Whole exome sequencing in 14 MAS-complicated sJIA patients revealed heterozygous protein-altering variants in fHLH-associated genes (LYST, UNC13D, and STXBP2) in 35.7% of patients compared to only 13.7% in uncomplicated sJIA patients. Here, UNC13D is linked to systemic-onset juvenile idiopathic arthritis.