CONGENITAL HEART DISEASE
Congenital heart disease (CHD) is a common birth defect, of which ventricular septal defects are collectively the most common type. Abnormal cardiac development originates from both environmental and genetic factors. Multiple studies postulate that mutations in several genes could be implicated in CHD. The transcription factor GATA4 forms a complex with TBX5 which interacts with a heart muscle protein, α-myosin heavy chain. Another factor, the homeobox (developmental) gene, NKX2-5 also interacts with MYH6. Mutations of all these proteins are associated with both atrial and ventricular septal defects. In addition, NKX2-5 is associated with defects in the electrical conduction of the heart and TBX5 is related to the Holt-Oram syndrome which includes electrical conduction defects and abnormalities of the upper limb (Srivastava, D., 2006, Cell). Atrioventricular septal defect (AVSD) can also be caused by mutation in the gene encoding cell adhesion molecule CRELD1. Bone morphogenetic protein 4 (BMP4) was shown to have a critical role in functional heart formation in model animals; the loss of this protein resulted in various developmental defects (McCulley, D. J. et al., 2008, Dev Dyn).
The GATA4 gene (7 exons) spans ~55.8 kb of genomic DNA and is located on chromosome 8p23, ~11.6 Mb from p-telomere. Probes for each of the 7 exons of GATA4 and two probes upstream and downstream of the gene are included in the P311-A2 probemix.
The NKX2-5 gene (2 exons) spans ~3.2 kb of genomic DNA and is located on chromosome 5q35, ~172.5 Mb from p-telomere. For each exon, two probes are included. The TBX5 gene (10 exons) spans ~52.2 kb of genomic DNA and is located on chromosome 12q24, ~113.3 Mb from p-telomere. Probes for 8 of the 10 exons are included, with two probes for exon 9 and 10. The BMP4 gene (5 exons) spans ~4.8 kb of genomic DNA and is located on chromosome 14q22, ~53.5 Mb from p-telomere. Probes for 4 of the 5 exons of BMP4 are included. The CRELD1 gene (11 exons) spans ~11.6 kb of genomic DNA and is located on chromosome 3p25, ~10 Mb from p-telomere. Probes for exons 3 and 10 are included.
This probemix furthermore contains 3 probes for chromosome region 22q11 (DiGeorge). In addition, 10 reference probes are included in this probemix, detecting several different autosomal chromosomal locations.