et al. (2020) | No | - |
48 | Support | Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome | Tamberg L et al. (2020) | No | - |
49 | Support | - | Abe-Hatano C et al. (2021) | No | - |
50 | Support | - | Hiraide T et al. (2021) | No | - |
51 | Support | - | Liu L et al. (2021) | No | ASD, DD |
52 | Support | - | Miyamoto S et al. (2021) | No | DD, epilepsy/seizures |
53 | Support | - | Sarkar D et al. (2021) | No | - |
54 | Support | - | Pode-Shakked B et al. (2021) | No | ASD, epilepsy/seizures |
55 | Support | - | Mahjani B et al. (2021) | Yes | - |
56 | Support | - | Sirp A et al. (2021) | No | - |
57 | Support | - | Rhine CL et al. (2022) | Yes | - |
Rare Variants (51)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
- | - | translocation | De novo | NA | - | 27841880 | Redin C , et al. (2016) | |
- | - | copy_number_loss | Unknown | - | Unknown | 24398791 | Pham J , et al. (2014) | |
- | - | translocation | De novo | NA | Simplex | 18627065 | Kalscheuer VM , et al. (2008) | |
- | - | copy_number_loss | Familial | Paternal | Simplex | 30504930 | Guo H , et al. (2018) | |
c.1153C>T | p.Arg385Ter | stop_gained | De novo | NA | - | 32429945 | Wang J et al. (2020) | |
c.2032C>T | p.Arg678Ter | stop_gained | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
- | - | translocation | Familial | - | Multi-generational | 27179618 | Maduro V , et al. (2016) | |
c.469C>T | p.Arg157Ter | stop_gained | De novo | NA | - | 22670824 | Hamdan FF , et al. (2012) | |
c.158C>G | p.Ser53Ter | stop_gained | De novo | NA | - | 28191889 | Stessman HA , et al. (2017) | |
c.673C>T | p.Gln225Ter | stop_gained | De novo | NA | Simplex | 28831199 | Li J , et al. (2017) | |
c.826C>T | p.Arg276Ter | stop_gained | De novo | NA | - | 27479843 | Lelieveld SH et al. (2016) | |
c.1726C>T | p.Arg576Ter | stop_gained | De novo | NA | - | 28191889 | Stessman HA , et al. (2017) | |
c.990G>A | p.? | splice_site_variant | De novo | NA | Simplex | 29695756 | Mary L , et al. (2018) | |
c.2039G>A | p.Arg680His | missense_variant | De novo | NA | - | 28708303 | Chrot E , et al. (2017) | |
c.850C>T | p.His284Tyr | missense_variant | Unknown | - | - | 28554332 | Bowling KM , et al. (2017) | |
c.1182T>G | p.Asp394Glu | splice_site_variant | De novo | NA | - | 31178897 | Gao C , et al. (2019) | |
c.1726C>T | p.Arg576Ter | stop_gained | De novo | NA | Simplex | 29695756 | Mary L , et al. (2018) | |
c.1927G>T | p.Glu643Ter | stop_gained | De novo | NA | Simplex | 29695756 | Mary L , et al. (2018) | |
c.520C>T | p.Arg174Ter | stop_gained | De novo | NA | Simplex | 25167861 | Redin C , et al. (2014) | |
c.1489+1G>T | p.? | splice_site_variant | De novo | NA | - | 28191889 | Stessman HA , et al. (2017) | |
c.1296G>A | p.Ser432= | splice_region_variant | De novo | NA | - | 29158550 | Popp B , et al. (2017) | |
c.873C>A | p.Tyr291Ter | stop_gained | De novo | NA | Multiplex | 29695756 | Mary L , et al. (2018) | |
c.482T>C | p.Leu161Pro | missense_variant | De novo | NA | Simplex | 33951346 | Liu L et al. (2021) | |
c.1726C>T | p.Arg576Ter | stop_gained | De novo | NA | Simplex | 33644862 | Hiraide T et al. (2021) | |
c.1739G>A | p.Arg580Gln | missense_variant | Unknown | - | Unknown | 26666243 | Lim EC , et al. (2015) | |
c.1153C>T | p.Arg385Ter | stop_gained | De novo | NA | Simplex | 25356899 | Hamdan FF , et al. (2014) | |
