title: Functionally significant, rare transcription factor variants in tetralogy of Fallot.
abstract: OBJECTIVE
  Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF).
  
  
  RESULTS
  We sequenced the coding, 5'UTR, and 3'UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1) in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network.
  
  
  CONCLUSIONS
  This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3-13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Töpf
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Griffin
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Elise
authors.initials: E
authors.lastname: Glen
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Soemedi
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Brown
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Darroch
authors.initials: D
authors.lastname: Hall
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Thahira J
authors.initials: TJ
authors.lastname: Rahman
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jyrki J
authors.initials: JJ
authors.lastname: Eloranta
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland; Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Jüngst
authors.affiliation: Bristol Royal Hospital for Children, Bristol, United Kingdom.
authors.forename: A Graham
authors.initials: AG
authors.lastname: Stuart
authors.affiliation: Paediatric Cardiology, Freeman Hospital Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Institute of Cardiovascular Sciences, The University of Manchester, Manchester, United Kingdom.
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Keavney
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
mesh_terms: D018628:Gene Dosage; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000503:physiopathology; D006801:Humans; D009154:Mutation / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D017422:Sequence Analysis, DNA; D013771:Tetralogy of Fallot / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D014157:Transcription Factors
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