Browsing Faculty of Dental Sciences by Author "Abate, F."
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- ItemOpen AccessAssociation Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations.(SAGE JOURNALS, 2016-10-01) Gowans, L.J.J.; Adeyemo, W.L.; Eshete, M.; Mossey, P.A.; Busch, T.; Aregbesola, B.; Donkor, P.; Arthur, F.K.; Bello, S.A.; Martinez, A.; Li, M.; Augustine-Akpan, E.A.; Deressa, W.; Twumasi, P.; James, O.; Deribew, M.; Agbenorku, P.; Oti, A.A.; Braimah, R.; Plange-Rhule, G.; Gesses, M.; Obiri-Yeboah, S.; Oseni, G.O.; Olaitan, P.B.; Abdur-Rahman, L.A.; Abate, F.; Hailu, T.; Gravem, P.; Ogunlewe, M.O.; Buxo, C.J.; Marazita, M.L.; Adeyemo, A.A.; Murray, J.C.; Butali, A.Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10(-3)), 8q24 (rs987525, P = 1.22 × 10(-3)), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29 In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.
- ItemOpen AccessGenomic analyses in African populations identify loci for cleft palate(Oxford Academic, 2019-03-15) Butali, A.; Mossey, P.A.; Adeyemo, W.L.; Eshete, M.A.; Gowans, L.J.J.; Busch, T.; Jain, D.; Yu, W.; Huan, L.; Laurie, C.C.; Laurie, C.A.; Nelson, S.; Li, M.; Sanchez-Lara, P.A.; Magee, W.P.; Magee, K.S.; Auslander, A.; Brindopke, F.; Kay, D.M.; Caggana, M.; Romitti, P.A.; Mills, J.L.; Audu, R.; Onwuamah, C.; Oseni, G.O.; Owais, A.; James, O.; Olaitan, P.B.; Aregbesola, B.S.; Braimah, R.O.; Oginni, F.O.; Oladele, A.O.; Bello, S.A.; Rhodes, J.; Shiang, R.; Donkor, P.; Obiri-Yeboah, S.; Arthur, F.K.N.; Twumasi, P.; Agbenorku, P.; Plange-Rhule, G.; Oti, A.; Ogunlewe, M.O.; Oladega, A.A.; Adekunle, A.A.; Erinoso, A.O.; Adamson, O.O.; Elufowoju, A.A.; Ayelomi, O.I.; Hailu, T.; Hailu, A.; Demissie, Y.; Derebew, M.; Eliason, S.; Romero-Bustillous, M.; Lo, C.; Park, J.; Desai, S.; Mohammed, M.; Abate, F.; Abdur-Rahman, L.O.; Anand, D.; Saadi, I.; Oladugba, A.V.; Lachke, S.A.; Amendt, B.A.; Rotimi, C.N.; Marazita, M.L.; Cornell, R.A.; Murray, J.C.; Adeyemo, A.A.Orofacial clefts are common developmental disorders that pose significant clinical, economical and psychological problems. We conducted genome-wide association analyses for cleft palate only (CPO) and cleft lip with or without palate (CL/P) with ~17 million markers in sub-Saharan Africans. After replication and combined analyses, we identified novel loci for CPO at or near genome-wide significance on chromosomes 2 (near CTNNA2) and 19 (near SULT2A1). In situ hybridization of Sult2a1 in mice showed expression of SULT2A1 in mesenchymal cells in palate, palatal rugae and palatal epithelium in the fused palate. The previously reported 8q24 was the most significant locus for CL/P in our study, and we replicated several previously reported loci including PAX7 and VAX1.
