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

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.