de Carvalho et al. (2017) recently reported another five individuals with classic SMS phenotypes caused by two novel mutations in IFIH1 (c.992C.T/p.Thr331Ile or c.992C.G/p.Thr331Arg). All five patients tested demonstrated a remarkably upregulation of IFN-induced transcripts. Both of these variants were associated with increased IFN-β expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA5. Taken together, SMS is caused by a spectrum of gain-of-function mutations in IFIH1 or RIG-1. Here, IFIH1 is linked to Smith-Magenis syndrome.