- ItemOpen AccessIdentification of paternal uniparental disomy on chromosome 22 and a de novo deletion on chromosome 18 in individuals with orofacial clefts(Wiley, 2018-11-01) Oseni, G.O.; Jain, D.; Mossey, P.A.; Busch, T.D.; Gowans, L.J.J.; Eshete, M.A.; Adeyemo, W.L.; Laurie, C.A.; Laurie, C.C.; Owais, A.; Olaitan, P.B.; Aregbesola, B.S.; Oginni, F.O.; Bello, S.A.; Donkor, P.; Audu, R.; Onwuamah, C.; Obiri-Yeboah, S.; Plange-Rhule, G.; Ogunlewe, M.O.; James, O.; Hailu, T.; Abate, F.; Abdur-Rahman, L.O.; Oladugba, A.V.; Marazita, M.L.; Murray, J.C.; Adeyemo, A.A.; Butali, A.BACKGROUND: Orofacial clefts are the most common malformations of the head and neck region. Genetic and environmental factors have been implicated in the etiology of these traits. METHODS: We recently conducted genotyping of individuals from the African population using the multiethnic genotyping array (MEGA) to identify common genetic variation associated with nonsyndromic orofacial clefts. The data cleaning of this dataset allowed for screening of annotated sex versus genetic sex, confirmation of identify by descent and identification of large chromosomal anomalies. RESULTS: We identified the first reported orofacial cleft case associated with paternal uniparental disomy (patUPD) on chromosome 22. We also identified a de novo deletion on chromosome 18. In addition to chromosomal anomalies, we identified cases with molecular karyotypes suggesting Klinefelter syndrome, Turner syndrome and Triple X syndrome. CONCLUSION: Observations from our study support the need for genetic testing when clinically indicated in order to exclude chromosomal anomalies associated with clefting. The identification of these chromosomal anomalies and sex aneuploidies is important in genetic counseling for families that are at risk. Clinicians should share any identified genetic findings and place them in context for the families during routine clinical visits and evaluations.
- ItemOpen AccessLoss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate(SAGE JOURNALS, 2018-01-01) Eshete, M.A.; Liu, H.; Li, M.; Adeyemo, W.L.; Gowans, L.J.J.; Mossey, P.A.; Busch, T.; Deressa, W.; Donkor, P.; Donkor, P.; Olaitan, P.B.; Aregbesola, B.S.; Braimah, R.O.; Oseni, G.O.; Oginni, F.; Audu, R.; Onwuamah, C.; James, O.; Augustine-Akpan, E.; Rahman, L.A.; Ogunlewe, M.O.; Arthur, F.K.N.; Bello, S.A.; Agbenorku, P.; Twumasi, P.; Abate, F.; Hailu, A.; Demissie, Y.; Hailu, A.; Plange-Rhule, G.; Obiri-Yeboah, S.; Dunnwald, M.M.; Gravem, P.E.; Marazita, M.L.; Adeyemo, A.A.; Murray, J.C.; Cornell, R.A.; Butali, A.In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome. To identify rare mutations in GRHL3 that might explain the missing heritability for CPO, we sequenced GRHL3 in cases of CPO from Africa. We recruited participants from Ghana, Ethiopia, and Nigeria. This cohort included case-parent trios, cases and other family members, as well as controls. We sequenced exons of this gene in DNA from a total of 134 nonsyndromic cases. When possible, we sequenced them in parents to identify de novo mutations. Five novel mutations were identified: 2 missense (c.497C>A; p.Pro166His and c.1229A>G; p.Asp410Gly), 1 splice site (c.1282A>C p.Ser428Arg), 1 frameshift (c.470delC; p.Gly158Alafster55), and 1 nonsense (c.1677C>A; p.Tyr559Ter). These mutations were absent from 270 sequenced controls and from all public exome and whole genome databases, including the 1000 Genomes database (which includes data from Africa). However, 4 of the 5 mutations were present in unaffected mothers, indicating that their penetrance is incomplete. Interestingly, 1 mutation damaged a predicted sumoylation site, and another disrupted a predicted CK1 phosphorylation site. Overexpression assays in zebrafish and reporter assays in vitro indicated that 4 variants were functionally null or hypomorphic, while 1 was dominant negative. This study provides evidence that, as in Caucasian populations, mutations in GRHL3 contribute to the risk of nonsyndromic CPO in the African population.
