title: Rare functional variants in genome-wide association identified candidate genes for nonsyndromic clefts in the African population.
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.
authors: Department of Oral Pathology, Radiology and Medicine, College of Dentistry University of Iowa, Iowa City, IA.
authors: Azeez
authors: A
authors: Butali
authors: Peter
authors: P
authors: Mossey
authors: Wasiu
authors: W
authors: Adeyemo
authors: Mekonen
authors: M
authors: Eshete
authors: Lauren
authors: L
authors: Gaines
authors: Ramat
authors: R
authors: Braimah
authors: Babatunde
authors: B
authors: Aregbesola
authors: Jennifer
authors: J
authors: Rigdon
authors: Christian
authors: C
authors: Emeka
authors: James
authors: J
authors: Olutayo
authors: Olugbenga
authors: O
authors: Ogunlewe
authors: Akinola
authors: A
authors: Ladeinde
authors: Fikre
authors: F
authors: Abate
authors: Taye
authors: T
authors: Hailu
authors: Ibrahim
authors: I
authors: Mohammed
authors: Paul
authors: P
authors: Gravem
authors: Milliard
authors: M
authors: Deribew
authors: Mulualem
authors: M
authors: Gesses
authors: Adebowale
authors: A
authors: Adeyemo
authors: Mary
authors: M
authors: Marazita
authors: Jeffrey
authors: J
authors: Murray
mesh_terms: D044383:Black People / Q000235:genetics*; D001921:Brain / Q000002:abnormalities*; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D020690:GTPase-Activating Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D051258:MafB Transcription Factor / Q000235:genetics; D051763:PAX7 Transcription Factor / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: C500429:ARHGAP29 protein, human; D020690:GTPase-Activating Proteins; C490407:MAFB protein, human; D051258:MafB Transcription Factor; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human
keywords: Africa; GWAS; rare variants