Gene: TCF4

Alternate names for this Gene: CDG2T|E2-2|FECD3|ITF-2|ITF2|PTHS|SEF-2|SEF2|SEF2-1|SEF2-1A|SEF2-1B|SEF2-1D|TCF-4|bHLHb19

Gene Summary: This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described.

Gene is located in Chromosome: 18

Location in Chromosome : 18q21.2

Description of this Gene: transcription factor 4

Type of Gene: protein-coding

rs12607857 in TCF4 gene and Age at menarche PMID 30595370 2019 Leveraging Polygenic Functional Enrichment to Improve GWAS Power.

rs11659559 in TCF4 gene and Alopecia PMID 28196072 2017 Genetic prediction of male pattern baldness.

rs11152369 in TCF4 gene and Attention deficit hyperactivity disorder PMID 23453885 2013 Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.

rs11152369 in TCF4 gene and Bipolar Disorder PMID 23453885 2013 Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.

rs613872 in TCF4 gene and Body mass index PMID 30239722 2019 Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry.

rs11152369 in TCF4 gene and Child Development Disorders, Pervasive PMID 23453885 2013 Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.

PMID 28540026 2017 Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

rs1452787 in TCF4 gene and Cholangitis, Sclerosing PMID 22821403 2013 Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.

rs1568303086 in TCF4 gene and Cryptorchidism PMID 21671391 2011 The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

PMID 24077912 2014 The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.

rs12607679 in TCF4 gene and Duration of sleep PMID 30804565 2019 Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways.

PMID 30846698 2019 Genome-wide association study identifies genetic loci for self-reported habitual sleep duration supported by accelerometer-derived estimates.

rs1057521070 in TCF4 gene and Dysmorphic features PMID 21671391 2011 The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

PMID 26087656 2015 Association of TCF4 polymorphisms and Fuchs' endothelial dystrophy: a meta-analysis.

PMID 27072915 2016 Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system.

PMID 22045651 2012 Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.

PMID 22678594 2012 Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome.

PMID 22581936 2012 Clinical application of exome sequencing in undiagnosed genetic conditions.

PMID 22335494 2013 Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome.

PMID 23185296 2012 A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.

PMID 22460224 2012 Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.

PMID 22712893 2012 Development, cognition, and behaviour in Pitt-Hopkins syndrome.

PMID 28807867 2017 Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4.

PMID 18728071 2008 Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.

PMID 17436255 2007 Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).

PMID 21533127 2011 Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.

PMID 17478476 2007 Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.

PMID 21245398 2011 Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.

PMID 18081026 2008 A loss-of-function mutation in the FTSJ1 gene causes nonsyndromic X-linked mental retardation in a Japanese family.

PMID 19235238 2009 Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.

PMID 20825314 2010 E2-2 protein and Fuchs's corneal dystrophy.

PMID 19938247 2009 Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.

PMID 18627065 2008 Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.

PMID 17436254 2007 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.

rs613872 in TCF4 gene and Fuchs Endothelial Dystrophy PMID 20825314 2010 E2-2 protein and Fuchs's corneal dystrophy.

rs1568303086 in TCF4 gene and Global developmental delay PMID 24077912 2014 The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.

PMID 21671391 2011 The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

rs9636107 in TCF4 gene and Intelligence PMID 31374203 2019 Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

rs11152363 in TCF4 gene and Major Depressive Disorder PMID 29942085 2018 Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.

PMID 23453885 2013 Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.

PMID 29700475 2018 Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

PMID 30718901 2019 Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.

PMID 29662059 2018 Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways.

rs11152363 in TCF4 gene and Mood Disorders PMID 29942085 2018 Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.

rs1555764170 in TCF4 gene and Movement Disorders PMID 22335494 2013 Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome.

PMID 27072915 2016 Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system.

PMID 22581936 2012 Clinical application of exome sequencing in undiagnosed genetic conditions.

PMID 21671391 2011 The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

PMID 23185296 2012 A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.

PMID 28807867 2017 Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4.

PMID 26087656 2015 Association of TCF4 polymorphisms and Fuchs' endothelial dystrophy: a meta-analysis.

PMID 22045651 2012 Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.

PMID 21533127 2011 Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.

PMID 22460224 2012 Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.

PMID 22678594 2012 Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome.

PMID 19938247 2009 Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.