- ItemOpen AccessA multi-ethnic genome-wide association study identifies novel loci for nonsyndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q31.(Oxford Academic, 2016-07-01) Leslie, E.J.; 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.; Lidral, A.C.; Valencia-Ramirez, L.C.; Lopez-Palacio, A.M.; Valencia, D.R.; Arcos-Burgos, M.; Czeizel, A.E.; Field, L.L.; Padilla, C.D.; Cutiongco-de la Paz, E.M.; Deleyiannis, F.; Christensen, K.; Munger, R.G.; Lie, R.T.; Wilcox, A.; Romitti, P.A.; Castilla, E.E.; Mereb, J.C.; Poletta, F.A.; Orioli, I.M.; Carvalho, F.M.; Hecht, J.T.; Blanton, S.H.; Buxo, C.J,; Butali, A.; Mossey, P.A.; James, O.; Braimah, R.O.; Aregbesola, B.S.; Eshete, M.A.; Abate, F.; Koruyucu, M.; Seymen, F.; Ma, L.; Enríquez de Salamanca, J.; Weinberg, S.; Moreno, L.; Murray, J.C.; Marazita, M.L.Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.
- ItemOpen AccessNon‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome(Wiley, 2020-06-17) Alade, A.A.; Buxo‐Martinez, C.J.; Mossey, P.A.; Gowans, L.J.J.; Eshete, M.A.; Adeyemo, W.L.; Naiker, T.; Awotoye, W.A.; Adeleke, C.; Busch, T.; Torano, A.M.; Bello, C.A.; Soto, M.; Ledesma, R.; Marquez, M.; Cordero, J.F.; Lopez‐Del Valle, L.M.; Salcedo, M.I.; Debs, N.; Li, M.; Petrin, A.; Olotu, J.; Aldous, C.; James, O.; Ogunlewe, M.O.; Abate, F.; Hailu, T.; Muhammed, I.; Gravem, P.; Deribew, M.; Gesses, M.; Hassan, M.; Pape, J.; Adeniyan, O.A.; Obiri‐Yeboah, S.; Arthur, F.K.N.; Oti, A.A.; Olatosi, O.; Miller, S.E.; Donkor, P.; Dunnwald, M.M.; Marazita, M.L.; Adeyemo, A.A.; Murray, J.C.; Butali, A.Background: The development of the face occurs during the early days of in-trauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well-organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA-binding (exon 3, 4) or protein-binding domains (exon 7–9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. Methods: We used PubMed with the search terms; "Van der Woude syndrome," “Popliteal pterygium syndrome,” "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percent-age of deleterious variants. Results: Twenty-one new mutations were identified from nine papers. The major-ity of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7–9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein-binding domain (exon 7–9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported non-sense mutations (p.Ser424*and p.Arg250*). Conclusion: Mutations in the protein and DNA-binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.
- ItemOpen AccessNovel IRF6 mutations in families with Van Der Woude syndrome and popliteal pterygium syndrome from sub-Saharan Africa.(Wiley, 2014-05-01) Butali, A.; Mossey, P.A.; Adeyemo, W.L.; Eshete, M.A.; Gaines, L.A.; Even, D.; Braimah, R.O.; Aregbesola, B.S.; Rigdon, J.V.; Emeka, C.I.; James, O.; Ogunlewe, M.O.; Ladeinde, A.L.; Abate, F.; Hailu, T.; Mohammed, I.; Gravem, P.E.; Deribew, M.; Gesses, M.; Adeyemo, A.A.; Murray, J.C.Orofacial clefts (OFC) are complex genetic traits that are often classified as syndromic or nonsyndromic clefts. Currently, there are over 500 types of syndromic clefts in the Online Mendelian Inheritance in Man (OMIM) database, of which Van der Woude syndrome (VWS) is one of the most common (accounting for 2% of all OFC). Popliteal pterygium syndrome (PPS) is considered to be a more severe form of VWS. Mutations in the IRF6 gene have been reported worldwide to cause VWS and PPS. Here, we report studies of families with VWS and PPS in sub-Saharan Africa. We screened the DNA of eight families with VWS and one family with PPS from Nigeria and Ethiopia by Sanger sequencing of the most commonly affected exons in IRF6 (exons 3, 4, 7, and 9). For the VWS families, we found a novel nonsense variant in exon 4 (p.Lys66X), a novel splice-site variant in exon 4 (p.Pro126Pro), a novel missense variant in exon 4 (p.Phe230Leu), a previously reported splice-site variant in exon 7 that changes the acceptor splice site, and a known missense variant in exon 7 (p.Leu251Pro). A previously known missense variant was found in exon 4 (p.Arg84His) in the PPS family. All the mutations segregate in the families. Our data confirm the presence of IRF6-related VWS and PPS in sub-Saharan Africa and highlights the importance of screening for novel mutations in known genes when studying diverse global populations. This is important for counseling and prenatal diagnosis for high-risk families.
- ItemOpen AccessThe prevalence, penetrance, and expressivity of etiologic IRF6 variants in orofacial clefts patients from sub-Saharan Africa(Wiley, 2017-01-01) Gowans, L.J.J.; Busch, T.D.; Mossey, P.A.; Eshete, M.A.; Adeyemo, W.L.; Aregbesola, B.; Donkor, P.; Arthur, F.K.; Agbenorku, P.; James, O.; Twumasi, P.; Braimah, R.; Oti, A.A.; Plange-Rhule, G.; Obiri-Yeboah, S.; Abate, F.; Hoyte-Williams, P.E.; Hailu, T.; Murray, J.C.; Butali, A.BACKGROUND: Orofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 (IRF6) (OMIM:607199) gene has been associated with the etiology of both syndromic and nonsyndromic orofacial clefts. The aim of this study was to show evidence of potentially pathogenic variants in IRF6 in orofacial clefts cohorts from Africa. METHODS: We carried out Sanger Sequencing on DNA from 184 patients with nonsyndromic orofacial clefts and 80 individuals with multiple congenital anomalies that presented with orofacial clefts. We sequenced all the nine exons of IRF6 as well as the 5' and 3' untranslated regions. In our analyses pipeline, we used various bioinformatics tools to detect and describe the potentially etiologic variants. RESULTS: We observed that potentially etiologic exonic and splice site variants were nonrandomly distributed among the nine exons of IRF6, with 92% of these variants occurring in exons 4 and 7. Novel variants were also observed in both nonsyndromic orofacial clefts (p.Glu69Lys, p.Asn185Thr, c.175-2A>C and c.1060+26C>T) and multiple congenital anomalies (p.Gly65Val, p.Lys320Asn and c.379+1G>T) patients. Our data also show evidence of compound heterozygotes that may modify phenotypes that emanate from IRF6 variants. CONCLUSIONS: This study demonstrates that exons 4 and 7 of IRF6 are mutational 'hotspots' in our cohort and that IRF6 mutants-induced orofacial clefts may be prevalent in the Africa population, however, with variable penetrance and expressivity. These observations are relevant for detection of high-risk families as well as genetic counseling. In conclusion, we have shown that there may be a need to combine both molecular and clinical evidence in the grouping of orofacial clefts into syndromic and nonsyndromic forms.
- ItemOpen AccessRare functional variants in genome-wide association identified candidate genes for nonsyndromic clefts in the African population.(Wiley, 2014-10-01) Butali, A.; Mossey, P.A.; Adeyemo, W.L.; Eshete, M.; Gaines, L.; Braimah, R.; Aregbesola, B.; Rigdon, J.; Emeka, C.; James, O.; Ogunlewe, M.O.; Ladeinde, A.L.; Abate, F.; Hailu, T.; Mohammed, I.; Gravem, P.; Deribew, M.; Gesses, M.; Adeyemo, A.; Marazita, M.L.; Murray, J.C.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.