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Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations

Granados-Riveron, Javier T.; Pope, Mark; Bu'Lock, Frances A.; Thornborough, Christopher; Eason, Jacqueline; Setchfield, Kerry; Ketley, Ami; Kirk, Edwin P.; Fatkin, Diane; Feneley, Michael P.; Harvey, Richard P.; Brook, David

Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations Thumbnail


Javier T. Granados-Riveron

Mark Pope

Frances A. Bu'Lock

Christopher Thornborough

Jacqueline Eason

Kerry Setchfield

Research Fellow

Edwin P. Kirk

Diane Fatkin

Michael P. Feneley

Richard P. Harvey

Professor of Human Genetics


Background: Variants of several genes encoding transcription modulators, signal transduction, and structural proteins are known to cause Mendelian congenital heart disease (CHD). NKX2-5 and GATA4 were the first CHD-causing genes identified by linkage analysis in large affected families. Mutations of TBX5 cause Holt–Oram syndrome, which includes CHD as a clinical feature. All three genes have a well-established role in cardiac development.

Design: In order to investigate the possible role of multiple mutations in CHD, a combined mutation screening was performed in NKX2-5, GATA4, and TBX5 in the same patient cohort. Samples from a cohort of 331 CHD patients were analyzed by polymerase chain reaction, double high-performance liquid chromatography and sequencing in order to identify changes in the NKX2-5, GATA4, and TBX5 genes.

Results: Two cases of multiple heterozygosity of putative disease-causing mutations were identified. One patient was found with a novel L122P NKX2-5 mutation in combination with the private A1443D mutation of MYH6. A patient heterozygote for a D425N GATA4 mutation carries also a private mutation of the MYH6 gene (V700M).

Conclusions: In addition to reporting two novel mutations of NKX2-5 in CHD, we describe families where multiple individual mutations seem to have an additive effect over the pathogenesis of CHD. Our findings highlight the usefulness of multiple gene mutational analysis of large CHD cohorts.

Journal Article Type Article
Publication Date Mar 1, 2012
Deposit Date Apr 25, 2014
Publicly Available Date Apr 25, 2014
Journal Congenital Heart Disease
Print ISSN 1747-079X
Electronic ISSN 1747-079X
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 7
Issue 2
Keywords Congenital heart disease, Mutations, Multiple heterozygosity
Public URL
Publisher URL


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