PMID 21245398 2011 Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.

PMID 18728071 2008 Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.

PMID 17478476 2007 Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.

PMID 22712893 2012 Development, cognition, and behaviour in Pitt-Hopkins syndrome.

PMID 20825314 2010 E2-2 protein and Fuchs's corneal dystrophy.

PMID 18627065 2008 Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.

PMID 18081026 2008 A loss-of-function mutation in the FTSJ1 gene causes nonsyndromic X-linked mental retardation in a Japanese family.

PMID 17436254 2007 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.

PMID 19235238 2009 Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.

PMID 17436255 2007 Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).

rs1057521070 in TCF4 gene and Muscle hypotonia PMID 19938247 2009 Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.

PMID 21533127 2011 Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.

PMID 21671391 2011 The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

PMID 19235238 2009 Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.

PMID 18728071 2008 Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.

PMID 17478476 2007 Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.

PMID 27072915 2016 Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an internet questionnaire system.

PMID 18081026 2008 A loss-of-function mutation in the FTSJ1 gene causes nonsyndromic X-linked mental retardation in a Japanese family.

PMID 22335494 2013 Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome.

PMID 20825314 2010 E2-2 protein and Fuchs's corneal dystrophy.

PMID 18627065 2008 Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome.

PMID 22712893 2012 Development, cognition, and behaviour in Pitt-Hopkins syndrome.

PMID 23185296 2012 A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.

PMID 26087656 2015 Association of TCF4 polymorphisms and Fuchs' endothelial dystrophy: a meta-analysis.

PMID 22678594 2012 Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome.

PMID 22581936 2012 Clinical application of exome sequencing in undiagnosed genetic conditions.

PMID 21245398 2011 Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.

PMID 22045651 2012 Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.

PMID 17436255 2007 Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).

PMID 17436254 2007 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.

PMID 22460224 2012 Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.

PMID 28807867 2017 Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4.

PMID 24077912 2014 The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.

rs1057519592 in TCF4 gene and PITT-HOPKINS SYNDROME PMID 22777675 2012 Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome.

PMID 25356899 2014 De novo mutations in moderate or severe intellectual disability.

PMID 20184619 2010 Two percent of patients suspected of having Angelman syndrome have TCF4 mutations.

PMID 19235238 2009 Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.

PMID 22045651 2012 Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum.

PMID 18728071 2008 Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients.

PMID 17436255 2007 Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome).

PMID 17436254 2007 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.

PMID 28631899 2017 Dual molecular diagnosis contributes to atypical Prader-Willi phenotype in monozygotic twins.

PMID 24077912 2014 The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.

PMID 21671391 2011 The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

PMID 22460224 2012 Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.

PMID 26633545 2016 Molecular diagnostic experience of whole-exome sequencing in adult patients.

PMID 28807867 2017 Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4.

PMID 26993267 2016 Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis.

rs28607662 in TCF4 gene and Prostate carcinoma PMID 29892016 2018 Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

rs11152369 in TCF4 gene and Schizophrenia PMID 23453885 2013 Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.

PMID 23894747 2013 A comprehensive family-based replication study of schizophrenia genes.

PMID 28540026 2017 Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.

PMID 21926974 2011 Genome-wide association study identifies five new schizophrenia loci.

PMID 19571811 2009 Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.

PMID 22688191 2012 Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.

PMID 30285260 2019 Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.

PMID 26198764 2015 Genome-wide association study of schizophrenia in Ashkenazi Jews.

PMID 31268507 2019 Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study.

PMID 31374203 2019 Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

PMID 25056061 2014 Biological insights from 108 schizophrenia-associated genetic loci.

PMID 19571808 2009 Common variants conferring risk of schizophrenia.

PMID 21791550 2011 Common variants at VRK2 and TCF4 conferring risk of schizophrenia.

rs599550 in TCF4 gene and Systolic Pressure PMID 30578418 2019 Trans-ethnic association study of blood pressure determinants in over 750,000 individuals.

rs1568303086 in TCF4 gene and Tall stature PMID 24077912 2014 The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine.

PMID 21671391 2011 The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria.

rs72932713 in TCF4 gene and Tonometry PMID 29617998 2018 Genome-wide association analyses identify new loci influencing intraocular pressure.

rs1011392 in TCF4 gene and mathematical ability PMID 30038396 2018 Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.