| Comparative analysis of IRF6 variants in families with Van der Woude syndrome and popliteal pterygium syndrome using public whole-exome databases. | |
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MedLine Citation:
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PMID: 23154523 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Purpose:Mutations in the transcription factor IRF6 cause allelic autosomal dominant clefting syndromes, Van der Woude syndrome, and popliteal pterygium syndrome. We compared the distribution of IRF6 coding and splice-site mutations from 549 families with Van der Woude syndrome or popliteal pterygium syndrome with that of variants from the 1000 Genomes and National Heart, Lung, and Blood Institute Exome Sequencing Projects.Methods:We compiled all published pathogenic IRF6 mutations and performed direct sequencing of IRF6 in families with Van der Woude syndrome or popliteal pterygium syndrome.Results:Although mutations causing Van der Woude syndrome or popliteal pterygium syndrome were nonrandomly distributed with significantly increased frequencies in the DNA-binding domain (P = 0.0001), variants found in controls were rare and evenly distributed in IRF6. Of 194 different missense or nonsense variants described as potentially pathogenic, we identified only two in more than 6,000 controls. PolyPhen and SIFT (sorting intolerant from tolerant) reported 5.9% of missense mutations in patients as benign, suggesting that use of current in silico prediction models to determine function can have significant false negatives.Conclusion:Mutation of IRF6 occurs infrequently in controls, suggesting that for IRF6 there is a high probability that disruption of the coding sequence, particularly the DNA-binding domain, will result in syndromic features. Prior associations of coding sequence variants in IRF6 with clefting syndromes have had few false positives.Genet Med advance online publication 15 November 2012Genetics in Medicine (2012); doi:10.1038/gim.2012.141. |
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Authors:
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Elizabeth J Leslie; Jennifer Standley; John Compton; Sherri Bale; Brian C Schutte; Jeffrey C Murray |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-11-15 |
Journal Detail:
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Title: Genetics in medicine : official journal of the American College of Medical Genetics Volume: - ISSN: 1530-0366 ISO Abbreviation: Genet. Med. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9815831 Medline TA: Genet Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA. |
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