Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth disorder recently shown to be caused by mutations in the heparan sulfate proteoglycan GPC3 [Pilia et al., Nat Genet; 12:241-247 1996]. We have used Southern blot analysis and polymerase chain reaction amplification of intra-exonic sequences to identify four new GPC3 mutations and further characterize three previously reported SGBS mutations. De novo GPC3 mutations were identified in 2 families. In general, the mutations were unique deletions ranging from less than 0.1 kb to more than 300 kb in length with no evidence of a mutational hot spot discerned. The lack of correlation between the phenotype of 18 affected males from these 7 families and the location and size of the GPC3 gene mutations suggest that SGBS is caused by a nonfunctional GPC3 protein.

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Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked gigantism syndrome characterized primarily by a coarse facies and somatic overgrowth which we have observed to be associated with an increased risk for embryonal tumors. Genetic linkage analysis for two SGBS kindreds in which X linked dominant inheritance was observed has been conducted for the X chromosome. The closest linkage to SGBS was observed for the Xq26 locus HPRT (Z max = 7.45, theta max = 0.00). SGBS-Xq marker recombinations map the disease locus to the DXS425-DXS1123 interval on Xq25-q27. This maps the disease locus to a region known to contain a previously characterized chromosomal translocation breakpoint found in a young girl with somatic overgrowth. This observation may have implications for the cloning of the SGBS gene.