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Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability.

TitleComplex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability.
Publication TypeJournal Article
Year of Publication2016
AuthorsMaduro V, Pusey BN, Cherukuri PF, Atkins P, Souich Cdu, Rupps R, Limbos M, Adams DR, Bhatt SS, Eydoux P, Links AE, Lehman A, Malicdan MC, Mason CE, Morimoto M, Mullikin JC, Sear A, Van Karnebeek C, Stankiewicz P, Gahl WA, Toro C, Boerkoel CF
JournalOrphanet J Rare Dis
Date Published2016 05 14
KeywordsAlternative Splicing, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Child, Facies, Female, Humans, Hyperventilation, Intellectual Disability, Mutation, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Protein Isoforms, Transcription Factor 4, Transcription Factors, Translocation, Genetic

BACKGROUND: Mutations 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.

RESULTS: Using 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.

CONCLUSIONS: Although 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.

Alternate JournalOrphanet J Rare Dis
PubMed ID27179618
PubMed Central IDPMC4868023
Grant ListR01 NS076465 / NS / NINDS NIH HHS / United States