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 Deleyiannis; Kaare 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

doi:10.1016/j.ajhg.2016.02.014

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

128 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 language	English
Pages (from-to)	744-754
Number of pages	11
Journal	American Journal of Human Genetics
Volume	98
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2016.02.014
Publication status	Published - 7 Apr 2016

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Leslie, E. J., Liu, H., Carlson, J. C., Shaffer, J. R., Feingold, E., Wehby, G., Laurie, C. A., Jain, D., Laurie, C. C., Doheny, K. F., McHenry, T., Resick, J., Sanchez, C., Jacobs, J., Emanuele, B., Vieira, A. R., Neiswanger, K., Standley, J., Czeizel, A. E., ... 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

@article{cec226d7af8e4aef9c1551bb4dc82f91,

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

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.",

author = "Leslie, {Elizabeth J.} and Huan Liu and Carlson, {Jenna C.} and Shaffer, {John R.} and Eleanor Feingold and George Wehby and Laurie, {Cecelia A.} and Deepti Jain and Laurie, {Cathy C.} and Doheny, {Kimberly F.} and Toby McHenry and Judith Resick and Carla Sanchez and Jennifer Jacobs and Beth Emanuele and Vieira, {Alexandre R.} and Katherine Neiswanger and Jennifer Standley and Czeizel, {Andrew E.} and Frederic Deleyiannis and Kaare Christensen and Munger, {Ronald G.} and Lie, {Rolv T.} and Allen Wilcox and Romitti, {Paul A.} and Field, {L. Leigh} and Padilla, {Carmencita D.} and {Cutiongco-De La Paz}, {Eva Maria C.} and Lidral, {Andrew C.} and Valencia-Ramirez, {Luz Consuelo} and Lopez-Palacio, {Ana Maria} and Valencia, {Dora Rivera} and Mauricio Arcos-Burgos and Castilla, {Eduardo E.} and Mereb, {Juan C.} and Poletta, {Fernando A.} and Orioli, {I{\^e}da M.} and Carvalho, {Flavia M.} and Hecht, {Jacqueline T.} and Blanton, {Susan H.} and Bux{\'o}, {Carmen J.} and Azeez Butali and Mossey, {Peter A.} and Adeyemo, {Wasiu L.} and Olutayo James and Braimah, {Ramat O.} and Aregbesola, {Babatunde S.} and Eshete, {Mekonen A.} and Milliard Deribew and Mine Koruyucu and Figen Seymen and Lian Ma and {De Salamanca}, {Javier Enr{\'i}quez} and Weinberg, {Seth M.} and Lina Moreno and Cornell, {Robert A.} and Murray, {Jeffrey C.} and Marazita, {Mary L.}",

year = "2016",

month = apr,

day = "7",

doi = "10.1016/j.ajhg.2016.02.014",

language = "English",

volume = "98",

pages = "744--754",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

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, AE, 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

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.

PY - 2016/4/7

Y1 - 2016/4/7

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

SN - 0002-9297

VL - 98

SP - 744

EP - 754

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

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

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