Here we report four unrelated severe cases of childhood-onset SLE secondary to mutations in five different genes: C1QC, SLC7A7, MAN2B1, PTEN and STAT1. We discuss novel clinical insights gained from the genetic discovery in each case, summarize current knowledge of monogenic forms of SLE and suggest clinical features which should alert clinicians to suspect monogenic etiology in SLE patients. This evidence concerns the gene STAT1 and systemic lupus erythematosus.