A Rare SAT1 Variant in Early-Onset SLE: Case Report with Case-Control Functional Assay

Background SAT1 (Xp22) is an X-linked gene that encodes spermidine/spermine N 1 -acetyltransferase. Rare SAT1 variants have been reported in early-onset systemic lupus erythematosus among males.[1,2] We report a case of a male diagnosed with systemic lupus erythematosus (SLE) at 6 years of age who carries a rare, predicted damaging variant in SAT1. Methods Trio whole genome sequencing (WGS) was performed on the proband and both biological parents. Variant annotation and filtering were used to prioritize rare coding variants with predicted functional impact, and segregation was confirmed within the trio. Case-control functional assays on fibroblasts were performed using the proband and 2 independent controls. One was internal laboratory reference control (healthy individual) and the second was a (non-SLE control). diABZI (STING agonist) time-course western blots and an interferon-stimulated gene (ISG) qPCR panel were performed under unstimulated and stimulated conditions. Case The patient presented at 6 years of age with fever, malar rash, a Kawasaki-like inflammatory picture and macrophage activation syndrome (MAS). An echocardiogram demonstrated pericardial effusion, and mild left main coronary artery (LMCA) dilation. Following Kawasaki disease therapy with intravenous immunoglobulin, he developed nephrotic-range proteinuria and hypertension, which led to a kidney biopsy confirming class IV lupus nephritis. Laboratory testing showed leukopenia, hemolytic anemia, thrombocytopenia, hypocomplementemia, and positive ANA, anti-dsDNA, anti-Sm, and anti-RNP autoantibodies. He was treated with pulse methylprednisolone, mycophenolate sodium, and ACE inhibition. Neurologic and neurodevelopmental features emerged later in his disease course: absence epilepsy was identified earlier in adolescence (13 years) and was responsive to valproic acid, and upper-motor-neuron–patterned findings (hyperreflexia and clonus) were observed (starting at age 16 years, mild intellectual disability and ADHD became evident around mid-adolescence (15 years). Whole genome sequencing of the proband and parents identified an X-linked hemizygous SAT1 missense variant: NM_002970.3:c.26C>A (p.Ala9Asp) on Xp22 inherited from mom. This variant has a CADD = 31, 5/5 pathogenicity tools deleterious. In functional assays, the proband ISG qPCR panel showed higher induction of several ISGs (IFI44, RSAD2, MX1, IRF7, CXCL1, CCL2) after diABZI compared with controls. In the ISD experiment, the control sample showed stronger pTBK1 and pSTING responses than the proband. Conclusion We identified a previously unknown variant in SAT1, with evidence demonstrating its association with early-onset SLE in a male diagnosed at an extreme young age. In addition to bioinformatic tools predicting the variant is deleterious, our functional validation studies provide evidence for downstream immune dysregulation. Our report provides important evidence for the causal nature of this rare variant for monogenic lupus. References [1.] Xu L. Ann Rheum Dis 2022;81:1712-21. [2.] Zhao C. Immunity 2023;56:2508-22.