Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin

Abstract

Williams syndrome (WS) is a neurodevelopmental disorder with a variable phenotype. Molecular genetic studies have indicated that hemizygosity 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 minimal critical deletion region in 63 patients using 10 microsatellite markers and 5 fluorescence in situ hybridization (FISH) probes on chromosome 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 defined by the satellite markers. In all informative cases deleted at ELN, the deletion extends from D7S489U to D7S1870. The genetic distance between these two markers is about 2 cM. Of the 51 informative patients with 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 analysis for LIMK1, a candidate gene previously implicated in the WS phenotype, did not show any mutations in our WS patients not deleted for ELN. LIMK1 deletions were found in all elastin-deletion cases who had WS. One case, who has isolated, supravalvular aortic stenosis and an elastin deletion, was not deleted for LIMK1. It remains to be determined if haploinsufficiency of LIMK1 is responsible in part for the WS phenotype or is simply deleted due to its close proximity to the elastin locus.

Refinement of the genomic structure of STX1A and mutation analysis in nondeletion Williams syndrome patients

“…All individuals met the clinical criteria for WS by history and physical findings, but had normal karyotypes. Four of the individuals had been reported previously [Nickerson et al, 1995;Wu et al, 1998] and the other was newly enrolled for the present study (Fig. 1).…”

“…Our previous studies showed that the majority of WS carry a similar sized deletion spanning an identical number of genes [Wu et al, 1998]. This renders the characterization of genes that contribute to specific features difficult.…”

“…To confirm the exonintron boundaries of the STX1A gene, PCR primers were designed using the previously published sequence as a starting point. Products from both BACs and total human genomic DNA were amplified according to a published protocol [Wu et al, 1998], sized by agarose gel electrophoresis, purified by GeneClean Kit (Bio 101), and sequenced directly in the Baylor College of Medicine sequencing facility.…”

“…Prior to entering the study, molecular analyses of the WS region was performed on all individuals, using 10 polymorphic markers within the common deletion region and FISH analyses with a ELN-5′ probe, LIMK1 probe [Wu et al, 1998] and a STX1A probe [Osborne et al, 1997]. No deletions were detected in any of the five study subjects.…”

Zebrafish gene knockdowns imply roles for human YWHAG in infantile spasms and cardiomegaly

“…WBS patients show mental retardation with a specific cognitive-behavioral profile, supravalvular aortic stenosis, infantile hypercalcemia, a hoarse voice, and distinctive dysmorphic features including an elfin-like face and edematous eyes. The prevalence of WBS in the population is approximately one in 7,500-20,000 (Ewart et al, 1993;Stromme et al, 2002;Wu et al, 1998). Almost all deletions of 7q11.23 in patients with WBS have arisen by de novo mechanisms.…”