Department of Oral Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, PA 15261, USA.
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.
唇腭裂是所有人类先天缺陷的很大一部分，其具有显著的终生发病率和复杂的病因。几项研究表明，遗传因素似乎在唇腭裂的病因中起着重要作用。人类染色体 9q21 区域在前几份报告中被认为包含可能的唇腭裂基因座。此外，一个特定的区域（9q22.3-34.1）被认为有大约 45%的可能性携带唇腭裂易感基因。对跨越 9q22.3-34.11 区域的 50 个 SNP 进行精细作图，以检测其在美国、西班牙、土耳其、危地马拉和中国的家庭中与唇腭裂的相关性。我们进行了基于家庭的分析，发现 STOM(rs306796)与危地马拉家庭的唇腭裂存在关联的证据（P=0.004），并且在所有的多病例家庭中都存在关联（P=0.002）。同一 SNP 在美国家庭中也显示出边缘相关性（P=0.04）。在名义值为 0.05 的情况下，其他 SNP 也与唇腭裂和唇腭裂亚组存在关联。STOM 和 PTCH 基因以及附近的 FOXE1 的 SNP 与危地马拉和中国家庭的唇腭裂表型进一步相关。基因优先级分析显示，在 339 个存在于该区域的基因中，PTCH 和 STOM 排在前 14 位候选基因中，与唇腭裂相关。我们的研究结果支持这样的假设，即 9q22.32-34.1 区域包含唇腭裂易感基因。具有其他人群的进一步研究应该集中在这些基因座上，以进一步研究这些基因在人类唇腭裂中的参与情况。
