Produção Nacional
Revisado por pares
A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3
2016; Elsevier BV; Volume: 98; Issue: 4 Linguagem: Inglês
10.1016/j.ajhg.2016.02.014
ISSN1537-6605
AutoresElizabeth J. Leslie, Huan Liu, Jenna C. Carlson, John R. Shaffer, Eleanor Feingold, George L. Wehby, Cecelia Laurie, Deepti Jain, Cathy C. Laurie, Kimberly F. Doheny, Toby McHenry, Judith Resick, Carla Sanchez, Jennifer Jacobs, Beth Emanuele, Alexandre R. Vieira, Katherine Neiswanger, Jennifer Standley, Andrew E. Czeizel, Frederic W.‐B. Deleyiannis, Kaare Christensen, Ronald G. Munger, Rolv T. Lie, Allen J. Wilcox, Paul A. Romitti, L. Leigh Field, Carmencita D. Padilla, Eva Maria C. Cutiongco–de la Paz, Andrew C. Lidral, Luz Consuelo Valencia‐Ramirez, Ana María López-Palacio, Dora Rivera Valencia, Mauricio Arcos‐Burgos, Eduardo E. Castilla, Juan C. Mereb, Fernando A. Poletta, Iêda M. Orioli, Flávia Martinez de Carvalho, Jacqueline T. Hecht, Susan H. Blanton, Carmen J. Buxó, Azeez Butali, Peter Mossey, Wasiu Lanre Adeyemo, Olutayo James, Ramat Oyebunmi Braimah, Babatunde S. Aregbesola, Mekonen Eshete, Milliard Deribew, Mine Koruyucu, Figen Seymen, Lian Ma, Javier Salamanca, Seth M. Weinberg, Lina M. Moreno, Robert A. Cornell, Jeffrey C. Murray, Mary L. Marazita,
Tópico(s)Pediatric Hepatobiliary Diseases and Treatments
ResumoCleft 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.
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