Rare functional variants in genome-wide association identified candidate genes for nonsyndromic clefts in the African population

Azeez Butali; Peter Mossey; Wasiu Adeyemo; Mekonen Eshete; Lauren Gaines; Ramat Braimah; Babatunde Aregbesola; Jennifer Rigdon; Christian Emeka; James Olutayo; Olugbenga Ogunlewe; Akinola Ladeinde; Fikre Abate; Taye Hailu; Ibrahim Mohammed; Paul Gravem; Milliard Deribew; Mulualem Gesses; Adebowale Adeyemo; Mary Marazita; Jeffrey Murray

doi:10.1002/ajmg.a.36691

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Rare functional variants in genome-wide association identified candidate genes for nonsyndromic clefts in the African population

Journal article

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Rare functional variants in genome-wide association identified candidate genes for nonsyndromic clefts in the African population

Azeez Butali, Peter Mossey, Wasiu Adeyemo, Mekonen Eshete, Lauren Gaines, Ramat Braimah, Babatunde Aregbesola, Jennifer Rigdon, Christian Emeka, James Olutayo, …

American journal of medical genetics. Part A, Vol.164A(10), pp.2567-2571

10/2014

DOI: 10.1002/ajmg.a.36691

PMCID: PMC4169286

PMID: 25081408

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Abstract

Nonsyndromic clefts of the lip and palate (NSCLP) are complex genetic traits. Together, they are classified as one of the most common birth defects with a prevalence of 1/700 live births. Genome-wide association studies (GWAS) for nonsyndromic cleft lip with or without cleft palate (NSCL[P]) revealed significant association for common single nucleotide polymorphisms near genes involved in craniofacial development i.e., MAFB, PAX7, VAX1, ARHGAP29 (ABCA4 locus), and IRF6. Sequencing of protein coding regions of the NSCL(P) GWAS candidate genes or adjacent genes suggest a role for rare functional variants. Replication studies in the African population did not observe any significant association with the GWAS candidate genes. On the other hand, the role of rare functional variants in GWAS candidate genes has not been evaluated in the African population. We obtained saliva samples from case triads in Nigeria and Ethiopia for Sanger sequencing of the GWAS candidate genes (MAFB, PAX7, VAX1, ARHGAP29, and IRF6) in order to identify rare functional variants. A total of 220 African samples (140 Nigerians and 80 Ethiopians) were sequenced and we found the following new rare variants- p.His165Asn in the MAFB gene, p.Asp428Asn in the PAX7, a splice-site variant that creates a new donor splice-site in PAX7. We also found three previously reported missense variants p.Gly466Ser in PAX7; p.Leu913Ser and Arg955His in ARHGAP29. No de novo mutations were found. Future genome-wide association and sequencing studies should be conducted using samples from Africa in order to identify new molecular genetic factors that contribute to the etiology of NSCLP.

Cleft Lip - genetics

Genome-Wide Association Study

MafB Transcription Factor - genetics

Humans

PAX7 Transcription Factor - genetics

Polymorphism, Single Nucleotide - genetics

Cleft Palate - genetics

African Continental Ancestry Group - genetics

Brain - abnormalities

GTPase-Activating Proteins - genetics

Sequence Analysis, DNA - methods

Details

Title: Subtitle: Rare functional variants in genome-wide association identified candidate genes for nonsyndromic clefts in the African population
Creators: Azeez Butali - Department of Oral Pathology, Radiology and Medicine, College of Dentistry University of Iowa, Iowa City, IA
Peter Mossey
Wasiu Adeyemo
Mekonen Eshete
Lauren Gaines
Ramat Braimah
Babatunde Aregbesola
Jennifer Rigdon
Christian Emeka
James Olutayo
Olugbenga Ogunlewe
Akinola Ladeinde
Fikre Abate
Taye Hailu
Ibrahim Mohammed
Paul Gravem
Milliard Deribew
Mulualem Gesses
Adebowale Adeyemo
Mary Marazita
Jeffrey Murray
Resource Type: Journal article
Publication Details: American journal of medical genetics. Part A, Vol.164A(10), pp.2567-2571
DOI: 10.1002/ajmg.a.36691
PMID: 25081408
PMCID: PMC4169286
NLM abbreviation: Am J Med Genet A
ISSN: 1552-4825
eISSN: 1552-4833
Publisher: United States
Grant note: K99/R00 DE022378 / NIDCR NIH HHS K99 DE022378 / NIDCR NIH HHS R00 DE022378 / NIDCR NIH HHS DE-016148 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS R37 DE008559 / NIDCR NIH HHS DE-08559 / NIDCR NIH HHS U01 DE020057 / NIDCR NIH HHS
Language: English
Date published: 10/2014
Academic Unit: Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025339202771

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