IRF6) Gene Disorders (Popliteal Pterygium Syndrome and Van Der Woude Syndrome)

Interferon Regulatory Factor 6 (IRF6) gene disorders (Popliteal Pterygium syndrome and Van der Woude syndrome) Contact details Introduction Regional Genetics Service Van der Woude syndrome (VWS; MIM) and Popliteal Pterygium syndrome (PPS) are Levels 4-6, Barclay House allelic autosomal dominant disorders caused by pathogenic variants in the interferon 37 Queen Square regulatory factor 6 gene (IRF6; MIM *607199). VWS is the most common form of cleft London, WC1N 3BH lip and/or palate accounting for 1-2% of cases. Lip pits and/or sinuses are cardinal T +44 (0) 20 7762 6888 features of the syndrome present in 70-80% of patients. PPS combines the symptoms F +44 (0) 20 7813 8578 of VWS with popliteal webs, unusual nails, syndactyly, ankyloblepharon and genital abnormalities. Samples required It has been proposed that orofacial development is affected in VWS as a result of 5ml venous blood in plastic EDTA haploinsufficiency with protein truncating pathogenic variants commonly identified bottles (>1ml from neonates) throughout the IRF6 gene. The features of PPS are thought to result from dominant negative pathogenic variants (generally missense) in the DNA binding domain of the Prenatal testing must be arranged in advance, through a Clinical protein. Confirmation of diagnosis enables prenatal testing for PPS and clarification of Genetics department if possible. recurrence risk for VWS (50% as opposed to 3-5% for isolated cleft/lip palate families). Amniotic fluid or CV samples should The IRF6 gene (1q32-q41) has 9 exons (exons 1 and 2 are non-coding). c.250C>T be sent to Cytogenetics for p.(Arg84Cys) and c.251G>A p.(Arg84His) are recurrent pathogenic variants identified dissecting and culturing, with in PPS patients. A variety of point variants and small deletions have been identified in instructions to forward the sample to the Regional Molecular Genetics VWS located throughout the IRF6 gene. laboratory for analysis Referrals A completed DNA request card should accompany all samples Referrals are only accepted via a Clinical Geneticist or cleft surgeon. Testing of other family members will be possible upon identification of a Patient details pathogenic variant in the index case. To facilitate accurate testing and Prenatal testing for Popliteal Pterygium syndrome reporting please provide patient demographic details (full name, date of Prenatal testing is available for families in whom pathogenic variants causing PPS have birth, address and ethnic origin), details been identified or in whom appropriate family studies have been undertaken. Please of any relevant family history and full contact the laboratory to discuss. contact details for the referring clinician Service offered Analysis is by next generation sequencing of the entire coding region of IRF6 (Agilent SureSelect and Illumina NextSeq). A minimum coverage of 30 reads is required to call a variant. In-house validation attributes a minimum sensitivity of 97.5% (with 95% confidence) for regions covered >30x. This assay is not currently validated to detect large deletions / duplications. All clinically relevant variants are confirmed by Sanger sequence analysis. Known benign polymorphisms and sequence variants which are unlikely to be pathogenic are not reported. Testing for known pathogenic variants in relatives of patients with confirmed PPS / VWS mutations by sanger sequencing. Contact details for Consultant Cleft Geneticist at Great Ormond Street Dr M Lees, Clinical Genetics, Great Ormond Street Hospital, Level 4 Barclay House, 37 Queen Square, London WC1N 3BH Target reporting time 8 weeks for routine screen in an index case. 4 weeks for familial testing. Please contact the laboratory for urgent cases. Version 10 .

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