Identification and characterization of a susceptibility gene or genes for congenital heart disease and oesophageal atresia at human chromosome 17q21.3- q23.3. (360G-Wellcome-079973_Z_06_Z)

Congenital heart defects (CHD) are present in nearly 1% of all newborns and continue to be a significant cause of death in infancy. They may occur in isolation or in association with other birth defects, as with the 22q11 deletion syndrome, for example. Case reports from the human cytogenetics literature point to a susceptibility locus for CHD together with oesophageal atresia at human chromosome 17q21.3-q23.3. This evidence is supported by the finding that mice with a chromosomally engineered deletion within this region,6.8 Mb in size, have CHD, though not oesophageal atresia. The aim of the proposed research is to identify the susceptibility gene for congenital heart defect at human chromosome 17q21.3-q23.3 using further mouse chromosome engineering, BAC 'rescue' of a smaller nested deletion and then targeted mutagenesis of selected candidate genes. In parallel, DNA samples from patients with CHD and oesophageal atresia will be studied by array-based comparative genomic hybridization, with a view to refining the critical region for both of these defects. Subsidiary aims of the project are the identification of the gene responsible for oesophageal atresia at chromosome 17q21.3, and the identification of othersusceptibility loci for CHD and oesophageal atresia elsewhere in the human genome.