Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate

Lord Jephthah Joojo Gowans, Ganiyu Oseni, Peter A. Mossey, Wasiu Lanre Adeyemo, Mekonen A. Eshete, Tamara D. Busch, Peter Donkor, Solomon Obiri-Yeboah, Gyikua Plange-Rhule, Alexander A. Oti, Arwa Owais, Peter B. Olaitan, Babatunde S. Aregbesola, Fadekemi Oginni, Seidu A. Bello, Rosemary Audu, Chika Onwuamah, Pius Agbenorku, Mobolanle O. Ogunlewe, Lukman O. Abdur-RahmanMary L. Marazita, A. A. Adeyemo, Jeffrey C. Murray, Azeez Butali

Research output: Contribution to journalArticle

5 Citations (Scopus)
109 Downloads (Pure)

Abstract

Objective: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate.

Patients and Method: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature.

Results: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene.

Conclusion: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P.

Original languageEnglish
Pages (from-to)736-742
Number of pages7
JournalCleft Palate-Craniofacial Journal
Volume55
Issue number5
Early online date28 Feb 2018
DOIs
Publication statusPublished - 1 May 2018

Fingerprint

Cleft Lip
Cleft Palate
Genetic Databases
Soft Palate
Human Genome
African Americans
Genes
Sequence Analysis
DNA

Keywords

  • Cleft lip and/or cleft palate
  • DNA sequencing
  • GREM1 gene
  • Soft palate cleft
  • Sub-Saharan Africans

Cite this

Gowans, Lord Jephthah Joojo ; Oseni, Ganiyu ; Mossey, Peter A. ; Adeyemo, Wasiu Lanre ; Eshete, Mekonen A. ; Busch, Tamara D. ; Donkor, Peter ; Obiri-Yeboah, Solomon ; Plange-Rhule, Gyikua ; Oti, Alexander A. ; Owais, Arwa ; Olaitan, Peter B. ; Aregbesola, Babatunde S. ; Oginni, Fadekemi ; Bello, Seidu A. ; Audu, Rosemary ; Onwuamah, Chika ; Agbenorku, Pius ; Ogunlewe, Mobolanle O. ; Abdur-Rahman, Lukman O. ; Marazita, Mary L. ; Adeyemo, A. A. ; Murray, Jeffrey C. ; Butali, Azeez. / Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate. In: Cleft Palate-Craniofacial Journal. 2018 ; Vol. 55, No. 5. pp. 736-742.
@article{3e7fc6e2192d4d32b3f8c93ac3de4d0a,
title = "Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate",
abstract = "Objective: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate.Patients and Method: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature.Results: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene.Conclusion: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P.",
keywords = "Cleft lip and/or cleft palate, DNA sequencing, GREM1 gene, Soft palate cleft, Sub-Saharan Africans",
author = "Gowans, {Lord Jephthah Joojo} and Ganiyu Oseni and Mossey, {Peter A.} and Adeyemo, {Wasiu Lanre} and Eshete, {Mekonen A.} and Busch, {Tamara D.} and Peter Donkor and Solomon Obiri-Yeboah and Gyikua Plange-Rhule and Oti, {Alexander A.} and Arwa Owais and Olaitan, {Peter B.} and Aregbesola, {Babatunde S.} and Fadekemi Oginni and Bello, {Seidu A.} and Rosemary Audu and Chika Onwuamah and Pius Agbenorku and Ogunlewe, {Mobolanle O.} and Abdur-Rahman, {Lukman O.} and Marazita, {Mary L.} and Adeyemo, {A. A.} and Murray, {Jeffrey C.} and Azeez Butali",
note = "The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by National Institute of Dental and Craniofacial Research (R00 DE022378) and the Robert Wood Johnson Foundation (72429; A.B.); the National Institutes of Health (R37 DE-08559, J.C.M.; and DE-016148, M.L.M.) and the Ghana Cleft Foundation (L.J.J.G.).",
year = "2018",
month = "5",
day = "1",
doi = "10.1177/1055665618754948",
language = "English",
volume = "55",
pages = "736--742",
journal = "Cleft Palate-Craniofacial Journal",
issn = "1055-6656",
publisher = "American Cleft Palate-Craniofacial Association",
number = "5",

