Variant Analyses of Candidate Genes in Orofacial Clefts in Multi-Ethnic Populations

Mary Li; Joy Olotu; Carmen J. Buxo-Martinez; Peter A. Mossey; Deepti Anand; Tamara Busch; Azeez Alade; Lord J. J. Gowans; Mekonen Eshete; Wasiu L. Adeyemo; Thirona Naicker; Waheed O. Awotoye; Sagar Gupta; Chinyere Adeleke; Valeria Bravo; Siyong Huang; Olatunbosun O. Adamson; Ada M. Toraño; Carolina A. Bello; Mairim Soto; Marilyn Soto; Ricardo Ledesma; Myrellis Marquez; Jose F. Cordero; Lydia M. Lopez-Del Valle; Maria I. Salcedo; Natalio Debs; Aline Petrin; Hannah Malloy; Khalid Elhadi; Olutayo James; Mobolanle O. Ogunlewe; Fekir Abate; Abiye Hailu; Ibrahim Mohammed; Paul Gravem; Milliard Deribew; Mulualem Gesses; Mohaned Hassan; John Pape; Solomon Obiri-Yeboah; Fareed K. N. Arthur; Alexander A. Oti; Peter Donkor; Mary L. Marazita; Salil A. Lachke; Adebowale A. Adeyemo; Jeffrey C. Murray; Azeez Butali

doi:10.1111/odi.13932

Variant Analyses of Candidate Genes in Orofacial Clefts in Multi-Ethnic Populations

Mary Li, Joy Olotu, Carmen J. Buxo-Martinez, Peter A. Mossey, Deepti Anand, Tamara Busch, Azeez Alade, Lord J. J. Gowans, Mekonen Eshete, Wasiu L. Adeyemo, Thirona Naicker, Waheed O. Awotoye, Sagar Gupta, Chinyere Adeleke, Valeria Bravo, Siyong Huang, Olatunbosun O. Adamson, Ada M. Toraño, Carolina A. Bello, Mairim SotoMarilyn Soto, Ricardo Ledesma, Myrellis Marquez, Jose F. Cordero, Lydia M. Lopez-Del Valle, Maria I. Salcedo, Natalio Debs, Aline Petrin, Hannah Malloy, Khalid Elhadi, Olutayo James, Mobolanle O. Ogunlewe, Fekir Abate, Abiye Hailu, Ibrahim Mohammed, Paul Gravem, Milliard Deribew, Mulualem Gesses, Mohaned Hassan, John Pape, Solomon Obiri-Yeboah, Fareed K. N. Arthur, Alexander A. Oti, Peter Donkor, Mary L. Marazita, Salil A. Lachke, Adebowale A. Adeyemo, Jeffrey C. Murray, Azeez Butali (Lead / Corresponding author)

Dentistry

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

4 Citations (Scopus)

282 Downloads (Pure)

Abstract

Objectives: Cleft lip with/without cleft palate and cleft palate only are congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. Affecting ~1.2/1000 live births world-wide, these orofacial clefts impose significant social and financial burdens on affected individuals and their families. Orofacial clefts have a complex etiology resulting from genetic variants combined with environmental covariates. Recent genome-wide association studies and whole-exome sequencing for orofacial clefts identified significant genetic associations and variants in several genes. Of these, we investigated the role of common/rare variants in SHH, RORA, MRPL53, ACVR1, and GDF11.

Materials and methods: We sequenced these five genes in 1255 multi-ethnic cleft lip with/without palate and cleft palate only samples in order to find variants that may provide potential explanations for the missing heritability of orofacial clefts. Rare and novel variants were further analyzed using in-silico predictive tools.

Results: 19 total variants of interest were found, with variant types including stop-gain, missense, synonymous, intronic, and splice-site variants. Of these, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11.

Conclusion: This study provides evidence that variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts in various populations.

Original language	English
Pages (from-to)	1921-1935
Number of pages	15
Journal	Oral Diseases
Volume	28
Issue number	7
Early online date	1 Jun 2021
DOIs	https://doi.org/10.1111/odi.13932
Publication status	Published - Oct 2022

Keywords

candidate gene
congenital birth defect
craniofacial genetics
genome-wide association studies
novel variants
whole-exome sequencing

ASJC Scopus subject areas

Otorhinolaryngology
General Dentistry

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10.1111/odi.13932

Author Accepted ManuscriptAccepted author manuscript, 14 MB

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Li, M., Olotu, J., Buxo-Martinez, C. J., Mossey, P. A., Anand, D., Busch, T., Alade, A., Gowans, L. J. J., Eshete, M., Adeyemo, W. L., Naicker, T., Awotoye, W. O., Gupta, S., Adeleke, C., Bravo, V., Huang, S., Adamson, O. O., Toraño, A. M., Bello, C. A., ... Butali, A. (2022). Variant Analyses of Candidate Genes in Orofacial Clefts in Multi-Ethnic Populations. Oral Diseases, 28(7), 1921-1935. https://doi.org/10.1111/odi.13932

