Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome
Abstract Background The development of the face occurs during the early days of intrauterine 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...
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1355 |
| _version_ | 1797301034998038528 |
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| author | Azeez A. Alade Carmen J. Buxo‐Martinez Peter A. Mossey Lord J.J. Gowans Mekonen A. Eshete Wasiu L. Adeyemo Thirona Naicker Waheed A. Awotoye Chinyere Adeleke Tamara Busch 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 Mary Li Aline Petrin Joy Olotu Colleen Aldous James Olutayo Modupe O. Ogunlewe Fekir Abate Taye Hailu Ibrahim Muhammed Paul Gravem Milliard Deribew Mulualem Gesses Mohaned Hassan John Pape Oluwole A. Adeniyan Solomon Obiri‐Yeboah Fareed K.N. Arthur Alexander A. Oti Olubukola Olatosi Sara E. Miller Peter Donkor Martine M. Dunnwald Mary L. Marazita Adebowale A. Adeyemo Jeffrey C. Murray Azeez Butali |
| author_facet | Azeez A. Alade Carmen J. Buxo‐Martinez Peter A. Mossey Lord J.J. Gowans Mekonen A. Eshete Wasiu L. Adeyemo Thirona Naicker Waheed A. Awotoye Chinyere Adeleke Tamara Busch 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 Mary Li Aline Petrin Joy Olotu Colleen Aldous James Olutayo Modupe O. Ogunlewe Fekir Abate Taye Hailu Ibrahim Muhammed Paul Gravem Milliard Deribew Mulualem Gesses Mohaned Hassan John Pape Oluwole A. Adeniyan Solomon Obiri‐Yeboah Fareed K.N. Arthur Alexander A. Oti Olubukola Olatosi Sara E. Miller Peter Donkor Martine M. Dunnwald Mary L. Marazita Adebowale A. Adeyemo Jeffrey C. Murray Azeez Butali |
| author_sort | Azeez A. Alade |
| collection | DOAJ |
| description | Abstract Background The development of the face occurs during the early days of intrauterine 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 percentage of deleterious variants. Results Twenty‐one new mutations were identified from nine papers. The majority 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 nonsense 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. |
| first_indexed | 2024-03-07T23:15:38Z |
| format | Article |
| id | doaj.art-0abb9e91af0b4d64a4c82a601537aef8 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:15:38Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-0abb9e91af0b4d64a4c82a601537aef82024-02-21T11:08:50ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-08-0188n/an/a10.1002/mgg3.1355Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndromeAzeez A. Alade0Carmen J. Buxo‐Martinez1Peter A. Mossey2Lord J.J. Gowans3Mekonen A. Eshete4Wasiu L. Adeyemo5Thirona Naicker6Waheed A. Awotoye7Chinyere Adeleke8Tamara Busch9Ada M. Toraño10Carolina A. Bello11Mairim Soto12Marilyn Soto13Ricardo Ledesma14Myrellis Marquez15Jose F. Cordero16Lydia M. Lopez‐Del Valle17Maria I. Salcedo18Natalio Debs19Mary Li20Aline Petrin21Joy Olotu22Colleen Aldous23James Olutayo24Modupe O. Ogunlewe25Fekir Abate26Taye Hailu27Ibrahim Muhammed28Paul Gravem29Milliard Deribew30Mulualem Gesses31Mohaned Hassan32John Pape33Oluwole A. Adeniyan34Solomon Obiri‐Yeboah35Fareed K.N. Arthur36Alexander A. Oti37Olubukola Olatosi38Sara E. Miller39Peter Donkor40Martine M. Dunnwald41Mary L. Marazita42Adebowale A. Adeyemo43Jeffrey C. Murray44Azeez Butali45Department of Oral Pathology, Radiology and Medicine College of Dentistry University of Iowa Iowa City IA USADental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDepartment of Orthodontics University of Dundee Dundee United KingdomKomfo Anokye Teaching Hospital and Kwame Nkrumah University of Science and Technology Kumasi GhanaSchool of Public Health Addis Ababa University Addis Ababa EthiopiaDepartment of Oral and Maxillofacial Surgery University of Lagos Lagos NigeriaSchool of clinical medicine KwaZulu‐Natal University Durban South AfricaDepartment of Oral Pathology, Radiology and Medicine College of Dentistry University of Iowa Iowa City IA USADepartment of Oral Pathology, Radiology and Medicine College of Dentistry University of Iowa Iowa City IA USADepartment of Oral Pathology, Radiology and Medicine College of Dentistry University of Iowa Iowa City IA USADental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDental and Craniofacial Genomics Core University of Puerto Rico School of Dental Medicine