Genome-Wide Sequencing Identified Rare Genetic Variants for Childhood-Onset Monogenic Lupus

J Rheumatol. 2023 May;50(5):671-675. doi: 10.3899/jrheum.220513. Epub 2022 Nov 15.


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 sequencing [WGS] or whole exome sequencing) in patients suspected of monogenic lupus, and focused on 36 monogenic lupus genes. We prioritized rare (minor allele frequency < 1%) exonic, nonsynonymous, and splice variants with predicted pathogenicity classified as deleterious variants (Combined Annotation Dependent Depletion [CADD], PolyPhen2, and Sorting Intolerant From Tolerant [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) > 1 kb in size. We created additive non-HLA and HLA SLE genetic risk scores (GRSs) using common SLE-risk single-nucleotide polymorphisms. 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 (SD 3.2) years. We identified predicted damaging variants in 9 (13%) patients who were significantly younger at diagnosis compared to those without a predicted damaging variant (6.8 [SD 2.1] years vs 9.2 [SD 3.2] years, P = 0.01). We did not identify damaging CNVs. There was no significant association between non-HLA or HLA SLE GRSs and the odds of carrying ≥ 1 rare variant in multivariate analyses.

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

Keywords: genetic studies; pediatric rheumatic diseases; systemic lupus erythematosus.

MeSH terms

  • Base Sequence
  • Child
  • Exome Sequencing
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Lupus Erythematosus, Systemic* / genetics
  • Male
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA