Table 1. Genotypes considered as type I interferonopathies in this manuscript, with protein function, link to interferon signaling, proposed molecular mechanism, and currently recognized associated clinical phenotypes
GeneProtein functionSensing/activation pathway related to type I interferon signalingMutation effectMajor patient phenotypes
TREX1DeoxyribonucleaseCytosolic DNALOF (recessive or dominant-negative)AGS, FCL, SLE
SAMHD1Control of dNTP pool (┬▒nuclease)Cytosolic DNA (┬▒cytosolic RNA)LOF (recessive)AGS, FCL, CVD
TMEM173Transduction of cytosolic type I interferon signalCytosolic DNA (┬▒cytosolic RNA)GOF (dominant)SAVI, FCL
RNASEH2ARibonucleaseCytosolic RNA:DNA hybridsLOF (recessive)AGS
RNASEH2BRibonucleaseCytosolic RNA:DNA hybridsLOF (recessive)AGS, SP
RNASEH2CRibonucleaseCytosolic RNA:DNA hybridsLOF (recessive)AGS
POLA1PolymeraseCytosolic RNA:DNA hybridsX-linked recessiveXLPDR
ADAR1RNA editingCytosolic RNALOF (recessive or dominant-negative)AGS, DSH, BSN, SP
IFIH1dsRNA sensorCytosolic RNAGOF (dominant)AGS, SP, SMS
RIG-IdsRNA sensorCytosolic RNAGOF (dominant)Atypical SMS
SKIV2LRNA helicaseCytosolic RNALOF (recessive)THES
UPS18Inhibition of ISG transcriptionIFNAR1 signalingLOF (recessive)pseudo-TORCH
ISG15Inhibition of ISG transcriptionIFNAR1 signalingLOF (recessive)MSMD, ICC
PSMB8ProteasomeUnknownLOF (recessive)PRAAS
PSMB4ProteasomeUnknownLOF (recessive)PRAAS
PSMA3ProteasomeUnknownLOF (recessive)PRAAS
ACP5Phosphatase activity related to osteopontinUnknownLOF (recessive)SPENCD, SLE, cytopenias
C1qAlternative complement pathway activityUnknownLOF (recessive)SLE

BSN, bilateral striatal necrosis; CVD, cerebrovascular disease; DSH, dyschromatosis symmetrica hereditaria; FCL, familial chilblain lupus; GOF, gain-of-function; ICC, intracranial calcification; LOF, loss-of-function; MSMD, Mendelian susceptibility to mycobacterial disease; PRAAS, proteasome-associated autoinflammatory syndrome; SAVI, STING-associated vasculopathy with onset in infancy; SMS, Singleton-Merten syndrome; SP, spastic paraparesis; SPENCD, spondyloenchondrodysplasia; XLPDR, X-linked reticulate pigmentary disorder.