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

Melissa C Misztal; Fangming Liao; Madeline Couse; Jingjing Cao; Daniela Dominguez; Lynette Lau; Christian R Marshall; Sergey Naumenko; Andrea M Knight; Deborah M Levy; Linda T Hiraki

doi:10.3899/jrheum.220513

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.

Authors

Affiliations

¹ M. Misztal, MHSc, Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
² F. Liao, MSc, D. Dominguez, MSc, A.M. Knight, MSc, MD, D.M. Levy, MSc, MD, Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada.
³ M. Couse, MSc, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ J. Cao, MSc, Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, and The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ L. Lau, MSc, Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ C.R. Marshall, PhD, The Centre for Applied Genomics, The Hospital for Sick Children, and Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁷ S. Naumenko, PhD, Department of Biostatistics, Harvard Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁸ L.T. Hiraki, MD, ScD, Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, and Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada. linda.hiraki@sickkids.ca.

PMID: 36379578
DOI: 10.3899/jrheum.220513

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Grants and funding

CIHR/Canada