title: Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Maduro
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Barbara N
authors.initials: BN
authors.lastname: Pusey
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Praveen F
authors.initials: PF
authors.lastname: Cherukuri
authors.affiliation: Department of Medical Genetics, University of British Columbia, Children's and Women's Health Centre of BC, Vancouver, BC, Canada.|Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Atkins
authors.affiliation: Department of Medical Genetics, University of British Columbia, Children's and Women's Health Centre of BC, Vancouver, BC, Canada.|Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Christèle
authors.initials: C
authors.lastname: du Souich
authors.affiliation: Department of Medical Genetics, University of British Columbia, Children's and Women's Health Centre of BC, Vancouver, BC, Canada.|Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Rupps
authors.affiliation: Sunny Hill Health Centre for Children, Vancouver, BC, Canada.
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Limbos
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Samarth S
authors.initials: SS
authors.lastname: Bhatt
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Patrice
authors.initials: P
authors.lastname: Eydoux
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Links
authors.affiliation: Department of Medical Genetics, University of British Columbia, Children's and Women's Health Centre of BC, Vancouver, BC, Canada.|Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: May C
authors.initials: MC
authors.lastname: Malicdan
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.|The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, New York, NY, USA.|The Feil Family Brain and Mind Research Institute (BMRI), New York, NY, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.affiliation: Department of Medical Genetics, University of British Columbia, Children's and Women's Health Centre of BC, Vancouver, BC, Canada.|Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Morimoto
authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Department of General Practice, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sear
authors.affiliation: Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Clara
authors.initials: C
authors.lastname: Van Karnebeek
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.|NHGRI, National Institutes of Health, Bethesda, MD, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA. cboerkoel@gmail.com.|Department of Medical Genetics, University of British Columbia, Children's and Women's Health Centre of BC, Vancouver, BC, Canada. cboerkoel@gmail.com.|Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada. cboerkoel@gmail.com.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002648:Child; D019066:Facies; D005260:Female; D006801:Humans; D006985:Hyperventilation / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D020033:Protein Isoforms; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors
keywords: Gene expression; Intellectual disability; Pitt-Hopkins syndrome; Promoter utilization; RNAseq; TCF4; Transcriptome; Translocation