c.193G>T | p.Glu65Ter | stop_gained | Familial | Paternal | Simplex | 30564305 | Guo H , et al. (2018) | |
c.836C>T | p.Pro279Leu | missense_variant | Familial | Maternal | - | 27824329 | Wang T , et al. (2016) | |
c.964G>A | p.Gly322Ser | missense_variant | Familial | Maternal | - | 27824329 | Wang T , et al. (2016) | |
c.1705C>T | p.Leu569Phe | missense_variant | De novo | NA | Simplex | 29695756 | Mary L , et al. (2018) | |
c.1733G>A | p.Arg578His | missense_variant | De novo | NA | Simplex | 29695756 | Mary L , et al. (2018) | |
c.1841C>T | p.Ala614Val | missense_variant | De novo | NA | Simplex | 29695756 | Mary L , et al. (2018) | |
c.1627del | p.Ser543GlnfsTer15 | frameshift_variant | De novo | NA | - | 30375316 | Tan A , et al. (2018) | |
c.1146+1G>A | - | splice_site_variant | De novo | NA | Simplex | 34580403 | Pode-Shakked B et al. (2021) | |
c.990G>A | p.Ser330= | synonymous_variant | De novo | NA | Simplex | 22495309 | O'Roak BJ , et al. (2012) | |
c.1726C>T | p.Arg576Ter | stop_gained | De novo | NA | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1730A>G | p.Glu577Gly | missense_variant | De novo | NA | Simplex | 33958710 | Miyamoto S et al. (2021) | |
2240+G(delC) | 747-! | frameshift_variant | De novo | NA | Simplex | 25363760 | De Rubeis S , et al. (2014) | |
c.1738C>T | p.Arg580Trp | missense_variant | De novo | NA | Simplex | 33624935 | Abe-Hatano C et al. (2021) | |
- | - | translocation | De novo | NA | Multiplex (monozygotic twins) | 22521361 | Talkowski ME , et al. (2012) | |
c.1805C>T | p.Thr602Ile | missense_variant | De novo | NA | Simplex | 34580403 | Pode-Shakked B et al. (2021) | |
c.1662del | p.Thr555ProfsTer9 | frameshift_variant | De novo | NA | Simplex | 29695756 | Mary L , et al. (2018) | |
c.2263_2264del | p.Ser755LeufsTer57 | frameshift_variant | De novo | NA | - | 28708303 | Chrot E , et al. (2017) | |
c.7dup | p.Ser3PhefsTer2 | frameshift_variant | Familial | Paternal | Simplex | 30564305 | Guo H , et al. (2018) | |
c.672delinsGG | p.Ser224ArgfsTer33 | frameshift_variant | De novo | NA | - | 28554332 | Bowling KM , et al. (2017) | |
c.209_212del | p.Asn70MetfsTer10 | frameshift_variant | De novo | NA | Simplex | 25167861 | Redin C , et al. (2014) | |
c.119_127delinsCAAAG | p.Phe40SerfsTer7 | frameshift_variant | De novo | NA | - | 28191889 | Stessman HA , et al. (2017) | |
c.1180C>T | p.Gln394Ter | stop_gained | De novo | NA | Simplex | 25533962 | Deciphering Developmental Disorders Study (2014) | |
c.237G>A | p.Trp79Ter | stop_gained | Familial | Maternal | Multiplex (monozygotic twins) | 31398340 | Ruzzo EK , et al. (2019) | |
c.1487-5G>A | p.Arg495_Gly496insAla? | splice_site_variant | Unknown | Not maternal | Simplex | 25167861 | Redin C , et al. (2014) | |
c.1171G>A | p.Glu391Lys | splice_site_variant | De novo | NA | Simplex | 25533962 | Deciphering Developmental Disorders Study (2014) |
Common Variants (3)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
c.146-23634T>G;c.452-23634T>G;c.74-23634T>G;c.140-23634T>G;c.19+22808T>G;c.560-23634T>G;c.416-23634T | - | intron_variant | - | - | - | 21791550 | Steinberg S , et al. (2011) | |
c.146-23634T>G;c.452-23634T>G;c.74-23634T>G;c.140-23634T>G;c.19+22808T>G;c.560-23634T>G;c.416-23634T | - | intron_variant | - | - | - | 19571808 | Stefansson H , et al. (2009) | |
G>GA | - | intergenic_variant | - | - | - | 29483656 | Pardias AF , et al. (2018) |
SFARI Gene score
High Confidence


Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
Score Delta: Decreased from 3S to 1
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
10/1/2021

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
7/1/2021

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
4/1/2021

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
1/1/2021

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
10/1/2020

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
7/1/2020

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
4/1/2020

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
1/1/2020

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
10/1/2019

Decreased from 3S to 1
New Scoring Scheme
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
Reports Added
[New Scoring Scheme]7/1/2019

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
4/1/2019

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
1/1/2019

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
10/1/2018

Decreased from 3S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
7/1/2018

Decreased from 3.3 + S to 3S
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
4/1/2018

Decreased from 3S to 3.3 + S
Description
3S
Reports Added
[The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectu...2017] [Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.2018] [Analysis of the expression pattern of the schizophrenia-risk and intellectual disability gene TCF4 in the developing and adult brain suggests a rol...2018] [Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis.2018]10/1/2017

Increased from S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550). Two de novo loss-of-function variants in TCF4 have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and from a cohort of Chinese ASD probands (Guo et al., 2017). Maternally-inherited damaging missense variants in TCF4 were identified in two ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.
7/1/2017

Increased from S to S
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550).
4/1/2017

Increased from S to S
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550).
Reports Added
[Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases.2014] [Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.2008] [Parent-child exome sequencing identifies a de novo truncating mutation in TCF4 in non-syndromic intellectual disability.2012] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic en...2007] [Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).2007] [TCF4 deletions in Pitt-Hopkins Syndrome.2008] [Pitt-Hopkins Syndrome.2012] [Development, cognition, and behaviour in Pitt-Hopkins syndrome.2012] [Common variants conferring risk of schizophrenia.2009] [Common variants at VRK2 and TCF4 conferring risk of schizophrenia.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Next-generation sequencing using a pre-designed gene panel for the molecular diagnosis of congenital disorders in pediatric patients.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [A common molecular signature in ASD gene expression: following Root 66 to autism.2016] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1.2016] [Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neoc...2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Neurodevelopmental models of transcription factor 4 deficiency converge on a common ion channel as a potential therapeutic target for Pitt Hopkins ...2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [The schizophrenia- and autism-associated gene, transcription factor 4 regulates the columnar distribution of layer 2/3 prefrontal pyramidal neurons...2017] [De novo mutations in moderate or severe intellectual disability.2014] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]1/1/2017

Increased from S to S
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550).
10/1/2016

Increased from S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550).
Reports Added
[Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neoc...2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]7/1/2016

Increased from S to S
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550).
4/1/2016

Increased from S to S
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550).
Reports Added
[Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases.2014] [Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.2008] [Parent-child exome sequencing identifies a de novo truncating mutation in TCF4 in non-syndromic intellectual disability.2012] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic en...2007] [Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).2007] [TCF4 deletions in Pitt-Hopkins Syndrome.2008] [Pitt-Hopkins Syndrome.2012] [Development, cognition, and behaviour in Pitt-Hopkins syndrome.2012] [Common variants conferring risk of schizophrenia.2009] [Common variants at VRK2 and TCF4 conferring risk of schizophrenia.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Next-generation sequencing using a pre-designed gene panel for the molecular diagnosis of congenital disorders in pediatric patients.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [A common molecular signature in ASD gene expression: following Root 66 to autism.2016] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1.2016] [Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability.2016]1/1/2016

Increased from S to S
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550).
Reports Added
[Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases.2014] [Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.2008] [Parent-child exome sequencing identifies a de novo truncating mutation in TCF4 in non-syndromic intellectual disability.2012] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic en...2007] [Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).2007] [TCF4 deletions in Pitt-Hopkins Syndrome.2008] [Pitt-Hopkins Syndrome.2012] [Development, cognition, and behaviour in Pitt-Hopkins syndrome.2012] [Common variants conferring risk of schizophrenia.2009] [Common variants at VRK2 and TCF4 conferring risk of schizophrenia.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Next-generation sequencing using a pre-designed gene panel for the molecular diagnosis of congenital disorders in pediatric patients.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [A common molecular signature in ASD gene expression: following Root 66 to autism.2016]10/1/2015

