A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3
A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3
复制标题
DOI：
10.1016/j.ajhg.2016.02.014
复制
发表时间：
2016-04-07
影响因子：
9.8
通讯作者：
Marazita, Mary L.
中科院分区：
文献类型：
--
作者：
Leslie, Elizabeth J.;Liu, Huan;Marazita, Mary L.
腭裂（CP）是一种常见的出生缺陷，每2,500例活产婴儿中就有1例发生。大约一半的CP婴儿有综合征形式，表现出其他身体和认知障碍。另一半患有非综合征型CP，迄今为止，与非综合征型CP风险相关的基因很少。为了确定这些风险因素，我们对这种疾病进行了全基因组关联研究。我们发现GRHL 3的错义变异与全基因组显著相关（p.Thr454Met [c.1361C>T]; rs 41268753; p = 4.08 x 10（-9）），并在病例和对照受试者的独立样本中重复了该结果。在发现和复制样本中，rs 41268753均增加了CP风险（OR = 8.3，95%CI 4.1-16.8; OR = 2.16，95%CI 1.43-3.27）。在荧光素酶反式激活试验中，p.Thr454Met的活性约为野生型GRHL 3的三分之一，并且在斑马鱼胚胎中，干扰了胚胎发育。我们的结论是，这种突变是一种病因变异的非综合征型CP，是少数几个功能变异的非综合征型口面裂。这一发现推进了我们对颅面发育遗传基础的理解，并可能最终导致复发风险预测，治疗和预后的改善。
Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 x 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.