POS0165 WHOLE EXOME SEQUENCING TO IDENTIFY RARE INFLAMMATORY VARIANTS IN AN IRISH COHORT WITH CHRONIC NONBACTERIAL OSTEOMYELITIS (CNO)

Background Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory disease affecting bone which predominantly occurs in the paediatric population. It frequently associated with pustulosis, psoriasis, bowel and arthritis, particular enthesitis-related arthritis. Activation of NLRP3 inflammasome has been implicated both human mouse models disease. Objectives To identify candidate list rare, deleterious variants known genes an Irish cohort CNO. Methods 41 unrelated children CNO were recruited. Whole exome sequencing was performed on blood using Agilent SureSelect XT Human All Exon V6 kits Illumina HiSeq 3000 150bp paired-end reads. Reads aligned to hg19 reference genome. After preprocessing, hard filtered quality by depth(QD) > 2.0, read depth (DP) >10 genotype (GQ) >20. Synonymous MAF 0.01 excluded from further analysis. Remaining against existing databases be inborn errors immunity, autoimmunity or autoinflammation. The Gene Damage Index (GDI) used are least tolerant variance CADD phred-like scores predicted deleterious. Genes >=2 patients included manually checked Integrative Genomics Viewer (IGV). Results filtering low-quality, synonymous common variants, 17,293 database 581 genes. 350 201 intolerant identified. excluding those present one individual only, ranking manual inspection IGV, 25 remained. same variant IL17RA, NLRP1 KMT2D 3 individuals (Table 1). IL17RA belongs Th17 pathway involved psoriasis pathogenesis. several autoinflammatory diseases including psoriasis. None carrying these have One 1 st -degree family history Rare found two each following IL-17 signalling/Th17 differentiation pathway: IL17RB, IL17RE, IL25, HIF1A This suggests that may play role pathogenesis proportion Conclusion IL17 +/- pathways, provide targets for investigation elucidated through gene-/pathway-based burden testing matched control References [1]McKenna A, et al. Genome Analysis Toolkit: MapReduce framework analyzing next-generation DNA data. Res. 2010 Sep 1;20(9):1297–303. [2]Itan Y, gene damage index as gene-level approach prioritizing variants. Proc Natl Acad Sci U S A. 2015;112(44):13615–20. [3]Rentzsch P, CADD: Predicting deleteriousness throughout Nucleic Acids 2019 Jan 8;47(D1):D886–94. Table 1. Sample Variant Effect gnomAD OR p-value 16 22- 17586757-T>C Nonsynonymous 24.5 0.04 0.0034 11.06 0.003 37 p.W320R 42 5 17- 5462417- C>A 26.2 0.0058 6.47 9 p.Q533H 38 2 12- 49434409-G>A 21.3 0.0056 6.75 11 p.P2382S 21 10 IL17RB 3-53889368-G>A 29.7 0.024 0.0061 4.05 0.09 40 p.G177R 7 IL17RE 3-9957033-C>A 24.9 0.0086 3.19 0.13 43 pL400M IL25 14-23845076-G>A 34 0.0085 3.02 0.15 24 p.R174H 14-62187212-G>C 23.7 0.0026 9.9 0.02 15 p.V74L Disclosure Interests Daire O’Leary Grant/research support from: AbbVie SOBI Nordic Pharma Newman Fellowship Rheumatology, Orla Killeen: declared, Anthony G Wilson: declared