A SUBMICROSCOPIC DELETION IN XQ26 ASSOCIATED WITH FAMILIAL SITUS AMBIGUUS

Abnormal left-right-axis formation results in heterotaxy, a multiple-m alformation syndrome often characterized by severe heart defects, sple nic abnormalities, and gastrointestinal malrotation. Previously we had studied a large family in which a gene for heterotaxy, HTX1, was mapp ed to a 19-cM region in Xq24-q27.1. Further analysis of this family ha s revealed two recombinations that place HTX1 between DXS300 and DXS10 62, an interval spanning similar to 1.3 Mb in Xq26.2. In order to prov ide independent confirmation of HTX1 localization, a PCR-based search for submicroscopic deletions in this region was performed in unrelated males with sporadic or familial heterotaxy. A cluster of sequence-tag ged sites failed to amplify in an individual who also had a deceased, affected brother. FISH identified the mother as a carrier of the delet ion, which arose as a new mutation from the maternal grandfather. The deletion interval spans 600-1,100 kb and lies wholly within the 1.3-Mb region identified by recombination. Discovery of this deletion suppor ts localization of HTX1 to Xq26.2 and reveals the first molecular-gene tic abnormality associated with human left-right-asymmetry defects.