Human Gene Module / Chromosome 18 / TCF4

TCF4Transcription factor 4

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
15 / 73
Rare Variants / Common Variants
70 / 4
EAGLE Score
13.5
Strong Learn More
Aliases
TCF4, E2-2,  ITF-2,  ITF2,  PTHS,  SEF-2,  SEF2,  SEF2-1,  SEF2-1A,  SEF2-1B,  SEF2-1D,  TCF-4,  bHLHb19
Associated Syndromes
Pitt-Hopkins syndrome, Pitt-Hopkins syndrome, ID, schizophrenia
Chromosome Band
18q21.2
Associated Disorders
DD/NDD, ADHD, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

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. A second de novo protein-truncating variant in TCF4 in an ASD proband from the Autism Sequencing Consortium was reported in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified TCF4 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Two additional de novo loss-of-function variants and three potentially damaging de novo missense variants in the TCF4 gene were reported in ASD probands from the MSSNG cohort and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified TCF4 as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

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.

External Links
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Human
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Mouse
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Rat
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SFARI Genomic Platforms
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Reports related to TCF4 (73 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 -
58 Support - Brea-Fernández AJ et al. (2022) No -
59 Support - Papes F et al. (2022) No -
60 Support - Popp B et al. (2022) No Epilepsy/seizures
61 Support - Wang Y et al. (2022) No -
62 Support - Zhou X et al. (2022) Yes -
63 Support - Shimelis H et al. (2023) No Stereotypy
64 Support - Aldeeri AA et al. (2023) No -
65 Support - Yuan B et al. (2023) Yes -
66 Positive Association - Jung K et al. (2023) No -
67 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
68 Support - Davis BA et al. (2023) No -
69 Support - et al. () No -
70 Support - et al. () No -
71 Support - et al. () Yes -
72 Support - et al. () No DD
73 Support - et al. () No Stereotypy
Rare Variants   (70)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss Unknown - - 36475376 Shimelis H et al. (2023)
- - copy_number_loss Unknown - Unknown 24398791 Pham J , et al. (2014)
c.655G>C p.Asp219His missense_variant De novo - - 38374498 et al. ()
c.1165C>T p.Arg389Cys missense_variant De novo - - 38177409 et al. ()
c.469C>T p.Arg157Ter stop_gained Unknown - Unknown 38287090 et al. ()
- - translocation De novo - Simplex 18627065 Kalscheuer VM , et al. (2008)
c.549+2T>G - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1153C>T p.Arg385Ter stop_gained De novo - - 32429945 Wang J et al. (2020)
- - copy_number_loss Familial Paternal Simplex 30504930 Guo H , et al. (2018)
c.2185+1G>A p.? splice_site_variant De novo - - 36881370 Yuan B et al. (2023)
c.369+1G>T - splice_site_variant Unknown - - 36475376 Shimelis H et al. (2023)
c.2032C>T p.Arg678Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.469C>T p.Arg157Ter stop_gained De novo - - 22670824 Hamdan FF , et al. (2012)
c.2045G>A p.Arg682Gln missense_variant Unknown - Multiplex 38438125 et al. ()
- - translocation Familial - Multi-generational 27179618 Maduro V , et al. (2016)
c.158C>G p.Ser53Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.673C>T p.Gln225Ter stop_gained De novo - Simplex 28831199 Li J , et al. (2017)
c.1705C>T p.Leu569Phe missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2147C>T p.Ala716Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.826C>T p.Arg276Ter stop_gained De novo - - 27479843 Lelieveld SH et al. (2016)
c.1726C>T p.Arg576Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.990G>A p.? splice_site_variant De novo - Simplex 29695756 Mary L , et al. (2018)
c.2039G>A p.Arg680His missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.1182T>G p.Asp394Glu splice_site_variant De novo - - 31178897 Gao C , et al. (2019)
c.1572A>G p.Gln524%3D splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1726C>T p.Arg576Ter stop_gained De novo - Simplex 29695756 Mary L , et al. (2018)
c.1927G>T p.Glu643Ter stop_gained De novo - Simplex 29695756 Mary L , et al. (2018)
c.2182C>T p.Arg728Ter stop_gained De novo - Simplex 37543562 Sheth F et al. (2023)
c.520C>T p.Arg174Ter stop_gained De novo - Simplex 25167861 Redin C , et al. (2014)
c.1489+1G>T p.? splice_site_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1296G>A p.Ser432= splice_region_variant De novo - - 29158550 Popp B , et al. (2017)
c.873C>A p.Tyr291Ter stop_gained De novo - Multiplex 29695756 Mary L , et al. (2018)
c.850C>T p.His284Tyr missense_variant Unknown - - 28554332 Bowling KM , et al. (2017)
c.482T>C p.Leu161Pro missense_variant De novo - Simplex 33951346 Liu L et al. (2021)
c.187C>T p.Pro63Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1726C>T p.Arg576Ter stop_gained De novo - Simplex 33644862 Hiraide T et al. (2021)
c.1153C>T p.Arg385Ter stop_gained De novo - Simplex 25356899 Hamdan FF , et al. (2014)
c.1165C>T p.Arg389Cys missense_variant De novo - Simplex 35908153 Popp B et al. (2022)
c.1165C>T p.Arg389Cys missense_variant Unknown - Simplex 35908153 Popp B et al. (2022)
c.2045G>A p.Arg682Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1739G>A p.Arg580Gln missense_variant Unknown - Unknown 26666243 Lim EC , et al. (2015)
c.1705C>T p.Leu569Phe missense_variant De novo - Simplex 29695756 Mary L , et al. (2018)
c.1733G>A p.Arg578His missense_variant De novo - Simplex 29695756 Mary L , et al. (2018)
c.1841C>T p.Ala614Val missense_variant De novo - Simplex 29695756 Mary L , et al. (2018)
c.1627del p.Ser543GlnfsTer15 frameshift_variant De novo - - 30375316 Tan A , et al. (2018)
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.1146+1G>A - splice_site_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.990G>A p.Ser330= synonymous_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1726C>T p.Arg576Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1730A>G p.Glu577Gly missense_variant De novo - Simplex 33958710 Miyamoto S et al. (2021)
2240+G(delC) 747-! frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1738C>T p.Arg580Trp missense_variant De novo - Simplex 33624935 Abe-Hatano C et al. (2021)
- - translocation De novo - Multiplex (monozygotic twins) 22521361 Talkowski ME , et al. (2012)
c.2045G>A p.Arg682Gln missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1805C>T p.Thr602Ile missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.1662del p.Thr555ProfsTer9 frameshift_variant De novo - Simplex 29695756 Mary L , et al. (2018)
c.2263_2264del p.Ser755LeufsTer57 frameshift_variant De novo - - 28708303 Chrot E , et al. (2017)
c.632_633insAT p.Phe211LeufsTer24 frameshift_variant Unknown - - 36475376 Shimelis H et al. (2023)
c.672delinsGG p.Ser224ArgfsTer33 frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.7dup p.Ser3PhefsTer2 frameshift_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.209_212del p.Asn70MetfsTer10 frameshift_variant De novo - Simplex 25167861 Redin C , et al. (2014)
c.1849G>A p.Val617Ile missense_variant Familial Paternal Multiplex 36574749 Aldeeri AA et al. (2023)
c.119_127delinsCAAAG p.Phe40SerfsTer7 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1180C>T p.Gln394Ter stop_gained De novo - 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 - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.304+19048G>A;c.232+19048G>A;c.178+19048G>A;c.610+19048G>A - intron_variant - - - 37258574 Jung K et al. (2023)
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
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 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.

