Zucchero Theresa M, Cooper Margaret E, Maher Brion S, Daack-Hirsch Sandra, Nepomuceno Buena, Ribeiro Lucilene, Caprau Diana, Christensen Kaare, Suzuki Yasushi, Machida Junichiro, Natsume Nagato, Yoshiura Koh-Ichiro, Vieira Alexandre R, Orioli Ieda M, Castilla Eduardo E, Moreno Lina, Arcos-Burgos Mauricio, Lidral Andrew C, Field L Leigh, Liu You-e, Ray Ajit, Goldstein Toby H, Schultz Rebecca E, Shi Min, Johnson Marla K, Kondo Shinji, Schutte Brian C, Marazita Mary L, Murray Jeffrey C
University of Iowa, Iowa City 52242, USA.
N Engl J Med. 2004 Aug 19;351(8):769-80. doi: 10.1056/NEJMoa032909.
Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene.
We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6.
Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9)); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child.
DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.
唇裂或腭裂（或二者并发）是一种常见的出生缺陷，由遗传和环境因素共同导致。我们通过检查大量患病患者及其家族，并评估一个特定的候选基因，来寻找导致这种复杂性状的特定遗传因素。
我们将编码干扰素调节因子6（IRF6）的基因确定为候选基因，这是基于该基因与常染色体显性遗传形式的唇腭裂——范德伍迪综合征有关。该基因中的一个单核苷酸多态性导致在氨基酸位置274处出现缬氨酸或异亮氨酸（V274I）。我们对来自亚洲、欧洲和南美洲有血缘关系的10个群体的1968个家族中的8003名个体进行了V274I的传递不平衡检验、单倍型和连锁分析以及病例对照分析，并确定了与IRF6基因变异相关的唇裂或腭裂风险。
在整个群体数据集中发现了缬氨酸（V）等位基因过度传递的有力证据（P<10-9）；此外，来自南美洲和亚洲的一些个体群体的结果非常显著。IRF6基因的变异对唇裂或腭裂的遗传贡献率为12%，并使已有一个患病孩子的家族中复发风险增加了两倍。
与IRF6相关的DNA序列变异是唇裂（无论是否伴有腭裂）的主要促成因素。单基因变异对唇裂或腭裂的影响是遗传咨询中的一个重要考虑因素。
