DELINEATION OF THE COMMON CRITICAL REGION IN WILLIAMS-SYNDROME AND CLINICAL CORRELATION OF GROWTH, HEART-DEFECTS, ETHNICITY, AND PARENTAL ORIGIN

Williams syndrome (WS) is a neurodevelopmental disorder with a variabl e phenotype. Molecular genetic studies have indicated that hemizygosit y at the elastin locus (ELN) may account for the cardiac abnormalities seen in WS, but that mental retardation and hypercalcemia are likely caused by other genes flanking ELN. In this study, we defined the mini mal critical deletion region in 63 patients using 10 microsatellite ma rkers and 5 fluorescence in situ hybridization (FISH) probes on chromo some 7q, flanking ELN. The haplotype analyses showed the deleted cases to have deletions of consistent size, as did the FISH analyses using genomic probes for the known ends of the commonly deleted region defin ed by the satellite markers. In all informative cases deleted at ELN, the deletion extends from D7S489U to D751870. The genetic distance bet ween these two markers is about 2 cM. Of the 51 informative patients w ith deletions, 29 were maternal and 22 were paternal in origin. There was no evidence for effects on stature by examining gender, ethnicity, cardiac status, or parental origin of the deletion. Heteroduplex anal ysis for LIMK1, a candidate gene previously implicated in the WS pheno type, did not show any mutations in our WS patients not deleted for EL N. LIMK1 deletions were found in all elastin-deletion cases who had WS , One case, who has isolated, supravalvular aortic stenosis and an ela stin deletion, was not deleted for LIMK1. It remains to be determined if haploinsufficiency of LIMK1 is responsible in part for the WS pheno type or is simply deleted due to its close proximity to the elastin lo cus. (C) 1998 Wiley-Liss, Inc.