TY - JOUR
T1 - A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3
AU - Leslie, Elizabeth J.
AU - Liu, Huan
AU - Carlson, Jenna C.
AU - Shaffer, John R.
AU - Feingold, Eleanor
AU - Wehby, George
AU - Laurie, Cecelia A.
AU - Jain, Deepti
AU - Laurie, Cathy C.
AU - Doheny, Kimberly F.
AU - McHenry, Toby
AU - Resick, Judith
AU - Sanchez, Carla
AU - Jacobs, Jennifer
AU - Emanuele, Beth
AU - Vieira, Alexandre R.
AU - Neiswanger, Katherine
AU - Standley, Jennifer
AU - Czeizel, Andrew E.
AU - Deleyiannis, Frederic
AU - Christensen, Kaare
AU - Munger, Ronald G.
AU - Lie, Rolv T.
AU - Wilcox, Allen
AU - Romitti, Paul A.
AU - Field, L. Leigh
AU - Padilla, Carmencita D.
AU - Cutiongco-De La Paz, Eva Maria C
AU - Lidral, Andrew C.
AU - Valencia-Ramirez, Luz Consuelo
AU - Lopez-Palacio, Ana Maria
AU - Valencia, Dora Rivera
AU - Arcos-Burgos, Mauricio
AU - Castilla, Eduardo E.
AU - Mereb, Juan C.
AU - Poletta, Fernando A.
AU - Orioli, Iêda M.
AU - Carvalho, Flavia M.
AU - Hecht, Jacqueline T.
AU - Blanton, Susan H.
AU - Buxó, Carmen J.
AU - Butali, Azeez
AU - Mossey, Peter A.
AU - Adeyemo, Wasiu L.
AU - James, Olutayo
AU - Braimah, Ramat O.
AU - Aregbesola, Babatunde S.
AU - Eshete, Mekonen A.
AU - Deribew, Milliard
AU - Koruyucu, Mine
AU - Seymen, Figen
AU - Ma, Lian
AU - De Salamanca, Javier Enríquez
AU - Weinberg, Seth M.
AU - Moreno, Lina
AU - Cornell, Robert A.
AU - Murray, Jeffrey C.
AU - Marazita, Mary L.
N1 - This work was supported by grants from the NIH including X01-HG007845 and R01-DE016148 (to M.L.M.), and genotyping and data cleaning were provided via an NIH contract to the Johns Hopkins Center for Inherited Disease Research (HHSN268201200008I). The replication studies were funded by NIH grants R01-DE020895 (to G.L.W.) and U01-DE018993 to Dr. Terri Beaty at Johns Hopkins University School of Public Health. See the Supplemental Acknowledgments for additional grant support and full acknowledgments.
PY - 2016/3/24
Y1 - 2016/3/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84964895172&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2016.02.014
DO - 10.1016/j.ajhg.2016.02.014
M3 - Article
C2 - 27018472
AN - SCOPUS:84964895172
SN - 0002-9297
VL - 98
SP - 744
EP - 754
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -
