ArticleOrphanet journal of rare diseases2016
Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability.
Article in Orphanet journal of rare diseases, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 28 citations in OpenAlex.
- An attempt to explain what intrinsically disordered TCF4 does in its spare time when PTHS-related mutations prevent it from doing its job.Cell communication and signaling : CCS · 2025Review
- Article
- Comparative Transcriptomics Data Profiling Reveals E2F Targets as an Important Biological Pathway Overexpressed in Intellectual Disability Disorder.Bioinformatics and biology insights · 2024Article
- Deciphering the role of precursor miR-12136 and miR-8485 in the progression of intellectual disability (ID).IBRO neuroscience reports · 2022Article
- Functional consequences of TCF4 missense substitutions associated with Pitt-Hopkins syndrome, mild intellectual disability, and schizophrenia.The Journal of biological chemistry · 2021Article
- Molecular and Cellular Function of Transcription Factor 4 in Pitt-Hopkins Syndrome.Developmental neuroscience · 2021Review
- Article
- Region and Cell Type Distribution of TCF4 in the Postnatal Mouse Brain.Frontiers in neuroanatomy · 2020Article
- Evolution and Comprehensive Analysis of DNaseI Hypersensitive Sites in Regulatory Regions of Primate Brain-Related Genes.Frontiers in genetics · 2019Article
- Evaluation of Diagnostic Yield in Fetal Whole-Exome Sequencing: A Report on 45 Consecutive Families.Frontiers in genetics · 2019Article
- Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis.European journal of human genetics : EJHG · 2018Article
- Prioritization of Variants Detected by Next Generation Sequencing According to the Mutation Tolerance and Mutational Architecture of the Corresponding Genes.International journal of molecular sciences · 2018Review
- 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.Molecular psychiatry · 2018Article
- The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk GeneMolecular neuropsychiatry · 2017Article
- Molecular Mechanisms of Transcription Factor 4 in Pitt Hopkins Syndrome.Current genetic medicine reports · 2017Article
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Authors and funding
22 authors at 7 institutions in 2 countries.
Funding
Abstract
backgroundMutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. To address the relationship between mutation of these transcripts and phenotype, we report a three-generation family segregating mild intellectual disability with a chromosomal translocation disrupting TCF4.
resultsUsing whole genome sequencing, we detected a complex unbalanced karyotype disrupting TCF4 (46,XY,del(14)(q23.3q23.3)del(18)(q21.2q21.2)del(18)(q21.2q21.2)inv(18)(q21.2q21.2)t(14;18)(q23.3;q21.2)(14pter®14q23.3::18q21.2®18q21.2::18q21.1®18qter;18pter®18q21.2::14q23.3®14qter). Subsequent transcriptome sequencing, qRT-PCR and nCounter analyses revealed that cultured skin fibroblasts and peripheral blood had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Although the derivative chromosome generated a PLEKHG3-TCF4 fusion transcript, the increased levels of TCF4 mRNA arose from transcript variants originating distal to the translocation breakpoint, not from the fusion transcript.
conclusionsAlthough validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS are partially rescued by overexpression of those short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain.
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