Whole‐Exome Sequencing Reveals Overlap Between Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis and Familial Hemophagocytic Lymphohistiocytosis

Abstract

Objective Macrophage activation syndrome (MAS), a life-threatening complication of systemic Juvenile Idiopathic Arthritis (SJIA), resembles Familial Hemophagocytic Lymphohistiocytosis (FHLH), a constellation of autosomal recessive immune disorders resulting from deficiency in cytolytic pathway proteins. We hypothesized that MAS predisposition in SJIA could be attributed to rare gene sequence variants affecting the cytotolytic pathway. Methods Whole exome sequencing (WES) was used in 14 SJIA/MAS patients and their parents to identify protein altering SNPs/indels in the known HLH-associated genes. To discover new candidate genes, the entire WES data were filtered to identify protein altering, rare recessive homozygous, compound heterozygous, and de novo variants with the potential to affect the cytolytic pathway. Results Heterozygous protein-altering rare variants in the known genes (LYST, MUNC13-4, and STXBP2) were found in 5 of 14 SJIA/MAS patients (35.7%). This was in contrast to only 4 variants in 4 of 29 (13,7%) SJIA patients without MAS. Homozygosity and compound heterozygosity analysis applied to the entire WES data in SJIAMAS, revealed 3 recessive pairs in 3 genes, and 76 compound heterozygotes in 75 genes. We also identified 22 heterozygous rare protein altering variants that occurred in at least two patients. Many of the identified genes encode proteins with a role in actin and microtubule reorganization and vesicle-mediated transport. “Cellular assembly and organization” was the top cellular function category based on Ingenuity Pathways Analysis (p<3.10E-05). Conclusion WES performed in SJIA/MAS patients identified rare protein altering variants in the known HLH associated genes as well as new candidate genes.

Fire behind the fury: IL-18 and MAS

“…5 However, the cytokine storm reflected in plasma of patients with inherited HLH and MAS has been indistinguishable (elevated CXCL9/IFN-g, TNF-a, sIL-2Ra, IL-1, and IL-6). 6,7 Differentiating MAS from HLH is further confounded by recent observations of up to 40% of patients with MAS having monoallelic mutations in the common HLH-associated cytotoxicityregulating genes 8 (with uncertain impact of genetic dosage on pathogenesis). There is a clear need to understand the specific lesions in immune regulatory pathways that underlie unbridled inflammation in critically ill patients with MAS and HLH to facilitate diagnosis and optimize therapy.…”

2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative

“…The difficulties in making the diagnosis of MAS and its clinical heterogeneity, together with the recent advances in its treatment and in understanding of its pathophysiology and underlying genetic defects (11,(21)(22)(23), emphasize the need for accurate criteria to aid physicians in appropriately classifying patients as having MAS to facilitate enrollment into clinical studies. The recognition that the syndrome is clinically similar to hemophagocytic lymphohistiocytosis (HLH) has led some to recommend the use of the HLH-2004 diagnostic guidelines (24).…”

Hemophagocytic lymphohistiocytosis: A rare cause of recurrent encephalopathy

“…Recently whole exome sequencing of DNA from secondary HLH patients found variants in familial HLH related genes as well as new candidate genes (9).…”