A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41

Van der Woude syndrome (VWS) is a common form of syndromic cleft lip and pa late and accounts for similar to 2% of all cleft lip and palate cases. Dist inguishing characteristics include cleft lip with ol without cleft palate, isolated cleft palate, bilateral lip pits, hypodontia, normal intelligence, and an autosomal-dominant mode of transmission with a high degree of penet rance. Previously, the VWS locus was mapped to a 1.6-cM region in 1q32-q41 between D1S491 and D1S205, and a 4.4-Mb contig of YAC clones of this region was constructed. In the current investigation, gene-based and anonymous ST Ss were developed from the existing physical map and were then used to cons truct a contig of sequence-ready bacterial clones across the entire VWS cri tical region. All STSs and BAC clones were shared with the Sanger Centre, w hich developed a contig of PAC clones over the same region. A subset of 11 clones from both contigs was selected for high-throughput sequence analysis across the similar to 1.1-Mb region; all but two of these clones have been sequenced completely. Over 900 kb of genomic sequence, including the 350-k b VWS critical region, were analyzed and revealed novel polymorphisms, incl uding an 8-kb deletion/insertion, and revealed 4 known genes, 11 novel gene s, 9 putative genes, and 3 psuedogenes. The positional candidates LAMB3 GOS 2, HIRF6, and HSD11 were excluded as the VWS gene by mutation analysis. A p reliminary gene map for the VWS critical region is as follows: CEN-VWS33-VW S34-D1S491-VWS1-VWS19-LAMB3- GOS2-VGVS26-VWS25-HSD11-ADORA2BP-VWS17-VWS14-H IRF6-VWS2-VWS1-BD1S205-VWS23-VWS20-VWS30-VWS31-VWS35-VWS37-VWS38-HIPP-RNASE HIP-VWS40-VWS42-VWS41-TEL. The data provided here will help lead to the ide ntification of the VWS gene, and this study provides a model For how labora tories that have a regional interest in the human genome can contribute to the sequencing efforts of the entire human genome.