Increased from S to 1
Description
Defects in this gene are associated with Pitt-Hopkins syndrome (PTHS) [MIM:610954]. Patients with Pitt-Hopkins syndrome frequently exhibit stereotypic hand and head movements (summarized in Peippo and Ignatius, 2012). More recently, evaluation of 10 Pitt-Hopkins syndrome patients with psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery, including the Autism Diagnostic Interview-Revised (ADI-R), demonstrated that all participants displayed profound intellectual disability, severe impairments in social interactions, severe impairments in communication and language, and highly frequent stereotyped behavior, indicating that in classic Pitt-Hopkins syndrome the behavioral phenotype showed similarities to behaviors seen in ASD (Van Balkom et al., 2012). An intronic marker in TCF4 has demonstrated genome-wide association with schizophrenia in case-control meta-analyzes (PMIDs 19571808, 21791550).
Krishnan Probability Score
Score 0.57825403547268
Ranking 610/25841 scored genes
[Show Scoring Methodology]
ExAC Score
Score 0.99986654449982
Ranking 722/18225 scored genes
[Show Scoring Methodology]
Iossifov Probability Score
Score 0.804
Ranking 231/239 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.52286899570944
Ranking 499/18665 scored genes
[Show Scoring Methodology]
Zhang D Score
Score 0.28874841567625
Ranking 2903/20870 scored genes
[Show Scoring Methodology]
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
---|---|---|---|---|---|
AQP1 | aquaporin 1 (Colton blood group) | Human | Protein Binding | 358 | P29972 |
ASCL4 | achaete-scute family bHLH transcription factor 4 | Human | Protein Binding | 121549 | Q6XD76 |
C9ORF171 | chromosome 9 open reading frame 171 | Human | Protein Binding | 389799 | Q6ZQR2 |
CABP5 | calcium binding protein 5 | Human | Protein Binding | 56344 | Q9NP86 |
DEF6 | differentially expressed in FDCP 6 homolog (mouse) | Human | Protein Binding | 50619 | Q9H4E7 |
EPHB6 | EPH receptor B6 | Human | Protein Binding | 2051 | J3KQU5 |
EXOSC1 | exosome component 1 | Human | Protein Binding | 51013 | Q9Y3B2 |
FAH | fumarylacetoacetate hydrolase (fumarylacetoacetase) | Human | Protein Binding | 2184 | P16930 |
FERD3L | Fer3-like bHLH transcription factor | Human | Protein Binding | 222894 | Q96RJ6 |
FLJ32679 | Human | Protein Binding | 440321 | ||
GNG10 | guanine nucleotide binding protein (G protein), gamma 10 | Human | Protein Binding | 2790 | A0A024R156 |
GOLGA8EP | golgin A8 family, member E, pseudogene | Human | Protein Binding | 390535 | |
HAND2 | heart and neural crest derivatives expressed 2 | Human | Protein Binding | 9464 | P61296 |
INS | insulin | Human | Protein Binding | 3630 | I3WAC9 |
KCTD14 | potassium channel tetramerization domain containing 14 | Human | Protein Binding | 65987 | Q9BQ13 |
LGALS14 | lectin, galactoside-binding, soluble, 14 | Human | Protein Binding | 56891 | Q8TCE9 |
MAGOHB | mago-nashi homolog B (Drosophila) | Human | Protein Binding | 55110 | Q96A72 |
MATN3 | matrilin 3 | Human | Protein Binding | 4148 | O15232 |
MESP2 | Mesoderm posterior protein 2 | Human | Protein Binding | 145873 | Q0VG99 |
NEK8 | NIMA-related kinase 8 | Human | Protein Binding | 284086 | Q86SG6 |
NEU4 | sialidase 4 | Human | Protein Binding | 129807 | B3KR54 |
NEUROG3 | Neurogenin-3 | Human | Protein Binding | 50674 | Q9Y4Z2 |
NME7 | NME/NM23 family member 7 | Human | Protein Binding | 29922 | Q9Y5B8 |
NMUR2 | neuromedin U receptor 2 | Human | Protein Binding | 56923 | Q9GZQ4 |
NUDT10 | nudix (nucleoside diphosphate linked moiety X)-type motif 10 | Human | Protein Binding | 170685 | Q8NFP7 |
OSGIN1 | oxidative stress induced growth inhibitor 1 | Human | Protein Binding | 29948 | Q9UJX0 |
PATE1 | prostate and testis expressed 1 | Human | Protein Binding | 160065 | Q8WXA2 |
RAB41 | RAB41, member RAS oncogene family | Human | Protein Binding | 347517 | Q5JT25 |
REXO1L6P | REX1, RNA exonuclease 1 homolog (S. cerevisiae)-like 6, pseudogene | Human | Protein Binding | 441362 | |
RSPH14 | rhabdoid tumor deletion region gene 1 | Human | Protein Binding | 27156 | Q9UHP6 |
SEC14L4 | SEC14-like 4 (S. cerevisiae) | Human | Protein Binding | 284904 | B2RMR2 |
SIGLEC6 | sialic acid binding Ig-like lectin 6 | Human | Protein Binding | 946 | O43699 |
SMCP | sperm mitochondria-associated cysteine-rich protein | Human | Protein Binding | 4184 | P49901 |
TAL2 | T-cell acute lymphocytic leukemia 2 | Human | Protein Binding | 6887 | Q16559 |
TCF24 | Transcription factor 24 | Human | Protein Binding | 100129654 | Q7RTU0 |
TMEM213 | transmembrane protein 213 | Human | Protein Binding | 155006 | A2RRL7 |
TSSK3 | testis-specific serine kinase 3 | Human | Protein Binding | 81629 | Q96PN8 |
TWIST2 | twist family bHLH transcription factor 2 | Human | Protein Binding | 117581 | A0A024R4D4 |
ZDHHC24 | zinc finger, DHHC-type containing 24 | Human | Protein Binding | 254359 | Q6UX98 |
ZNF124 | zinc finger protein 124 | Human | Protein Binding | 7678 | Q15973 |
ZNF205-AS1 | ZNF205 antisense RNA 1 | Human | Protein Binding | 81854 |