Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations.
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.
Institute of Genetics, School of Biology, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
Javier T
JT
Granados-Riveron
Mark
M
Pope
Frances A
FA
Bu'lock
Christopher
C
Thornborough
Jacqueline
J
Eason
Kerry
K
Setchfield
Ami
A
Ketley
Edwin P
EP
Kirk
Diane
D
Fatkin
Michael P
MP
Feneley
Richard P
RP
Harvey
J David
JD
Brook
D024722:Cardiac Myosins / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D050991:GATA4 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006330:Heart Defects, Congenital / Q000235:genetics*; D006579:Heterozygote; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D018995:Myosin Heavy Chains / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C094239:MYH6 protein, human; C095552:NKX2-5 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains