The Australian autoinflammatory diseases registry (AADRY): A streamlined approach to the genetic and immunological evaluation of monogenic autoinflammatory diseases

Abstract

Introduction: Since the original publication in 1971 outlining two cases of FMF complicated by pulmonary amyloidosis, there have been only two studies looking at the status of monogenic autoinflammatory disorders (AIDs) in Australia. Clinicians caring for patients with an AID without a pathogenic mutation in known diseasecausing genes do not have a streamlined approach to further genetic evaluation. Objectives: The Australian Autoinflammatory Diseases Registry (AADRY) aims to provide clinicians with access to a research team to further evaluate patients without an established genetic diagnosis as well as to address limitations in the current knowledge of AIDs in Australia. Methods: Patients with suspected AIDs were recruited as trios. Whole exome sequencing (WES) was performed on whole blood or saliva using the Hiseq 4000 platform and Illumina Sureselect XT V5 library. A variant list was generated using a pipeline, variant caller and filtering strategy previously described. Initial filtering of the variants proceeded by excluding synonymous and common variants, and intronic variants more than 50 base pairs from an intron-exon junction. Sequence data quality was assessed by viewing the BAM file on the Integrated genomics viewer. Variant classification was based on ACMG consensus guidelines. Results: From September 2015 to June 2018, 34 index cases underwent WES. Initial curation analysis looked at autoinflammatory genes as per IUIS and ISSAID. A total of 77 variants in 34 patients were filtered with no pathogenic or likely pathogenic variants detected. The majority (82%) of variants were VUS. Nineteen trios underwent WES. Seventy-one de novo variants (mean 4 per index case), 77 AR variants (mean 4) and 253 potential CH variants (mean 13) were curated. Of the 5 families recruited with more than one symptomatic member, a likely pathogenic variant segregating with disease was found in one family. The pedigree demonstrated multiple generations symptomatic of various degrees of pustular acne and hidradenitis suppurtiva. A novel truncating variant in NCSTN (c.1485C>T) encoding nicastrin p.Glu454X segregated with disease. Conclusion: AADRY has curated the WES of 34 index cases, including 19 trios. A likely pathogenic variant was discovered in one family with a highly penetrant dominantly inherited dermatological phenotype. No clear genetic diagnosis has been made in the remaining index cases, however a number of candidate novel variants are being evaluated. Further work is now underway to gather data on patients with genetically defined AIDs so that the retrospective cohort of patients with an established diagnosis is captured.L6279738022019-06-11 <br />