Reports Added
[Confirming the contribution and genetic spectrum of de novo mutation in infantile spasms: Evidence from a Chinese cohort2021] [Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies2021]
1/1/2021
1
icon
1

Score remained at 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.

Reports Added
[Whole genome sequencing of 45 Japanese patients with intellectual disability2021] [Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
7/1/2020
1
icon
1

Score remained at 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.

Reports Added
[Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of the synaptic proteome2020]
4/1/2020
1
icon
1

Score remained at 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.

Reports Added
[The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing2020] [Tcf4 is required for correct brain development during embryogenesis2020]
1/1/2020
1
icon
1

Score remained at 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.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
3S
icon
1

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
3S
icon
3S

Decreased from 3S 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.

Reports Added
[Diagnostic Yields of Trio-WES Accompanied by CNVseq for Rare Neurodevelopmental Disorders.2019] [Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2019
3S
icon
3S

Decreased from 3S 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.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2018
3S
icon
3S

Decreased from 3S 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.

Reports Added
[Pitt-Hopkins Syndrome: A Unique Case Study.2018] [Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
3S
icon
3S

Decreased from 3S 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.

Reports Added
[Tcf4 regulates dendritic spine density and morphology in the adult brain.2018]
10/1/2017
S
icon
3S

Increased from 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.

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017] [Exome Pool-Seq in neurodevelopmental disorders.2017]
7/1/2017
S
icon
S

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
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
4/1/2017
S
icon
S

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
S
icon
S

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
[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]
10/1/2016
S
icon
S

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
[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
S
icon
S

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
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
4/1/2016
S
icon
S

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
S
icon
S

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]
Krishnan Probability Score

Score 0.57825403547268

Ranking 610/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99986654449982

Ranking 722/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Iossifov Probability Score

Score 0.804

Ranking 231/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.52286899570944

Ranking 499/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.28874841567625

Ranking 2903/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
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
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