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Research ArticlePediatric Rheumatology

Hemophagocytic Lymphohistiocytosis Gene Variants in Childhood-Onset Systemic Lupus Erythematosus With Macrophage Activation Syndrome

Piya Lahiry, Sergey Naumenko, Madeline Couse, Fangming Liao, Daniela Dominguez, Andrea Knight, Deborah M. Levy, Melissa Misztal, Lawrence W.K. Ng and Linda T. Hiraki
The Journal of Rheumatology October 2022, 49 (10) 1146-1151; DOI: https://doi.org/10.3899/jrheum.211200
Piya Lahiry
1P. Lahiry, MD, PhD, FRCPC, D. Dominguez, MD, MSc, D.M. Levy, MD, MSc, FRCPC, L.W.K. Ng, BSc, Division of Rheumatology, SickKids;
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Sergey Naumenko
2S. Naumenko, PhD, The Centre for Computational Medicine, Research Institute, SickKids;
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Madeline Couse
3M. Couse, MSc, F. Liao, MSc, M. Misztal, BSc, Genetics & Genome Biology, Research Institute, SickKids;
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Fangming Liao
3M. Couse, MSc, F. Liao, MSc, M. Misztal, BSc, Genetics & Genome Biology, Research Institute, SickKids;
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Daniela Dominguez
1P. Lahiry, MD, PhD, FRCPC, D. Dominguez, MD, MSc, D.M. Levy, MD, MSc, FRCPC, L.W.K. Ng, BSc, Division of Rheumatology, SickKids;
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Andrea Knight
4A. Knight, MD, FRCPC, Division of Rheumatology and Research Institute, SickKids;
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Deborah M. Levy
1P. Lahiry, MD, PhD, FRCPC, D. Dominguez, MD, MSc, D.M. Levy, MD, MSc, FRCPC, L.W.K. Ng, BSc, Division of Rheumatology, SickKids;
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Melissa Misztal
3M. Couse, MSc, F. Liao, MSc, M. Misztal, BSc, Genetics & Genome Biology, Research Institute, SickKids;
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Lawrence W.K. Ng
1P. Lahiry, MD, PhD, FRCPC, D. Dominguez, MD, MSc, D.M. Levy, MD, MSc, FRCPC, L.W.K. Ng, BSc, Division of Rheumatology, SickKids;
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Linda T. Hiraki
5L.T. Hiraki, MD, FRCPC, ScD, Division of Rheumatology, SickKids, and Genetics & Genome Biology, Research Institute, SickKids, Toronto, Ontario, Canada.
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  • For correspondence: linda.hiraki@sickkids.ca
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Abstract

Objective Macrophage activation syndrome (MAS), a life-threatening complication of systemic lupus erythematosus (SLE), resembles familial hemophagocytic lymphohistiocytosis (HLH), an inherited disorder of hyperinflammation. We compared the proportion of patients with childhood-onset SLE (cSLE) with and without MAS who carried low-frequency HLH nonsynonymous variants.

Methods We enrolled patients from the Lupus Clinic at SickKids, Toronto. Demographic and clinical features were extracted from the SLE database and ancestry was genetically inferred using multiethnic genotyping array data. Patients with MAS (based on expert diagnosis) underwent either paired-end whole-exome sequencing (WES; read depth: 70-118X) or whole-genome sequencing (WGS). Patients without MAS had WGS (read depth: 37-40X). In 16 HLH genes, we prioritized low-frequency (minor allele frequency [MAF] < 0.05) exonic nonsynonymous variants. We compared the proportion of patients with and without MAS carrying HLH variants (Fisher exact test, P < 0.05). MAFs were compared to an ancestrally matched general population (Trans-Omics for Precision Medicine [TOPMed] and Genome Aggregation Database [gnomAD]).

Results The study included 81 patients with cSLE, 19 of whom had MAS. We identified 47 unique low-frequency nonsynonymous HLH variants. There was no difference in the proportion of patients with and without MAS carrying ≥ 1 HLH variants (37% vs 47%, P = 0.44). The MAS cohort did not carry more HLH variants when compared to an ancestrally matched general population.

Conclusion In a single-center multiethnic cSLE cohort, we found no difference in the proportion of patients with MAS carrying nonsynonymous HLH genetic variants compared to patients without MAS. To our knowledge, this is the first study to examine the frequency of HLH genetic variants in relation to MAS among patients with cSLE. Future studies are required to validate our findings.

Key Indexing Terms:
  • genetic studies
  • hemophagocytic lymphohistiocytosis
  • macrophage activation syndrome
  • pediatric systemic lupus erythematosus
  • whole-exome sequencing
  • whole-genome sequencing
  • Accepted for publication May 20, 2022.
  • Copyright © 2022 by the Journal of Rheumatology
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1 Oct 2022
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Hemophagocytic Lymphohistiocytosis Gene Variants in Childhood-Onset Systemic Lupus Erythematosus With Macrophage Activation Syndrome
Piya Lahiry, Sergey Naumenko, Madeline Couse, Fangming Liao, Daniela Dominguez, Andrea Knight, Deborah M. Levy, Melissa Misztal, Lawrence W.K. Ng, Linda T. Hiraki
The Journal of Rheumatology Oct 2022, 49 (10) 1146-1151; DOI: 10.3899/jrheum.211200

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Hemophagocytic Lymphohistiocytosis Gene Variants in Childhood-Onset Systemic Lupus Erythematosus With Macrophage Activation Syndrome
Piya Lahiry, Sergey Naumenko, Madeline Couse, Fangming Liao, Daniela Dominguez, Andrea Knight, Deborah M. Levy, Melissa Misztal, Lawrence W.K. Ng, Linda T. Hiraki
The Journal of Rheumatology Oct 2022, 49 (10) 1146-1151; DOI: 10.3899/jrheum.211200
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Keywords

GENETIC STUDIES
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
MACROPHAGE ACTIVATION SYNDROME
PEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS
whole-exome sequencing
whole-genome sequencing

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Keywords

  • genetic studies
  • hemophagocytic lymphohistiocytosis
  • macrophage activation syndrome
  • pediatric systemic lupus erythematosus
  • whole-exome sequencing
  • whole-genome sequencing

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