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Introduction/Background Juvenile idiopathic arthritis (JIA) encompasses a group of heterogeneous rheumatic diseases of childhood onset. JIA can result in long term disability and remission is the main goal of treatment. However refractory disease can occur, which is defined as the absence of response to a standard disease therapy. A genetic basis for refractory disease has yet to explored, where deleterious rare variants complicate diagnosis or treatment outcome. This study aimed to investigate, through genetic analysis, whether children with JIA that is refractory carry rare genetic risk factors in genes linked to monogenic diseases. Description/Method Whole exome sequencing of 99 children with JIA was performed with the Agilent SureSelect Human All ExonV6 kit. All quality control, variant filtering and annotation was performed in Varseq (version 2.2.1). Variants with a read depth 1% (based on ExAC, gnomAD, gnomAD exome, NHLBI and 1KGp phase 3), classified as benign or likely benign on ClinVar, with a CADD PHRED score 0.7. Variants were annotated if they appeared in a gene from the primary immunodeficiency PanelApp (Martin et al., 2019), in a gene associated with an arthritis phenotype or in a gene that appeared on a paediatric monogenic gene list. The variants were then classified using ACMG guidelines (Richards et al., 2015) and benign, or likely benign, classified variants were removed. Discussion/Results A total of 470 variants were identified and we found that 20 out of the 99 children screened were heterozygous for at least one recognised variant in a gene linked to a monogenic disease. Five of these children carried more than one recognised variant linked to monogenic genes. Here we provide a number of illustrative examples: three genes, ADAR, ATP7B and MVK, were prioritised based on prior evidence of associated disease. The variant p.Pro193Ala (gnomAD allele frequency (GAD) 2.2x10-3) of ADAR has previously been deemed pathogenic in a homozygous or compound heterozygous state for Aicardi-Goutières syndrome. Adenosine deaminases (ADARs) catalyse the hydrolytic deamination of adenosine to inosine in dsRNA and is suggested to act as a suppressor of type 1 interferon-stimulated genes. Within ATP7B, two distinct variants were detected; p.Gln1142His (GAD 1.6x10-5) and p.Ile1148Thr (GAD 4.0x10-5) have previously been reported as pathogenic, in combination with a third variant, for Wilson’s disease and were carried by one individual in this cohort. ATP7B encodes copper-transporting ATPase 2, which supplies copper to ceruloplasmin. Variant p.Val377Ile (GAD 1.6x10-3) of MVK was detected in eight individuals in this cohort, interestingly five of these individuals also carried at least one HLA-DRB1 stop-gained variant. This MVK mutation has been confirmed as pathogenic in a homozygous or compound heterozygous state for mevalonate kinase deficiency. MVK converts mevalonic acid into mevalonate-5-phosphate in the cholesterol synthesis pathway. Additionally, two stop-gained loss of function HLA-DRB1 variants, p.Tyr107Ter and p.Gln125Ter, were detected in five and 20 individuals, respectively, in this cohort. HLA-DRB1 is a recognised susceptibility locus for JIA. Key learning points/Conclusion Screening of a cohort of 99 children with JIA that have refractory disease has revealed that individuals carry deleterious variants in genes linked to monogenic forms of disease. These results highlight that the genetic basis for refractory disease needs to be further investigated. Carrying additional genetic risk factors to disease may complicate disease outcome and genetic screening of children with refractory JIA may improve treatment outcome in the future.

Heterozygous disruptions ofHere we phenotyped 28 individuals from 17 families with pathogenicSpeech disorders were prevalent (23/25, 92%) and CAS was most common (22/25, 88%), with similar speech presentations across English and German. Speech was still impaired in adulthood, and some speech sounds (eg, 'th', 'r', 'ch', 'j') were never acquired. Language impairments (21/25, 84%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (13/26, 50%) and gross (13/26, 50%) motor impairment, anxiety (5/27, 19%), depression (6/27, 22%) and sleep disturbance (11/15, 44%). Physical features were common (22/27, 81%) but with no consistent pattern. Cognition ranged from average to mildly impaired and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition.Although we identify an increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of

Recent advances in Genetic Medicine are changing the landscape of testing available in the neonatal period. A move away from karyotype to microarray CGH testing, as first line chromosomal testing, has markedly improved diagnostic yield. This enhanced chromosomal testing, combined with the increased use of high-throughput sequencing of multiple genes, or of the whole exome (all protein coding genes), shows promise of a new era of diagnosis for genetic conditions, which present in infancy. This article provides an overview of the current genetic tests available in the neonatal setting, looks to the future of testing in the field and highlights important points to consider when undertaking genetic testing.

Objectives To investigate the relationships between interferon alpha (IFNα) and the clinical and serological phenotype of patients with systemic autoimmune rheumatic disease (SARDs) in order to determine whether a distinct subpopulation of patients can be identified. Methods We recruited patients with at least 1 SARD clinical feature and at least 1 SARD-related autoantibody from two NHS Trusts in Greater Manchester. A 6-gene interferon-stimulated gene (ISG) score was calculated in all patients, and in a subgroup, a 30-gene ISG score was produced using NanoString. A digital Single Molecule Array (Simoa) was used to measure plasma IFNα protein. In an exploratory analysis, whole blood RNA sequencing was conducted in 12 patients followed by RT-qPCR confirmation of expression of 6 nucleic acid receptors (NARs) in the whole cohort. Results Sixty three of 164 (38%) patients had a positive ISG score. The 3 measures of IFNα all correlated strongly with each other (p