Genetic heterogeneity of pediatric systemic lupus erythematosus with lymphoproliferation

Systemic lupus erythematosus (SLE) is a chronic, rare autoimmune disease. In recent years, multiple monogenic diseases with early onset autoimmunity and lymphoproliferation have been identified, such as autoimmune lymphoproliferative syndrome, rat sarcoma (RAS)-associated autoimmune leukoproliferative disease, signal transducer and activator of transcription 3 gain-of-function syndrome and interleukin-2 receptor α deficiency. Therefore, we performed whole-exome sequencing in children with SLE with lymphoproliferation to identify genes associated with these conditions. We enrolled 7 patients with SLE with lymphoproliferation from different families. Demographic data, clinical manifestations, laboratory and histopathologic findings, treatment, and outcome were documented. Whole-exome sequencing was performed in 7 patients and their families. Suspected variants were confirmed by Sanger sequencing. Protein levels were detected in patients with gene mutations by western blot. Four patients were male, and 3 were female. No consanguinity was reported within the 7 families. The average age at onset was 5.0 years (range: 1.2–10.0 years). The most common features were renal (7/7 patients) and hematologic (6/7 patients) involvement and recurrent fever (6/7 patients), while only 2 patients presented with skin involvement. Antinuclear antibodies at a titer of ≥1:320 were positive in all patients. All patients fulfilled four 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for the classification of SLE. We identified a somatic activating NRAS variant (c.38 A>G, p.G13C) in peripheral venous blood from 4 patients, at levels ranging from 8.8% to 42.8% in variant tissues that were absent from their parents. B cell lymphoma (BCL)-2-interacting mediator of cell death levels in peripheral blood mononuclear cells from 4 patients were markedly reduced, whereas those in the control were normal. Another 2 mutations, c.559C>T (p.Q187X) in the TNFAIP3 gene and c.3061G>A (p.E1021K) in the PIK3CD gene were detected in 2 patients. The SLE is a novel phenotype of somatic mutations in the NRAS gene and germline mutations in the PI3CKD gene. These genes, NRAS, TNFAIP3, and PIK3CD, should be considered candidates for children with SLE with lymphoproliferation. If patients with SLE and lymphoproliferation present with renal and hematologic involvement and recurrent fever, they need gene testing, especially male patients.