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Lookup NU author(s): Dr Ana TopfORCiD, Dr Helen GriffinORCiD, Dr Elise Glen, Rachel Soemedi, Dr Danielle Brown, Dr Darroch Hall, Dr Thahira Rahman, Dr John O'Sullivan, Professor Bernard Keavney, Professor Judith Goodship
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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).Methods and 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.Significance: 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.
Author(s): Topf A, Griffin HR, Glen E, Soemedi R, Brown DL, Hall D, Rahman TJ, Eloranta JJ, Jungst C, Stuart AG, O'Sullivan J, Keavney BD, Goodship JA
Publication type: Article
Publication status: Published
Journal: PLoS One
Year: 2014
Volume: 9
Issue: 8
Online publication date: 05/08/2014
Acceptance date: 27/03/2014
Date deposited: 30/10/2014
ISSN (electronic): 1932-6203
Publisher: Public Library of Science
URL: http://dx.doi.org/10.1371/journal.pone.0095453
DOI: 10.1371/journal.pone.0095453
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