ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1671

Identifying Rare Genetic Variants in Childhood-onset Monogenic Systemic Lupus Erythematosus

Melissa Misztal1, Fangming Liao2, Sergey Naumenko3, Andrea Knight4, Daniela Dominguez5, JingJing Cao2, Declan Webber6, Bhooma Thiruvahindrapuram7, Deborah Levy6, Andrew Paterson2, Earl D. Silverman8 and Linda Hiraki9, 1Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Oakville, ON, Canada, 2Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada, 3The Centre for Computational Medicine, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada, 4Division of Rheumatology, The Hospital for Sick Children and Department of Paediatrics, University of Toronto, Toronto, ON, Canada, 5Division of Rheumatology, The Hospital for Sick Children, Toronto, Canada, 6Division of Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada, 7The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, 8Division of Rheumatology, The Hospital for Sick Children, Translational Medicine, Research Institute, The Hospital for Sick Children, and Department of Paediatrics, University of Toronto., Toronto, ON, Canada, 9Division of Rheumatology, The Hospital for Sick Children, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, and Department of Paediatrics, University of Toronto., Toronto, ON, Canada

Meeting: ACR Convergence 2020

Keywords: , , ,

Session Information

Date: Monday, November 9, 2020

Title: Pediatric Rheumatology – Clinical Poster III: SLE, Vasculitis, & JDM

Session Type: Poster Session D

Session Time: 9:00AM-11:00AM

Background/Purpose: Among children diagnosed with systemic lupus erythematosus (SLE), there exists monogenic forms of SLE, where rare variants in a single gene lead to disease. The aim of this study was to calculate the burden of rare variants in monogenic SLE genes, in children suspected of monogenic SLE or lupus-like disease.

Methods: From the Hospital for Sick Children (SickKids) Lupus clinic, we identified patients suspected of monogenic SLE due to young-onset disease (< 11y), one or more affected first-degree relatives, and/or history of consanguinity. We completed paired end whole genome sequencing (WGS) using an Illumina HiSeq X platform (n=69) or paired end whole exome sequencing (WES) with an Illumina HiSeq 2500 platform (n=3). Variant calling was performed with GATK and HAS, and functional annotation with ANNOVAR. We prioritized rare exonic variants (MAF< 1%) based on predicted functional impact (frameshift, nonsynonymous and stop-gain) and 36 monogenic lupus genes. Chi-squared tests identified a subset of variants with an increased burden in monogenic SLE cases compared to relevant ethnic controls (Bonferroni correction p< 8.9E-4). Polyphen, SIFT and CADD scores (≥30) predicted damaging and/or deleterious variants.

Participants also underwent genotyping on the Illumina multiethnic MEGA or GSA array. Ancestry was genetically inferred using principal component and ADMIXTURE, or by self-report (Canada census ethnicity categories). Additive non-HLA and HLA SLE genetic risk scores (GRSs) were calculated using common risk single nucleotide polymorphisms. We tested the relationship between GRSs and the number of rare monogenic SLE variants with functional impact using Spearman correlation (rs) coefficients.

Results: The cohort included 72 suspected monogenic SLE patients, 65 with SLE and 7 with lupus-like disease (79% females), with a median age of diagnosis of 8 years (IQR=7,10). The majority of patients were admixed (33%) or European (29%). WGS analysis showed 1032 rare variants in monogenic SLE genes, with a median of 17 variants/gene (IQR= 10,32) and 14 variants/person (IQR=11,17). We identified 56 exonic variants with predicted functional impact, of which 18 variants in 24 patients had a significantly higher frequency in monogenic SLE cases compared to referent populations. We found 7 variants predicted to be disease-causing in 9 SLE patients, in genes: C1QA, C1QC, C1R, C4B, DNASE1L3 and MAN2B1 (Table).

In 68 individuals with calculated GRSs, we did not observe a correlation between the burden of rare monogenic SLE variants with functional impact and SLE HLA GRS (rs= 0.11, p=0.65) or non-HLA GRS (rs= 0.04, p=0.78) (Figure).

Conclusion: In our cohort of suspected monogenic SLE patients, WES/WGS identified a likely causal genetic variant in 13% of patients. We did not detect a significant correlation between the number of rare monogenic SLE variants with functional impact and non-HLA or HLA GRS. Studies with larger cohort sizes are needed to validate our findings.

Table. Frequency of predicted deleterious monogenic SLE variants in monogenic SLE cases compared to referent populations. (1) MAF reported for relevant referent population in gnomAD v2.1.1. (2) Chi-squared tests used to compare cSLE and referent variant frequencies. (3) Variant found in more than one monogenic cSLE patient.

Figure. Correlation between non-HLA GRS and rare monogenic SLE variants with functional impact*. *Data of 68 patients with non-HLA GRS and WGS data.

Disclosure: M. Misztal, None; F. Liao, None; S. Naumenko, None; A. Knight, None; D. Dominguez, None; J. Cao, None; D. Webber, None; B. Thiruvahindrapuram, None; D. Levy, None; A. Paterson, None; E. Silverman, None; L. Hiraki, None.

To cite this abstract in AMA style:

Misztal M, Liao F, Naumenko S, Knight A, Dominguez D, Cao J, Webber D, Thiruvahindrapuram B, Levy D, Paterson A, Silverman E, Hiraki L. Identifying Rare Genetic Variants in Childhood-onset Monogenic Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/identifying-rare-genetic-variants-in-childhood-onset-monogenic-systemic-lupus-erythematosus/. Accessed .

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