San Juan Puerto RicoDepartment of Oral Pathology, Radiology and Medicine College of Dentistry University of Iowa Iowa City IA USAIowa Institute of Oral Health ResearchUniversity of Iowa Iowa City IA USADepartment of Anatomy University of Port Harcourt Port Harcourt NigeriaSchool of clinical medicine KwaZulu‐Natal University Durban South AfricaDepartment of Oral and Maxillofacial Surgery University of Lagos Lagos NigeriaDepartment of Oral and Maxillofacial Surgery University of Lagos Lagos NigeriaSchool of Public Health Addis Ababa University Addis Ababa EthiopiaSchool of Public Health Addis Ababa University Addis Ababa EthiopiaSchool of Public Health Addis Ababa University Addis Ababa EthiopiaSchool of Public Health Addis Ababa University Addis Ababa EthiopiaSchool of Public Health Addis Ababa University Addis Ababa EthiopiaSchool of Public Health Addis Ababa University Addis Ababa EthiopiaDepartment of Oral Pathology, Radiology and Medicine College of Dentistry University of Iowa Iowa City IA USADepartment of Oral Pathology, Radiology and Medicine College of Dentistry University of Iowa Iowa City IA USANHS Foundation Trust, (Queens Hospital, Burton‐On‐Trent) Staffordshire United KingdomKomfo Anokye Teaching Hospital and Kwame Nkrumah University of Science and Technology Kumasi GhanaKomfo Anokye Teaching Hospital and Kwame Nkrumah University of Science and Technology Kumasi GhanaKomfo Anokye Teaching Hospital and Kwame Nkrumah University of Science and Technology Kumasi GhanaDepartment of Child Dental Health University of Lagos NigeriaIowa Institute of Oral Health ResearchUniversity of Iowa Iowa City IA USAKomfo Anokye Teaching Hospital and Kwame Nkrumah University of Science and Technology Kumasi GhanaDepartment of Anatomy University of Iowa Iowa City IA USAOral Biology Human Genetics University of Pittsburgh Pittsburgh PA USANational Human Genomic Research Institute Bethesda MD USADepartment of Pediatrics University of Iowa Iowa City IA USADepartment of Oral Pathology, Radiology and Medicine College of Dentistry University of Iowa Iowa City IA USAAbstract Background The development of the face occurs during the early days of intrauterine 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 percentage of deleterious variants. Results Twenty‐one new mutations were identified from nine papers. The majority 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 nonsense 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.https://doi.org/10.1002/mgg3.1355Combined Annotation Dependent Depletion scoreinterferon regulatory factor 6orofacial cleftPopliteal pterygium syndromeVan der Woude syndrome |
| spellingShingle | Azeez A. Alade Carmen J. Buxo‐Martinez Peter A. Mossey Lord J.J. Gowans Mekonen A. Eshete Wasiu L. Adeyemo Thirona Naicker Waheed A. Awotoye Chinyere Adeleke Tamara Busch 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 Mary Li Aline Petrin Joy Olotu Colleen Aldous James Olutayo Modupe O. Ogunlewe Fekir Abate Taye Hailu Ibrahim Muhammed Paul Gravem Milliard Deribew Mulualem Gesses Mohaned Hassan John Pape Oluwole A. Adeniyan Solomon Obiri‐Yeboah Fareed K.N. Arthur Alexander A. Oti Olubukola Olatosi Sara E. Miller Peter Donkor Martine M. Dunnwald Mary L. Marazita Adebowale A. Adeyemo Jeffrey C. Murray Azeez Butali Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome Molecular Genetics & Genomic Medicine Combined Annotation Dependent Depletion score interferon regulatory factor 6 orofacial cleft Popliteal pterygium syndrome Van der Woude syndrome |
| title | Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome |
| title_full | Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome |
| title_fullStr | Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome |
| title_full_unstemmed | Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome |
| title_short | Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome |
| title_sort | non random distribution of deleterious mutations in the dna and protein binding domains of irf6 are associated with van der woude syndrome |
| topic | Combined Annotation Dependent Depletion score interferon regulatory factor 6 orofacial cleft Popliteal pterygium syndrome Van der Woude syndrome |
| url | https://doi.org/10.1002/mgg3.1355 |
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