Novel Mutations in ACP5 and SAMHD1 in a Patient With Pediatric Systemic Lupus Erythematosus

BACKGROUND: The study of genetic predisposition to pediatric systemic lupus erythematosus (pSLE) has brought new insights into the pathophysiology of SLE, as it is hypothesized that genetic predisposition is greater in children. Furthermore, identifying genetic variants and linking disrupted genes to abnormal immune pathways and clinical manifestations can be beneficial for both diagnosis and treatment. Here, we identified genetic alterations in a patient with childhood-onset SLE and analyzed the immunological mechanisms behind them to support future diagnosis, prognosis, and treatment. METHODS: Whole exome sequencing (WES) was adopted for genetic analysis of a patient with childhood-onset SLE. Gene mutations were confirmed by Sanger sequencing. Clinical data of this patient were collected and summarized. Ingenuity Pathway Analysis was used to provide interacting genes of the perturbed genes. Online Enrichr tool and Cytoscape software were used to analysis the related pathways of these genes. RESULTS: We present a case of a 2-year-old girl who was diagnosed with idiopathic thrombocytopenic purpura (ITP) and SLE. The patient was characterized by cutaneous bleeding spots on both lower extremities, thrombocytopenia, decreased serum complements levels, increased urinary red blood cells, and positive ANA and dsDNA. The patient was treated with methylprednisolone and mycophenolate, but clinical remission could not be achieved. The genomic analysis identified three novel mutations in this pSLE patient, a double-stranded missense mutation in ACP5 (c.1152G>T and c.420G>A) and a single-stranded mutation in SAMHD1 (c.1423G>A). Bioinformatic analysis showed that these two genes and their interacting genes are enriched in the regulation of multiple immune pathways associated with SLE, including cytokine signaling and immune cell activation or function. Analysis of the synergistic regulation of these two genes suggests that abnormalities in the type I interferon pathway caused by genetic variants may contribute to the pathogenesis of SLE. CONCLUSION: The combined complexity of polymorphisms in the coding regions of ACP5 and SAMHD1 influences the susceptibility to SLE. Alterations in these genes may lead to abnormalities in the type I interferon pathway. Our study extends the spectrum of mutations in the ACP5 and SAMHD1 genes. The identification of these mutations could aid in the diagnosis of SLE with genetic counseling and suggest potential precise treatments for specific pathways.