Patients with AGS harbor mutations in genes that encode proteins involved in nucleic acid repair and sensing. TREX1 prevents retroelement DNA reverse transcription (i). SAMHD1 converts deoxyribonucleotide triphosphate (dNTP) into nucleoside and triphosphate (ii). RNase H2 (composed of the subunits RNASEH2A, RNASEH2B, and RNASEH2C) removes ribonucleotides (R) from DNA, a process that can occur during transcription (iii). ADAR1 destabilizes double-stranded RNA (dsRNA) by deaminating adenosine (A) to inosine (I) (iv). MDA5 (encoded by IFIH1) is a RIG-I–like receptor dsRNA helicase enzyme that serves as a dsRNA sensor to stimulate a type I IFN response (v). The IFIH1 mutation is the only known gain-of-function mutation; the other genes harbor loss-of-function mutations. Genetic variants of genes encoding TREX1, SAMHD1, RNase H2, and MDA5 are associated with SLE as well. Allelic mutations of genes encoding these proteins ultimately result in dysfunction and disease through accumulation of excess intracellular nucleic acid and inappropriate activation of innate immunity.