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A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2016-03-24 , DOI: 10.1016/j.ajhg.2016.02.014
Elizabeth J Leslie 1 , Huan Liu 2 , Jenna C Carlson 3 , John R Shaffer 4 , Eleanor Feingold 5 , George Wehby 6 , Cecelia A Laurie 7 , Deepti Jain 7 , Cathy C Laurie 7 , Kimberly F Doheny 8 , Toby McHenry 1 , Judith Resick 1 , Carla Sanchez 1 , Jennifer Jacobs 1 , Beth Emanuele 1 , Alexandre R Vieira 4 , Katherine Neiswanger 1 , Jennifer Standley 9 , Andrew E Czeizel 10 , Frederic Deleyiannis 11 , Kaare Christensen 12 , Ronald G Munger 13 , Rolv T Lie 14 , Allen Wilcox 15 , Paul A Romitti 16 , L Leigh Field 17 , Carmencita D Padilla 18 , Eva Maria C Cutiongco-de la Paz 19 , Andrew C Lidral 20 , Luz Consuelo Valencia-Ramirez 21 , Ana Maria Lopez-Palacio 22 , Dora Rivera Valencia 23 , Mauricio Arcos-Burgos 24 , Eduardo E Castilla 25 , Juan C Mereb 26 , Fernando A Poletta 25 , Iêda M Orioli 27 , Flavia M Carvalho 28 , Jacqueline T Hecht 29 , Susan H Blanton 30 , Carmen J Buxó 31 , Azeez Butali 32 , Peter A Mossey 33 , Wasiu L Adeyemo 34 , Olutayo James 34 , Ramat O Braimah 35 , Babatunde S Aregbesola 35 , Mekonen A Eshete 36 , Milliard Deribew 36 , Mine Koruyucu 37 , Figen Seymen 37 , Lian Ma 38 , Javier Enríquez de Salamanca 39 , Seth M Weinberg 1 , Lina Moreno 20 , Robert A Cornell 40 , Jeffrey C Murray 9 , Mary L Marazita 41
Affiliation  

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 × 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.

中文翻译:

非综合征性腭裂的全基因组关联研究确定了 GRHL3 的病因错义变异。

腭裂 (CP) 是一种常见的出生缺陷,每 2,500 名活产婴儿中就有 1 名发生。大约一半患有 CP 的婴儿有症状,表现出其他身体和认知障碍。另一半患有非综合征 CP,迄今为止,很少有与非综合征 CP 风险相关的基因被表征。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。我们发现了与 GRHL3 中的错义变体(p.Thr454Met [c.1361C>T];rs41268753;p = 4.08 × 10(-9))的全基因组显着关联,并将结果复制到独立的病例和对照样本中科目。在发现和复制样本中,rs41268753 增加了 CP 的风险(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测定中,p。Thr454Met 的活性约为野生型 GRHL3 的三分之一,在斑马鱼胚胎中,它会扰乱周皮发育。我们得出结论,该突变是非综合征性 CP 的病因变异,并且是迄今为止确定的非综合征性口颌裂的少数功能变异之一。这一发现加深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。
更新日期:2019-11-01
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