Confirmation of linkage of Van der Woude syndrome to chromosome 1q32: Evidence of association with STR alleles suggests possible unique origin of thedisease mutation

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression. Its clinical features are va riably expressed, but include cleft lip and/or cleft palate, lip pits and h ypodontia. All VWS families studied to date map the disease gene to a <2 cM region of chromosome 1q32, with no evidence of locus heterogeneity. The ai m of this study is to refine the localization of the VWS gene and to furthe r assess possible heterogeneity. We analyzed four multiplex VWS families. All available members were clinica lly assessed and genotyped for 19 short tandem repeat markers on chromosome 1 in the VWS candidate gene region. We performed two-point and multipoint limit of detection (LOD) score analyses using a high penetrance autosomal d ominant model. All families showed positive LOD scores without any recombin ation in the candidate region. The largest two-point LOD score was 5.87. Ou r assay method for short tandem repeat (STR) markers provided highly accura te size estimation of marker allele fragment sizes, and therefore enabled u s to determine the specific alleles segregating with the VWS gene in each o f our four families. We observed a striking pattern of STR allele sharing a t several closely linked loci among our four Caucasian VWS families recruit ed at three different locations in the US. These results suggest the possib ility of a unique origin for a mutation responsible for many or most cases of VWS.