@article{b499c2ddcb0340638823939faa9ae4bb,

title = "Variant Analyses of Candidate Genes in Orofacial Clefts in Multi-Ethnic Populations",

abstract = "Objectives: Cleft lip with/without cleft palate and cleft palate only are congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. Affecting ~1.2/1000 live births world-wide, these orofacial clefts impose significant social and financial burdens on affected individuals and their families. Orofacial clefts have a complex etiology resulting from genetic variants combined with environmental covariates. Recent genome-wide association studies and whole-exome sequencing for orofacial clefts identified significant genetic associations and variants in several genes. Of these, we investigated the role of common/rare variants in SHH, RORA, MRPL53, ACVR1, and GDF11.Materials and methods: We sequenced these five genes in 1255 multi-ethnic cleft lip with/without palate and cleft palate only samples in order to find variants that may provide potential explanations for the missing heritability of orofacial clefts. Rare and novel variants were further analyzed using in-silico predictive tools.Results: 19 total variants of interest were found, with variant types including stop-gain, missense, synonymous, intronic, and splice-site variants. Of these, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11.Conclusion: This study provides evidence that variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts in various populations.",

keywords = "candidate gene, congenital birth defect, craniofacial genetics, genome-wide association studies, novel variants, whole-exome sequencing",

author = "Mary Li and Joy Olotu and Buxo-Martinez, {Carmen J.} and Mossey, {Peter A.} and Deepti Anand and Tamara Busch and Azeez Alade and Gowans, {Lord J. J.} and Mekonen Eshete and Adeyemo, {Wasiu L.} and Thirona Naicker and Awotoye, {Waheed O.} and Sagar Gupta and Chinyere Adeleke and Valeria Bravo and Siyong Huang and Adamson, {Olatunbosun O.} and Tora{\~n}o, {Ada M.} and Bello, {Carolina A.} and Mairim Soto and Marilyn Soto and Ricardo Ledesma and Myrellis Marquez and Cordero, {Jose F.} and {Lopez-Del Valle}, {Lydia M.} and Salcedo, {Maria I.} and Natalio Debs and Aline Petrin and Hannah Malloy and Khalid Elhadi and Olutayo James and Ogunlewe, {Mobolanle O.} and Fekir Abate and Abiye Hailu and Ibrahim Mohammed and Paul Gravem and Milliard Deribew and Mulualem Gesses and Mohaned Hassan and John Pape and Solomon Obiri-Yeboah and Arthur, {Fareed K. N.} and Oti, {Alexander A.} and Peter Donkor and Marazita, {Mary L.} and Lachke, {Salil A.} and Adeyemo, {Adebowale A.} and Murray, {Jeffrey C.} and Azeez Butali",

note = "Funding Information: We are grateful to the families who voluntarily participated in this study in Puerto Rico, Ethiopia, Nigeria, Ghana, Iowa, and the Philippines. We are also grateful to all the administrative and research staff, students, nurses and resident doctors who assisted with participant recruitment, consent, and data collection. We appreciate the contribution of our late colleague, Muhammad Musa who designed and sequenced the ACVR1 gene in multiple populations. This research is supported by the National Institute of Dental and Craniofacial Research (R00 DE022378 and R01DE028300; A.B., R00 DE024571; C.B., R03 DE024776; S.A.L.) and the National Institute on Minority Health and Health Disparities (S21 MD001830; C.B., U54 MD007587; C.B.). Publisher Copyright: {\textcopyright} 2021 Wiley Periodicals LLC.",

year = "2022",

month = oct,

doi = "10.1111/odi.13932",

language = "English",

volume = "28",

pages = "1921--1935",

journal = "Oral Diseases",

issn = "1354-523X",

publisher = "Wiley",

number = "7",

}

Li, M, Olotu, J, Buxo-Martinez, CJ, Mossey, PA, Anand, D, Busch, T, Alade, A, Gowans, LJJ, Eshete, M, Adeyemo, WL, Naicker, T, Awotoye, WO, Gupta, S, Adeleke, C, Bravo, V, Huang, S, Adamson, OO, Toraño, AM, Bello, CA, Soto, M, Soto, M, Ledesma, R, Marquez, M, Cordero, JF, Lopez-Del Valle, LM, Salcedo, MI, Debs, N, Petrin, A, Malloy, H, Elhadi, K, James, O, Ogunlewe, MO, Abate, F, Hailu, A, Mohammed, I, Gravem, P, Deribew, M, Gesses, M, Hassan, M, Pape, J, Obiri-Yeboah, S, Arthur, FKN, Oti, AA, Donkor, P, Marazita, ML, Lachke, SA, Adeyemo, AA, Murray, JC & Butali, A 2022, 'Variant Analyses of Candidate Genes in Orofacial Clefts in Multi-Ethnic Populations', Oral Diseases, vol. 28, no. 7, pp. 1921-1935. https://doi.org/10.1111/odi.13932

TY - JOUR

T1 - Variant Analyses of Candidate Genes in Orofacial Clefts in Multi-Ethnic Populations

AU - Li, Mary

AU - Olotu, Joy

AU - Buxo-Martinez, Carmen J.

