A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

Elizabeth J. Leslie, Huan Liu, Jenna C. Carlson, John R. Shaffer, Eleanor Feingold, George Wehby, Cecelia A. 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 DeleyiannisKaare Christensen, Ronald G. Munger, Rolv T. Lie, Allen 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 Maria Lopez-Palacio, Dora Rivera Valencia, Mauricio Arcos-Burgos, Eduardo E. Castilla, Juan C. Mereb, Fernando A. Poletta, Iêda M. Orioli, Flavia M. Carvalho, Jacqueline T. Hecht, Susan H. Blanton, Carmen J. Buxó, Azeez Butali, Peter A. Mossey, Wasiu L. Adeyemo, Olutayo James, Ramat O. Braimah, Babatunde S. Aregbesola, Mekonen A. Eshete, Milliard Deribew, Mine Koruyucu, Figen Seymen, Lian Ma, Javier Enríquez De Salamanca, Seth M. Weinberg, Lina Moreno, Robert A. Cornell, Jeffrey C. Murray, Mary L. Marazita (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

122 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)744-754
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number4
Publication statusPublished - 24 Mar 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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