Background/Purpose: Monogenic systemic inflammatory diseases (MSID) are a heterogeneous group of rare conditions caused by single gene variants leading to immune dysregulation. Diagnostic yield of targeted gene panels in these patients is limited. Whole exome sequencing (WES) has been used in pediatric populations to identify a growing number of genes implicated in MSID. Such approaches to studying MSID in adults are rare in the literature. Here, we have clinically and genetically characterized a case series of adult patients with suspected MSID.

Methods: Our study included 14 adults with suspected MSID and non-diagnostic gene panels, assessed at St Michael’s Hospital, Toronto. We excluded patients with inflammation due to non-genetic causes.

Clinical and laboratory data were extracted and entered into a database. Targeted gene (n=31) panel testing on an exome backbone was performed at Genome Diagnostics, SickKids, using paired end sequencing on Illumina HiSeq 2500 platform to an average depth of ~120X following enrichment with the Agilent Clinical Research Exome V1 kit. After obtaining consent, sequence data was analyzed in a research setting using BWA aligner followed by variant calling with GATK, SAMtools, FreeBayes, and Platypus. Annotation was performed using SnpEff, Vcfanno, and custom scripts. Variants were filtered and prioritized using minor allele frequency < 0.01 in gnomAD, in silico prediction tools (CADD, SIFT, Polyphen, Vest3, Revel), conservation, segregation where parental data was available, and associations with known disorders or immunological pathways.

A definitive molecular diagnosis was provided if a likely pathogenic or pathogenic variant (as classified by the 2015 American College of Medical Geneticists criteria) was identified in a patient with a fully compatible phenotype. A probable diagnosis was defined as a variant of uncertain significance (VUS) in a gene associated with a condition identified in a patient with a compatible phenotype. A possible diagnosis was defined as a VUS in a gene involved in immune processes, but without a known associated condition.

Results: The majority of patients were male (64%) and European (57%). Age at study enrollment was between 22-52 years, with 36% having symptom onset before the age of 18. 42% had a family history of an immune-mediated disorder. WES provided one definite diagnosis (Aicardi Goutières Syndrome Type I; TREX1 homozygous deletions) and one probable diagnosis (Proteasome Associated Autoinflammatory Syndrome; digenic missense variants in PSMB4/PSMB8). Possible diagnoses were found in eight (57%) patients (VUS’s in STYK1, FAIM3, ARHGAP26, FGD2, IKBKAP, BLK, ASAP1, RRTOR, LILRA6, RNF21).

Conclusion: In a series of adults with suspected MSID, exome analysis identified variants leading to a probable or definite diagnosis in 14%, and possible diagnoses in 57% of patients. Our work shows that exome sequencing identifies potential genetic causes of systemic inflammatory disease in patients with negative gene panels. Future studies would include family-based analyses and functional validation of candidate variants. Larger multicenter studies will further define the role of WES in this population.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovering-variants-in-suspected-monogenic-systemic-inflammatory-disease-an-adult-case-series/