Abstract
The prevalence of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are believed to be higher in the Japanese than in Americans, Europeans or Africans. The purpose of this study was to investigate, in a Japanese population, relationships between CL/P or CPO and seven candidate genes (TGFB3, DLX3, PAX9, CLPTM1, TBX10, PVRL1, TBX22) that showed positive associations in other populations and are expressed in the oral/lip region in developing mice. We first searched for mutations in these genes among 112 CL/P and 16 CPO patients, and found a heterozygous missense mutation (640A>G, S214G) in exon 3 of PAX9 in two sibs with CL/P and their phenotypically normal mother from a Japanese family. A population-based case-control analysis and a family-based transmission disequilibrium test (TDT), using single nucleotide polymorphisms (SNPs), and two-SNP haplotypes of the genes, between the 112 CL/P cases with their parents and 192 controls indicated a significant association at one SNP site, IVS1+5321, in TGFB3 with a P-value of 0.0016. Population-based haplotyping revealed that the association was most significant for haplotype “A/A” consisting of IVS1+5321 and IVS1−1572; TDT also gave a P-value of 0.0252 in this haplotype.
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Acknowledgements
The participation of patients, their families and control individuals in the study is greatly appreciated. We also thank staff members of Tokyo Dental College Hospital and Nagasaki University Hospital who assisted in collecting blood samples and those of the Department of Human Genetics at Nagasaki University for excellent technical assistance. K. Yoshiura was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas (Medical Genome Science, No. 16012101); N. Niikawa by a Grant-in-Aid for Scientific Research (Category S, No. 13854024) and CREST from the Japan Science and Technology Agency Corporation (JST).
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Ichikawa, E., Watanabe, A., Nakano, Y. et al. PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses. J Hum Genet 51, 38–46 (2006). https://doi.org/10.1007/s10038-005-0319-8
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DOI: https://doi.org/10.1007/s10038-005-0319-8
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