BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare monogenic type I interferonopathy characterized by dysregulated inflammation and tissue damage that primarily affects the central nervous system. AGS is genetically diverse, with pathogenic variants across multiple genes, including TREX1, which drives excessive type I interferon (IFN) production. OBJECTIVE: This study investigated the genetic and molecular mechanisms underlying AGS in a family of two affected children, focusing on the role of METHODS: Genomic sequencing data were used to identify RESULTS: Two homozygous CONCLUSION: To our knowledge, our findings demonstrate, for the first time, the compound effect of two rare homozygous variants account for AGS. This also reiterates the importance of molecular and functional assessments of genomic variants identified by sequencing.