| Literature DB >> 27018472 |
Elizabeth J Leslie1, Huan Liu2, Jenna C Carlson3, John R Shaffer4, Eleanor Feingold5, George Wehby6, Cecelia A Laurie7, Deepti Jain7, Cathy C Laurie7, Kimberly F Doheny8, Toby McHenry1, Judith Resick1, Carla Sanchez1, Jennifer Jacobs1, Beth Emanuele1, Alexandre R Vieira4, Katherine Neiswanger1, Jennifer Standley9, Andrew E Czeizel10, Frederic Deleyiannis11, Kaare Christensen12, Ronald G Munger13, Rolv T Lie14, Allen Wilcox15, Paul A Romitti16, L Leigh Field17, Carmencita D Padilla18, Eva Maria C Cutiongco-de la Paz19, Andrew C Lidral20, Luz Consuelo Valencia-Ramirez21, Ana Maria Lopez-Palacio22, Dora Rivera Valencia23, Mauricio Arcos-Burgos24, Eduardo E Castilla25, Juan C Mereb26, Fernando A Poletta25, Iêda M Orioli27, Flavia M Carvalho28, Jacqueline T Hecht29, Susan H Blanton30, Carmen J Buxó31, Azeez Butali32, Peter A Mossey33, Wasiu L Adeyemo34, Olutayo James34, Ramat O Braimah35, Babatunde S Aregbesola35, Mekonen A Eshete36, Milliard Deribew36, Mine Koruyucu37, Figen Seymen37, Lian Ma38, Javier Enríquez de Salamanca39, Seth M Weinberg1, Lina Moreno20, Robert A Cornell40, Jeffrey C Murray9, Mary L Marazita41.
Abstract
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.Entities:
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Year: 2016 PMID： 27018472 PMCID： PMC4833215 DOI： 10.1016/j.ajhg.2016.02.014
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.043