Deletion of a 5-cM region at chromosome 8p23 is associated with a spectrumof congenital heart defects

Background-Cytogenetic evidence suggests that the haploinsufficiency of gre ater than or equal to 1 gene located in 8p23 behaves as a dominant mutation , impairing heart differentiation and leading to a wide spectrum of congeni tal heart defects (CHDs), including conotruncal lesions, atrial septal defe cts, atrioventricular canal defects, and pulmonary valve stenosis. An 8p he art-defect-critical region was delineated, and the zinc finger transcriptio n factor GATA4 was considered a likely candidate for these defects. We narr owed this region and excluded a major role of GATA4 in these CHDs. Methods and Results-We studied 12 patients (7 had CHD and 5 did not) with d istal 8p deletions from 9 families by defining their chromosome rearrangeme nts at the molecular level by fluorescent in situ hybridization and short-t andem repeat analysis. Subjects with 8p deletions distal to D8S1706, at app roximate to 10 cM from the 8Ia telomere, did not have CHD, whereas subjects with a deletion that included the more proximal region suffered from the s pectrum of heart defects reported in patients with 8p distal deletions. The 5-cM critical region is flanked distally by D8S1706 and WI-8327, both at a pproximate to 10 cM, and proximally by D8S1825, at 15 cM. Neither GATA4 nor angiopoietin-2 (ANGPT2; a gene in 8p23 involved in blood vessel formation) were found to be deleted in some of the critical patients. We also found t hat CHDs are not related to the parental origin of deletion. Conclusions-Haploinsufficiency for a gene between WI-8327 and D8S1825 is cr itical for heart development. A causal relationship does not seem to exist between GATA4 and ANGPT2 haploinsufficiency and CHDs.