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Research ArticleAccepted Articles

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

Melissa Misztal, Fangming Liao, Madeline Couse, Jingjing Cao, Daniela Dominguez, Lynette Lau, Christian R. Marshall, Sergey Naumenko, Andrea M. Knight, Deborah M. Levy and Linda T. Hiraki
The Journal of Rheumatology November 2022, jrheum.220513; DOI: https://doi.org/10.3899/jrheum.220513
Melissa Misztal
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Fangming Liao
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Madeline Couse
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Jingjing Cao
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Daniela Dominguez
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Lynette Lau
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Christian R. Marshall
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Sergey Naumenko
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Andrea M. Knight
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Deborah M. Levy
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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Linda T. Hiraki
Dr. Hiraki is supported by a CIHR Canada Research Chair and The Arthritis Society STARS Career Development award. Genetics & Genome Biology, Research Institute, The Hospital for Sick Children; Division of Rheumatology, The Hospital for Sick Children; The Centre for Applied Genomics, The Hospital for Sick Children; Department of Biostatistics, Harvard Chan School of Public Health; Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children; Department of Laboratory Medicine and Pathobiology, University of Toronto. Correspondence: Linda T. Hiraki, MD, FRCPC, ScD Clinician Scientist, Division of Rheumatology, Scientist Track, Research Institute, The Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto ON M5G 0A4 Email: linda.hiraki@sickkids.ca
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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 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.

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The Journal of Rheumatology
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1 Feb 2023
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Accepted manuscript
Genome-wide Sequencing Identified Rare Genetic Variants for Childhood-onset Monogenic Lupus
Melissa 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
The Journal of Rheumatology Nov 2022, jrheum.220513; DOI: 10.3899/jrheum.220513

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Accepted manuscript
Genome-wide Sequencing Identified Rare Genetic Variants for Childhood-onset Monogenic Lupus
Melissa 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
The Journal of Rheumatology Nov 2022, jrheum.220513; DOI: 10.3899/jrheum.220513
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