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, 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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)744-754
Number of pages11
JournalAmerican Journal of Human Genetics
Volume98
Issue number4
DOIs
Publication statusPublished - Apr 7 2016

Fingerprint

Genome-Wide Association Study
Cleft Palate
Live Birth
Zebrafish
Luciferases
Transcriptional Activation
Embryonic Structures
Genome
Recurrence
Mutation
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Leslie, E. J., Liu, H., Carlson, J. C., Shaffer, J. R., Feingold, E., Wehby, G., ... Marazita, M. L. (2016). A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3. American Journal of Human Genetics, 98(4), 744-754. https://doi.org/10.1016/j.ajhg.2016.02.014

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3. / Leslie, Elizabeth J.; Liu, Huan; Carlson, Jenna C.; Shaffer, John R.; Feingold, Eleanor; Wehby, George; Laurie, Cecelia A.; Jain, Deepti; Laurie, Cathy C.; Doheny, Kimberly F.; McHenry, Toby; Resick, Judith; Sanchez, Carla; Jacobs, Jennifer; Emanuele, Beth; Vieira, Alexandre R.; Neiswanger, Katherine; Standley, Jennifer; Czeizel, E.; Deleyiannis, Frederic; Christensen, Kaare; Munger, Ronald G.; Lie, Rolv T.; Wilcox, Allen; Romitti, Paul A.; Field, L. Leigh; Padilla, Carmencita D.; Cutiongco-De La Paz, Eva Maria C; Lidral, Andrew C.; Valencia-Ramirez, Luz Consuelo; Lopez-Palacio, Ana Maria; Valencia, Dora Rivera; Arcos-Burgos, Mauricio; Castilla, Eduardo E.; Mereb, Juan C.; Poletta, Fernando A.; Orioli, Iêda M.; Carvalho, Flavia M.; Hecht, Jacqueline T.; Blanton, Susan H.; Buxó, Carmen J.; Butali, Azeez; Mossey, Peter A.; Adeyemo, Wasiu L.; James, Olutayo; Braimah, Ramat O.; Aregbesola, Babatunde S.; Eshete, Mekonen A.; Deribew, Milliard; Koruyucu, Mine; Seymen, Figen; Ma, Lian; De Salamanca, Javier Enríquez; Weinberg, Seth M.; Moreno, Lina; Cornell, Robert A.; Murray, Jeffrey C.; Marazita, Mary L.

In: American Journal of Human Genetics, Vol. 98, No. 4, 07.04.2016, p. 744-754.

Research output: Contribution to journalArticle

Leslie, EJ, Liu, H, Carlson, JC, Shaffer, JR, Feingold, E, Wehby, G, Laurie, CA, Jain, D, Laurie, CC, Doheny, KF, McHenry, T, Resick, J, Sanchez, C, Jacobs, J, Emanuele, B, Vieira, AR, Neiswanger, K, Standley, J, Czeizel, E, Deleyiannis, F, Christensen, K, Munger, RG, Lie, RT, Wilcox, A, Romitti, PA, Field, LL, Padilla, CD, Cutiongco-De La Paz, EMC, Lidral, AC, Valencia-Ramirez, LC, Lopez-Palacio, AM, Valencia, DR, Arcos-Burgos, M, Castilla, EE, Mereb, JC, Poletta, FA, Orioli, IM, Carvalho, FM, Hecht, JT, Blanton, SH, Buxó, CJ, Butali, A, Mossey, PA, Adeyemo, WL, James, O, Braimah, RO, Aregbesola, BS, Eshete, MA, Deribew, M, Koruyucu, M, Seymen, F, Ma, L, De Salamanca, JE, Weinberg, SM, Moreno, L, Cornell, RA, Murray, JC & Marazita, ML 2016, 'A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3', American Journal of Human Genetics, vol. 98, no. 4, pp. 744-754. https://doi.org/10.1016/j.ajhg.2016.02.014
Leslie, Elizabeth J. ; Liu, Huan ; Carlson, Jenna C. ; Shaffer, John R. ; Feingold, Eleanor ; Wehby, George ; Laurie, Cecelia A. ; Jain, Deepti ; Laurie, Cathy C. ; Doheny, Kimberly F. ; McHenry, Toby ; Resick, Judith ; Sanchez, Carla ; Jacobs, Jennifer ; Emanuele, Beth ; Vieira, Alexandre R. ; Neiswanger, Katherine ; Standley, Jennifer ; Czeizel, E. ; Deleyiannis, Frederic ; Christensen, Kaare ; Munger, Ronald G. ; Lie, Rolv T. ; Wilcox, Allen ; Romitti, Paul A. ; Field, L. Leigh ; Padilla, Carmencita D. ; Cutiongco-De La Paz, Eva Maria C ; Lidral, Andrew C. ; Valencia-Ramirez, Luz Consuelo ; Lopez-Palacio, Ana Maria ; Valencia, Dora Rivera ; Arcos-Burgos, Mauricio ; Castilla, Eduardo E. ; Mereb, Juan C. ; Poletta, Fernando A. ; Orioli, Iêda M. ; Carvalho, Flavia M. ; Hecht, Jacqueline T. ; Blanton, Susan H. ; Buxó, Carmen J. ; Butali, Azeez ; Mossey, Peter A. ; Adeyemo, Wasiu L. ; James, Olutayo ; Braimah, Ramat O. ; Aregbesola, Babatunde S. ; Eshete, Mekonen A. ; Deribew, Milliard ; Koruyucu, Mine ; Seymen, Figen ; Ma, Lian ; De Salamanca, Javier Enríquez ; Weinberg, Seth M. ; Moreno, Lina ; Cornell, Robert A. ; Murray, Jeffrey C. ; Marazita, Mary L. / A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3. In: American Journal of Human Genetics. 2016 ; Vol. 98, No. 4. pp. 744-754.
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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, 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.

PY - 2016/4/7

Y1 - 2016/4/7

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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.

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