Whole exome sequencing of a cohort of patients with refractory JIA reveals rare genetic variants for paediatric monogenic diseases.

ObjectivesResearch of refractory disease in juvenile idiopathic arthritis (JIA) is limited, and a potential genetic contribution has yet to be investigated. This study aimed to explore the presence of rare monogenic disease gene coding variants in a refractory JIA population. MethodsCases were included with a record of inefficacy for methotrexate and [≥]1 biologic drug or exposure to methotrexate and [≥]2 biologic drugs for any reason. Whole exome sequencing data were analysed using VarSeq. rarity and pathogenicity filters were applied. Variants within an OMIM curated paediatric monogenic gene list, arthritis OMIM gene list, primary immunodeficiency gene panel (PanelApp) or gene reported for JIA drug response or toxicity (ClinPGX) were retained. ACMG classification excluded benign or likely benign variants. ResultsIn total, 83 individuals were included. Twelve variants were previously reported in other paediatric onset diseases with similar phenotypes to JIA. Seventeen variants were detected in twelve genes with an arthritis OMIM phenotype. Seventeen variants were detected within fourteen genes that were reported on the primary immunodeficiency panel (PanelApp) and were previously reported in a publication. A total of 39 variants were detected in genes from a JIA drug response or toxicity gene list (ClinPGX). ConclusionsThis study evidences that 66 individuals with refractory JIA carry rare variants associated with paediatric diseases, JIA susceptibility loci or drug response and toxicity. These variants could contribute to refractory disease, mimics of JIA/complicated phenotypes or effect treatment response. Longitudinal data are needed to confirm these findings.