Genome-wide Sequencing Identified Rare Genetic Variants for Childhood-onset Monogenic Lupus

Objective Genetics play an important role in systemic lupus erythematosus (SLE) pathogenesis. We calculated the prevalence of rare variants in known monogenic lupus genes, among children suspected of monogenic lupus.

Methods We completed paired end genome-wide sequencing (whole-genome or whole-exome) in patients suspected of monogenic lupus, and focused on 36 monogenic lupus genes. We prioritized rare (minor allele frequency <1%) nonsynonymous and splice variants with predicted pathogenicity classified as deleterious variants (CADD, Polyphen, SIFT scores). Additional filtering restricted to predicted damaging variants by considering reported zygosity. In those with WGS, n=69, we examined copy number variants (CNVs) >1kb in size. We created additive non-HLA and HLA SLE genetic risk scores (GRSs) using common SLE-risk SNPs. We tested the relationship between SLE-GRSs and the number of rare variants with multivariate logistic models, adjusted for sex, ancestry and age of diagnosis.

Results The cohort included 71 patients, 80% female, with a mean age at diagnosis of 8.9 years (SD 3.2 years). We identified predicted damaging variants in 9 patients (13%) who were significantly younger at diagnosis compared to those without a predicted damaging variant (6.8 years [SD 2.1] vs. 9.2 years [SD 3.2], P=0.013). We did not identify damaging CNVs. There was no significant association between non-HLA or HLA SLE-GRSs and the odds of carrying one or more rare variant in multivariate analyses.

Conclusion In a cohort of patients with suspected monogenic lupus who underwent genomewide sequencing, 13% carried rare variants for monogenic lupus. Additional studies are needed to validate our findings.