}

Gowans, LJJ, Oseni, G, Mossey, PA, Adeyemo, WL, Eshete, MA, Busch, TD, Donkor, P, Obiri-Yeboah, S, Plange-Rhule, G, Oti, AA, Owais, A, Olaitan, PB, Aregbesola, BS, Oginni, F, Bello, SA, Audu, R, Onwuamah, C, Agbenorku, P, Ogunlewe, MO, Abdur-Rahman, LO, Marazita, ML, Adeyemo, AA, Murray, JC & Butali, A 2018, 'Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate', Cleft Palate-Craniofacial Journal, vol. 55, no. 5, pp. 736-742. https://doi.org/10.1177/1055665618754948

Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate. / Gowans, Lord Jephthah Joojo; Oseni, Ganiyu; Mossey, Peter A.; Adeyemo, Wasiu Lanre; Eshete, Mekonen A.; Busch, Tamara D.; Donkor, Peter; Obiri-Yeboah, Solomon; Plange-Rhule, Gyikua; Oti, Alexander A.; Owais, Arwa; Olaitan, Peter B.; Aregbesola, Babatunde S.; Oginni, Fadekemi; Bello, Seidu A.; Audu, Rosemary; Onwuamah, Chika; Agbenorku, Pius; Ogunlewe, Mobolanle O.; Abdur-Rahman, Lukman O.; Marazita, Mary L.; Adeyemo, A. A.; Murray, Jeffrey C.; Butali, Azeez (Lead / Corresponding author).

In: Cleft Palate-Craniofacial Journal, Vol. 55, No. 5, 01.05.2018, p. 736-742.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate

AU - Gowans, Lord Jephthah Joojo

AU - Oseni, Ganiyu

AU - Mossey, Peter A.

AU - Adeyemo, Wasiu Lanre

AU - Eshete, Mekonen A.

AU - Busch, Tamara D.

AU - Donkor, Peter

AU - Obiri-Yeboah, Solomon

AU - Plange-Rhule, Gyikua

AU - Oti, Alexander A.

AU - Owais, Arwa

AU - Olaitan, Peter B.

AU - Aregbesola, Babatunde S.

AU - Oginni, Fadekemi

AU - Bello, Seidu A.

AU - Audu, Rosemary

AU - Onwuamah, Chika

AU - Agbenorku, Pius

AU - Ogunlewe, Mobolanle O.

AU - Abdur-Rahman, Lukman O.

AU - Marazita, Mary L.

AU - Adeyemo, A. A.

AU - Murray, Jeffrey C.

AU - Butali, Azeez

N1 - The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by National Institute of Dental and Craniofacial Research (R00 DE022378) and the Robert Wood Johnson Foundation (72429; A.B.); the National Institutes of Health (R37 DE-08559, J.C.M.; and DE-016148, M.L.M.) and the Ghana Cleft Foundation (L.J.J.G.).

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Objective: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate.Patients and Method: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature.Results: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene.Conclusion: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P.

AB - Objective: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate.Patients and Method: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature.Results: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene.Conclusion: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P.

KW - Cleft lip and/or cleft palate

KW - DNA sequencing

KW - GREM1 gene

KW - Soft palate cleft

KW - Sub-Saharan Africans

UR - http://www.scopus.com/inward/record.url?scp=85048578883&partnerID=8YFLogxK

U2 - 10.1177/1055665618754948

DO - 10.1177/1055665618754948

M3 - Article

C2 - 29489415

VL - 55

SP - 736

EP - 742

JO - Cleft Palate-Craniofacial Journal

JF - Cleft Palate-Craniofacial Journal

SN - 1055-6656

IS - 5

ER -