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Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability Maduro, Valerie; Pusey, Barbara N; Cherukuri, Praveen F; Atkins, Paul; du Souich, Christèle; Rupps, Rosemarie; Limbos, Marjolaine; Adams, David R; Bhatt, Samarth S; Eydoux, Patrice; Links, Amanda E; Lehman, Anna; Malicdan, May C; Mason, Christopher E; Morimoto, Marie; Mullikin, James C; Sear, Andrew; Van Karnebeek, Clara; Stankiewicz, Pawel; Gahl, William A; Toro, Camilo; Boerkoel, Cornelius F

Abstract

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.

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Title
Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability
Creator
Maduro, Valerie; Pusey, Barbara N; Cherukuri, Praveen F; Atkins, Paul; du Souich, Christèle; Rupps, Rosemarie; Limbos, Marjolaine; Adams, David R; Bhatt, Samarth S; Eydoux, Patrice; Links, Amanda E; Lehman, Anna; Malicdan, May C; Mason, Christopher E; Morimoto, Marie; Mullikin, James C; Sear, Andrew; Van Karnebeek, Clara; Stankiewicz, Pawel; Gahl, William A; Toro, Camilo; Boerkoel, Cornelius F
Contributor
Child and Family Research Institute
Publisher
BioMed Central
Date Issued
2016-05-14
Description
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.
Subject
Intellectual disability; Promoter utilization; Pitt-Hopkins syndrome; TCF4; Gene expression; Translocation; Transcriptome; RNAseq
Genre
Article
Type
Text
Language
eng
Date Available
2018-05-16
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0366888
URI
http://hdl.handle.net/2429/65942
Affiliation
Medicine, Faculty of; Other UBC; Non UBC; Family Practice, Department of; Medical Genetics, Department of; Pathology and Laboratory Medicine, Department of
Citation
Orphanet Journal of Rare Diseases. 2016 May 14;11(1):62
Publisher DOI
10.1186/s13023-016-0439-6
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
Maduro et al.
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)