title: Comparative analysis of IRF6 variants in families with Van der Woude syndrome and popliteal pterygium syndrome using public whole-exome databases.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Leslie
authors.forename: Jennifer
authors.initials: J
authors.lastname: Standley
authors.forename: John
authors.initials: J
authors.lastname: Compton
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
authors.forename: Brian C
authors.initials: BC
authors.lastname: Schutte
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D003560:Cysts / Q000235:genetics*; D030561:Databases, Nucleic Acid; D059472:Exome; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005385:Fingers / Q000002:abnormalities; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007719:Knee Joint / Q000002:abnormalities; D008046:Lip / Q000002:abnormalities; D038061:Lower Extremity Deformities, Congenital / Q000235:genetics*; D009154:Mutation; D059645:Mutation Rate; D020125:Mutation, Missense; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D013576:Syndactyly / Q000235:genetics*; D014564:Urogenital Abnormalities / Q000235:genetics*
chemical_list: C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors