Background There is strong evidence that genetics plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Genome wide association studies (GWAS) have identified >90 loci associated with SLE risk, which suggests SLE is a complex trait. Yet collectively these genes explain a small fraction of SLE heritability. Within the broad category of SLE, there are genetically distinct Mendelian/monogenic diseases, presenting with lupus features. Macrophage activation syndrome (MAS) is an increasing recognized complication of SLE. It shares similarities with familial hemophagocytic lymphohistiocytosis (HLH), a Mendelian disease. We hypothesize that whole exome (WES) and whole genome sequencing (WGS) of SLE patients suspected of carrying rare genetic variants with large effects, will identify variants and genes associated with SLE risk and MAS. This information has implication for therapy, screening as well as providing insights into the pathogenesis of SLE and MAS broadly.

Methods WGS on 8 cSLE patients with one of: (i) age diagnosis <10 y, (i) from families with multiple affected members with SLE; or (iii) evidence of consanguinity, and WES on 11 cSLE with MAS was completed at TCAG. Paired end sequencing completed using HiSeq X (WGS, read depth 37–40X) and Illumina HiSeq 2500 (WES, 70–118X) platforms. GATK and HAS were used for variant calling and ANNOVAR for functional annotation, with TCAG Small Variant annotation pipeline, v26.2, v.26.5. We initially focused on rare (minor allele frequency <0.01) gene coding regions from 36 known monogenic lupus, and 14 HLH genes.

Results WGS of cSLE patients revealed potential disease causing monogenic variants in known genes including SLC7A7 and DNASE1. All MAS-SLE patients heterozygous for ≥1 rare variant in HLH gene, with 5/14 heterozygous for exonic non-synonymous variants in PRF1, LYST, ITK and AP3B1.

Conclusions We identified candidate variants leading to monogenic lupus and MAS in SLE. Additional validation studies are planned to confirm our findings and elucidate the precise pathogenic mechanism leading to disease. These variants have the potential for prognostication, secondary screening of family members and improved therapy for patients and families.

Acknowledgements Childhood Arthritis and Rheumatology Research Alliance (CARRA) Small Grant, McLaughlin Centre, University of Toronto.