Confirmation of linkage of Van der Woude syndrome to chromosome 1q32: evidence of association with STR alleles suggests possible unique origin of the disease mutation.

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder with high penetrance and variable expression. Its clinical features are variably expressed, but include cleft lip and/or cleft palate, lip pits and hypodontia. 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 aim of this study is to refine the localization of the VWS gene and to further assess possible heterogeneity. We analyzed four multiplex VWS families. All available members were clinically 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 dominant model. All families showed positive LOD scores without any recombination in the candidate region. The largest two-point LOD score was 5.87. Our assay method for short tandem repeat (STR) markers provided highly accurate size estimation of marker allele fragment sizes, and therefore enabled us to determine the specific alleles segregating with the VWS gene in each of our four families. We observed a striking pattern of STR allele sharing at several closely linked loci among our four Caucasian VWS families recruited at three different locations in the US. These results suggest the possibility of a unique origin for a mutation responsible for many or most cases of VWS.