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. Here, MAN2B1 is linked to systemic lupus erythematosus.