Follow-up association studies of chromosome region 9q and nonsyndromic cleft lip/palate

Am J Med Genet A. 2010 Jul;152A(7):1701-10. doi: 10.1002/ajmg.a.33482.


Cleft lip/palate comprises a large fraction of all human birth defects, and is notable for its significant lifelong morbidity and complex etiology. Several studies have shown that genetic factors appear to play a significant role in the etiology of cleft lip/palate. Human chromosomal region 9q21 has been suggested in previous reports to contain putative cleft loci. Moreover, a specific region (9q22.3-34.1) was suggested to present a approximately 45% probability of harboring a cleft susceptibility gene. Fine mapping of 50 SNPs across the 9q22.3-34.11 region was performed to test for association with cleft lip/palate in families from United States, Spain, Turkey, Guatemala, and China. We performed family-based analyses and found evidence of association of cleft lip/palate with STOM (rs306796) in Guatemalan families (P = 0.004) and in all multiplex families pooled together (P = 0.002). This same SNP also showed borderline association in the US families (P = 0.04). Under a nominal value of 0.05, other SNPs also showed association with cleft lip/palate and cleft subgroups. SNPs in STOM and PTCH genes and nearby FOXE1 were further associated with cleft phenotypes in Guatemalan and Chinese families. Gene prioritization analysis revealed PTCH and STOM ranking among the top fourteen candidates for cleft lip/palate among 339 genes present in the region. Our results support the hypothesis that the 9q22.32-34.1 region harbors cleft susceptibility genes. Additional studies with other populations should focus on these loci to further investigate the participation of these genes in human clefting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • China
  • Chromosomes, Human, Pair 9 / genetics*
  • Cleft Lip / genetics*
  • Cleft Palate / genetics*
  • Family
  • Follow-Up Studies
  • Genetic Association Studies*
  • Genetic Markers
  • Guatemala
  • Haplotypes / genetics
  • Humans
  • Physical Chromosome Mapping
  • Polymorphism, Single Nucleotide / genetics


  • Genetic Markers

Grant support