A Preliminary Gene Map for the Van der Woude Syndrome Critical Region Derived from 900 kb of Genomic Sequence at 1q32–q41

  1. Brian C. Schutte1,7,
  2. Bryan C. Bjork1,4,7,
  3. Kevin B. Coppage1,7,
  4. Margaret I. Malik1,
  5. Simon G. Gregory5,
  6. Deborah J. Scott5,
  7. Luci M. Brentzell6,
  8. Yoriko Watanabe1,
  9. Michael J. Dixon6, and
  10. Jeffrey C. Murray1,2,3,4,8
  1. Departments of 1Pediatrics, 2Biological Sciences, and 3Preventive Medicine and Environmental Health, and 4Program in Genetics, University of Iowa, Iowa City, Iowa 52242 USA; 5Sanger Centre, Hinxton, Cambridgeshire B10 1SA, UK; and 6Departments of Dental Medicine and Surgery, University of Manchester, Manchester M13 9PT, UK

Abstract

Van der Woude syndrome (VWS) is a common form of syndromic cleft lip and palate and accounts for ∼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. 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 STSs were developed from the existing physical map and were then used to construct a contig of sequence-ready bacterial clones across the entire VWS critical region. All STSs and BAC clones were shared with the Sanger Centre, which 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 ∼1.1-Mb region; all but two of these clones have been sequenced completely. Over 900 kb of genomic sequence, including the 350-kb VWS critical region, were analyzed and revealed novel polymorphisms, including an 8-kb deletion/insertion, and revealed 4 known genes, 11 novel genes, 9 putative genes, and 3 psuedogenes. The positional candidates LAMB3, G0S2, HIRF6, and HSD11 were excluded as the VWS gene by mutation analysis. A preliminary gene map for the VWS critical region is as follows: CEN-VWS33-VWS34-D1S491-VWS1-VWS19-LAMB3G0S2-VWS26-VWS25-HSD11-ADORA2BP-VWS17-VWS14-HIRF6-VWS2-VWS18-D1S205-VWS23-VWS20-VWS30-VWS31-VWS35-VWS37VWS38-HIPP-RNASEH1P-VWS40-VWS42-VWS41-TEL. The data provided here will help lead to the identification of the VWS gene, and this study provides a model for how laboratories that have a regional interest in the human genome can contribute to the sequencing efforts of the entire human genome.

Footnotes

  • 7 These authors contributed equally to this work.

  • 8 Corresponding author.

  • E-MAIL Jeff-Murray{at}uiowa.edu; FAX (319) 335-6970.

    • Received May 27, 1999.
    • Accepted November 9, 1999.
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