SAT0531 NEXT GENERATION SEQUENCING AND AUTOINFLAMMATORY SYNDROMES: CLINICAL AND GENETICAL CORRELATION ON AN ADULT POPULATION FROM A REFERRAL THIRD-CARE CENTRE
Authors: J. R. Marques Soares, M. Antolin Mate, E. Garcia Arumi, E. Tizzano Ferrari, S. Bujan Rivas
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic autoinflammatory diseases (sAID) are a group of conditions with recurrent episodes of inflammation in absence of infection or autoimmune response. Its physiopathology mainly lies on mono/poligenic mutations involving genes related to the innate immune system response. Next Generation Sequencing (NGS) platformss have been a big step forward on sAID diagnosis, although a clinical and genetic correlation is still needed. Objectives: To review the sAID related gene panel variants identified using NGS sAID gene panel on a cohort of adult patients screened for sAID from a referral third-level hospital. To correlate genetic and clinical findings for sAID related variants identified in order to the clinical suspicion diagnosis of sAID. Methods: A retrospective review of a cohort of adult (≥ 16 yo) patients with available NGS sAID related gene panel (MiSeq Illumina sequencing platform including intron and exon variants from up to 17 sAID genes, with coverage depth &gt; x100) among 2014 and 2019 was performed. Demographic, clinical and genetic data were collected in a database. Genetic variants were classified according to the American College of Medical Genetics/Association for Molecular Pathology classification as benign/likely benign/variable of unknown significance (VUS)/likely pathogenic/pathogenic. In case of polymorphisms or lack of genetic data, the variants were named as unclassified. A description of the cohort and an analysis of the correlation assessment between clinical data and genetic findings were performed. Results: 246 out of 299 (82%) patients with NGS sAID gene panel had clinical data available. 170/246 (69%) were adult patients. The medium age was 48 yo, and the M/F ratio was 2.46. 87/170 (51%) adult patients presented 122 variants involving sAID genes (60/87 patients with a single variant). All the variants out of 7 seven were heterozygous variants. Variants were classified according to ACMG/AMP as follow: pathogenic/probably pathogenic: 22/122 (18%), unknown significance: 74/122 (60.6%), benign/probably benign: 6/122 (4.91%). 20/122 (16.4%) were unclassified variants or polymorphisms. The most frequent variants identified involved MEFV (54/122), NOD2/CARD15 (18/122) and TNFRSF1A (17/122 including 12 p.Arg121Gln variants) genes. 37/122 (30%) variants correlated with the clinical picture in 33 patients, allowing to confirm the suspected diagnosis. Among the 122 variants, 7 not previously communicated variants were identified. No somatic variants were found. Conclusion: NGS sAID related gene panel is a useful tool for sAID diagnosis. In this cohort of 170 adult patients from a referral third-level hospital, genetic tests identified sAID related variants in almost half of them. 20% of patients who underwent genetic NGS sAID related gene panel studies were finally diagnosed with sAID. The identification of a genetic variant (even pathogenic / likely pathogenic variant) is not diagnostic for sAID if there is not a suggestive clinical picture. Despite genetic findings, a careful evaluation of clinical – genetic correlation is needed to confirm the suspicion diagnosis, especially for low penetrance variants like TNFRSF1A p. Arg121Gln. References: Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study. Karacan I, Balamir A, Uğurlu S, et al. . Rheumatol Int. 2019 May;39(5):911-919. doi: 10.1007/s00296-019-04252-5. Epub 2019 Feb 19. Disclosure of Interests: None declared