AU - Mossey, Peter A.

AU - Anand, Deepti

AU - Busch, Tamara

AU - Alade, Azeez

AU - Gowans, Lord J. J.

AU - Eshete, Mekonen

AU - Adeyemo, Wasiu L.

AU - Naicker, Thirona

AU - Awotoye, Waheed O.

AU - Gupta, Sagar

AU - Adeleke, Chinyere

AU - Bravo, Valeria

AU - Huang, Siyong

AU - Adamson, Olatunbosun O.

AU - Toraño, Ada M.

AU - Bello, Carolina A.

AU - Soto, Mairim

AU - Soto, Marilyn

AU - Ledesma, Ricardo

AU - Marquez, Myrellis

AU - Cordero, Jose F.

AU - Lopez-Del Valle, Lydia M.

AU - Salcedo, Maria I.

AU - Debs, Natalio

AU - Petrin, Aline

AU - Malloy, Hannah

AU - Elhadi, Khalid

AU - James, Olutayo

AU - Ogunlewe, Mobolanle O.

AU - Abate, Fekir

AU - Hailu, Abiye

AU - Mohammed, Ibrahim

AU - Gravem, Paul

AU - Deribew, Milliard

AU - Gesses, Mulualem

AU - Hassan, Mohaned

AU - Pape, John

AU - Obiri-Yeboah, Solomon

AU - Arthur, Fareed K. N.

AU - Oti, Alexander A.

AU - Donkor, Peter

AU - Marazita, Mary L.

AU - Lachke, Salil A.

AU - Adeyemo, Adebowale A.

AU - Murray, Jeffrey C.

AU - Butali, Azeez

N1 - Funding Information: We are grateful to the families who voluntarily participated in this study in Puerto Rico, Ethiopia, Nigeria, Ghana, Iowa, and the Philippines. We are also grateful to all the administrative and research staff, students, nurses and resident doctors who assisted with participant recruitment, consent, and data collection. We appreciate the contribution of our late colleague, Muhammad Musa who designed and sequenced the ACVR1 gene in multiple populations. This research is supported by the National Institute of Dental and Craniofacial Research (R00 DE022378 and R01DE028300; A.B., R00 DE024571; C.B., R03 DE024776; S.A.L.) and the National Institute on Minority Health and Health Disparities (S21 MD001830; C.B., U54 MD007587; C.B.). Publisher Copyright: © 2021 Wiley Periodicals LLC.

PY - 2022/10

Y1 - 2022/10

N2 - Objectives: Cleft lip with/without cleft palate and cleft palate only are congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. Affecting ~1.2/1000 live births world-wide, these orofacial clefts impose significant social and financial burdens on affected individuals and their families. Orofacial clefts have a complex etiology resulting from genetic variants combined with environmental covariates. Recent genome-wide association studies and whole-exome sequencing for orofacial clefts identified significant genetic associations and variants in several genes. Of these, we investigated the role of common/rare variants in SHH, RORA, MRPL53, ACVR1, and GDF11.Materials and methods: We sequenced these five genes in 1255 multi-ethnic cleft lip with/without palate and cleft palate only samples in order to find variants that may provide potential explanations for the missing heritability of orofacial clefts. Rare and novel variants were further analyzed using in-silico predictive tools.Results: 19 total variants of interest were found, with variant types including stop-gain, missense, synonymous, intronic, and splice-site variants. Of these, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11.Conclusion: This study provides evidence that variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts in various populations.

AB - Objectives: Cleft lip with/without cleft palate and cleft palate only are congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. Affecting ~1.2/1000 live births world-wide, these orofacial clefts impose significant social and financial burdens on affected individuals and their families. Orofacial clefts have a complex etiology resulting from genetic variants combined with environmental covariates. Recent genome-wide association studies and whole-exome sequencing for orofacial clefts identified significant genetic associations and variants in several genes. Of these, we investigated the role of common/rare variants in SHH, RORA, MRPL53, ACVR1, and GDF11.Materials and methods: We sequenced these five genes in 1255 multi-ethnic cleft lip with/without palate and cleft palate only samples in order to find variants that may provide potential explanations for the missing heritability of orofacial clefts. Rare and novel variants were further analyzed using in-silico predictive tools.Results: 19 total variants of interest were found, with variant types including stop-gain, missense, synonymous, intronic, and splice-site variants. Of these, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11.Conclusion: This study provides evidence that variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts in various populations.

KW - candidate gene

KW - congenital birth defect

KW - craniofacial genetics

KW - genome-wide association studies

KW - novel variants

KW - whole-exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85108332247&partnerID=8YFLogxK

U2 - 10.1111/odi.13932

DO - 10.1111/odi.13932

M3 - Article

C2 - 34061439

SN - 1354-523X

VL - 28

SP - 1921

EP - 1935

JO - Oral Diseases

JF - Oral Diseases

IS - 7

ER -

Variant Analyses of Candidate Genes in Orofacial Clefts in Multi-Ethnic Populations

Abstract

Keywords

ASJC Scopus subject areas

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