Van der Woude syndrome (VWS) is the most common form of syndromic cleft lip and palate and accounts for about 2% of all cleft lip and palate cases. Distinguishing characteristics include cleft lip with or without cleft palate, isolated cleft palate, bilateral lip pits, hypodontia, normal intelligence, and an autosomal dominant mode of transmission with a high degree of penetrance.

The VWS locus has been mapped to a 1.6cM region of chromosome 1q32 by linkage analysis and the discovery of a microdeletion around D1S205. One 850 kb YAC, yCEPH785B2, contains both flanking markers, D1S491 and D1S205, and encompasses the microdeletion. Human bacterial artificial chromosome (BAC) clones have been isolated from the critical region by screening the Research Genetics human BAC library with STSs across the critical region. To date a complete contig has been constructed containing 10 BACs ranging from 90 to 300 kb in size. The minimum tiling path of 4 BACs suggest that the maximum size of the critical region is 610kb. The ends of the BACs were sequenced and 11 new STSs designed. One of the BAC-end sequence is identical to a previously unmapped EST (135676). This putative gene was excluded, since the end of this BAC maps outside the critical region. There are also 70 cosmids in the critical region, 48 of which have been mapped. Six new STS have been generated from cosmid sequence including a 12 allele STRP. Linkage analysis of VWS families containing critical recombinants is in progress.

SSCP analysis of affected family members has uncovered two new families with loss of heterozygosity at the VWS critical region. These microdeletions are equal to or greater in size than the original microdeletion. 32 genes which have been previously cytogenetically mapped to 1q32 have been excluded. Sequence from one of the BACs has shown identity to a human interferon regulatory factor and is currently being screened by mutational analysis as a new canditated gene. Additional transcription mapping and candidate screening are underway. Hybridization screens for transcription factors such as homeobox genes, which would have a high probability for involvement in VWS, have been negative to date.