Journal article
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, Vol.8(8), pp.e1355-n/a
08/2020
DOI: 10.1002/mgg3.1355
PMCID: PMC7434609
PMID: 32558391
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.
The study reported novel variants in IRF6 from patients with VWS. Updated the list of all IRF6 variants reported from 2013 to date and provide an insight into on how to use the Combined Annotation Dependent Depletion score for the prioritization of IRF6 variants.
Details
- Title: Subtitle
- Non‐random distribution of deleterious mutations in the DNA and protein‐binding domains of IRF6 are associated with Van Der Woude syndrome
- Creators
- Azeez A. Alade - University of IowaCarmen J. Buxo‐Martinez - University of Puerto Rico SystemPeter A. Mossey - University of DundeeLord J.J. Gowans - Kwame Nkrumah University of Science and TechnologyMekonen A. Eshete - Addis Ababa UniversityWasiu L. Adeyemo - University of LagosThirona Naicker - University of KwaZulu-NatalWaheed A. Awotoye - University of IowaChinyere Adeleke - University of IowaTamara Busch - University of IowaAda M. Toraño - University of Puerto Rico SystemCarolina A. Bello - University of Puerto Rico SystemMairim Soto - University of Puerto Rico SystemMarilyn Soto - University of Puerto Rico SystemRicardo Ledesma - University of Puerto Rico SystemMyrellis Marquez - University of Puerto Rico SystemJose F. Cordero - University of Puerto Rico SystemLydia M. Lopez‐Del Valle - University of Puerto Rico School of Dental MedicineMaria I. Salcedo - University of Puerto Rico SystemNatalio Debs - University of Puerto Rico SystemMary Li - University of IowaAline Petrin - University of IowaJoy Olotu - University of Port HarcourtColleen Aldous - University of KwaZulu-NatalJames Olutayo - University of LagosModupe O. Ogunlewe - University of LagosFekir Abate - Addis Ababa UniversityTaye Hailu - Addis Ababa UniversityIbrahim Muhammed - Addis Ababa UniversityPaul Gravem - Addis Ababa UniversityMilliard Deribew - Addis Ababa UniversityMulualem Gesses - Addis Ababa UniversityMohaned Hassan - University of IowaJohn Pape - University of IowaOluwole A. Adeniyan - Burton Hospitals NHS Foundation TrustSolomon Obiri‐Yeboah - Kwame Nkrumah University of Science and TechnologyFareed K.N. Arthur - Kwame Nkrumah University of Science and TechnologyAlexander A. Oti - Kwame Nkrumah University of Science and TechnologyOlubukola Olatosi - University of LagosSara E. Miller - University of IowaPeter Donkor - Kwame Nkrumah University of Science and TechnologyMartine M. Dunnwald - University of IowaMary L. Marazita - University of PittsburghAdebowale A. Adeyemo - National Human Genome Research InstituteJeffrey C. Murray - University of IowaAzeez Butali - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular genetics & genomic medicine, Vol.8(8), pp.e1355-n/a
- DOI
- 10.1002/mgg3.1355
- PMID
- 32558391
- PMCID
- PMC7434609
- NLM abbreviation
- Mol Genet Genomic Med
- ISSN
- 2324-9269
- eISSN
- 2324-9269
- Number of pages
- 8
- Grant note
- National Institute of Health/National Institute of Dental and Craniofacial Research (R00 DE022378; R00 DE024571; R01 DE28300) National Institute on Minority Health and Health Disparities (S21 MD001830; U54 MD007587)
- Language
- English
- Date published
- 08/2020
- Academic Unit
- Orthodontics; 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
- 9984284350902771
Metrics
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