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. and Brook, David (2012) Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations. Congenital Heart Disease, 7 (2). pp. 151-159. ISSN 1747-079X

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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.

Item Type: Article
Keywords: Congenital heart disease, Mutations, Multiple heterozygosity
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences > School of Biology
Identification Number:
Depositing User: Liu, Mr Zhenxing
Date Deposited: 25 Apr 2014 10:11
Last Modified: 04 May 2020 20:21

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