Genetic heterogeneity of pediatric systemic lupus erythematosus with lymphoproliferation

Abstract

Purpose: Systemic lupus erythematosus (SLE) is a rare autoimmune disease, which is more severe in case of pediatric onset. This may be due to greater involvement of genetic factors compared with adult forms. In recent years, multiple monogenic diseases with early-onset autoimmunity and lymphoproliferation have been identified, such as Autoimmune lymphoproliferative syndrome (ALPS), RAS-associated autoimmune leukoproliferative disease (RALD), Signal transducer and activator of transcription 3 (STAT3) Gain-of-Function (GOF) syndrome and Interleukin-2 receptor α (IL2RA) deficiency. Therefore, we performed whole exome sequencing in SLE children with lymphoproliferation to identify genes associated with these conditions. Methods: We enrolled seven SLE patients with lymphoproliferation, which are from different families. Demographic data, clinical manifestations, laboratory and histopathological findings, treatment, and outcome were documented. WES was performed in seven cases and their families. Suspected variants were confirmed by Sanger sequencing. Protein levels were detected in patients with gene mutations by Western blot. Results: Four patients were male, and three were female. No consanguinity was reported within the seven families. The average age at onset was 5.0 years (range from 1.2 to 10.0 years). The most common features were renal (7/7 patients), hematological (6/7 patients) involvement, and recurrent fever (6/7patients) while only two patients presented with skin involvement. Antinuclear antibodies ( ANA) at a titer of ≥1:320 was 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 four patients, at levels ranging from 8.8% to 42.8% in variant tissues, that was absent from their parents. BCL-2-Interacting Mediator of Cell Death (BIM) levels in peripheral blood mononuclear cells (PBMCs) from four patients were markedly reduced, whereas those in control was normal. Another two mutations, c.559C>T (p.Q187X) in the TNFAIP3 gene and c.3061G>A (p.E1021K) in PIK3CD gene, were detected in two patients, respectively. Conclusion: SLE is a novel phenotype of germline mutation in PI3CKD gene and somatic mutation in NRAS gene. These genes, NRAS , TNFAIP3 and PIK3CD , should be considered as candidates for SLE children with lymphoproliferation. If patients with SLE and lymphoproliferation presented with renal and hematological involvement, and recurrent fever, they need gene testing, especially in male patient.

Application of NGS Technology in Understanding the Pathology of Autoimmune Diseases

“…Based on WES in children with SLE with lymphoproliferation, Li et al demonstrated a novel phenotype of somatic mutations in the NRAS gene and germline mutations in the PI3CKD gene. According to the authors, these genes together with TNFAIP3 should be considered as candidates gene for testing in children with SLE with lymphoproliferation, particularly for male patients with renal and hematologic involvement and recurrent fevers [ 62 ].…”