Detailed mapping of a congenital heart disease gene in chromosome 3p25

Distal deletion of chromosome 3p25-pter (3p(-) syndrome) produces a distinc t clinical syndrome characterised by low birth weight, mental retardation, telecanthus, ptosis, and micrognathia. Congenital heart disease (CHD), typi cally atrioventricular septal defect (AVSD), occurs in about a third of pat ients. In total, approximately 25 cases of 3p(-) syndrome have been reporte d world wide. We previously analysed five cases and showed that (1) the 3p2 5-pter deletions were variable and (2) the presence of CHD correlated with the proximal extent of the deletion, mapping a CHD gene centromeric to D3S1 8. To define the molecular pathology of the 3p(-) syndrome further, we have now proceeded to analyse the deletion region in a total of 10 patients (fi ve with CHD), using a combination of FISH analysis and polymorphic markers, for up to 21 loci from 3p25-p26. These additional investigations further s upported the location of an AVSD locus within 3p25 and refined its localisa tion. Thus, the critical region was reduced to an interval between D3S1263 and D3S3594. Candidate 3p25 CHD genes, such as PMCA2 (ATP2B2), fibulin 2, T IMP4, and Sec13R, were shown to map outside the target interval. Additional ly, the critical region for the phenotypic features of the 3p(-) phenotype was mapped to D3S1317 to D3S17 (19-21 cM). These findings will accelerate t he identification of the 3p25 CHD susceptibility locus and facilitate inves tigations of the role of this locus in non-syndromic AVSDs, which are a com mon form of familial and isolated CHD.