Known pulmonary features of recognised monogenic interferonopathies

Pulmonary featuresIFNopathy (OMIM#)InheritanceGene (location)Protein functionPutative disease mechanismMutation effectClinical picture[Reference]
ILD/PAHSAVI (615934)ADTMEM173 (5q31.2)Cytosolic DNA signal transductionDNA sensingGOF leading to constitutive activation of sensitivity to cytosolic nucleic acidsSystemic and peripheral vessel inflammation, cutaneous vasculopathy (fingers, toes, cheeks and ears), distal tissue damage, nasal septum perforation, telangiectasia, ILD, DAH[15, 32, 61, 63, 66, 93–103]
ILD/PAHCANDLE/PRASS (256040, 177045, 602177 176843 613386)ARPSMB8 (6p21.32), PSMB9 (6p21.32), PSMB4 (1q21.3), PSMA3 (14q23.1), POMP (13q12.3ProteasomeProteasomeLOF causing proteasomal dysfunction leading to increased IFN signalling through an unknown mechanismRecurrent fever, severe growth retardation, violaceous periorbital changes, JMP, mild lymphocytic meningitis, headache, basal ganglia calcifications, ILD, non-erosive synovitis, arthralgia, myositis, recurrent infections, cytopenias, systemic hypertension, dyslipidaemia, elevated acute phase reactants and hypergammaglobulinaemia, joint contractures, muscular atrophy, microcytic anaemia and JMP, Japanese auto-inflammatory syndrome with lipodystrophy, Nakajo–Nishimura syndrome with nodular erythema, elongated and thickened fingers and emaciation, orofacial and dental abnormalities[65–82, 104]
ILD/DAHCOPA (601924)DN (dominant)COPA (1q23.2)Vesicle transportER–GolgiUnclearInflammatory arthritis, ILD with alveolar haemorrhages, PAH, glomerulonefritis[65, 105–115]
PAHAGS1 (225750)AR or DN (AD?)TREX1 (3p21.31)DeoxyribonucleaseDNA sensingLOF leading to increased DNA sensingProgressive familial encephalopathy, basal ganglia calcifications, white matter alterations[10, 17–19, 116]
PAHAGS7 (615846)ADMDA5/ IFIH1 (2q24.2)dsRNA sensingRNA sensingGOF leading to constitutive activation of sensitivity to cytosolic RNA nucleic acidsProgressive familial encephalopathy, basal ganglia calcifications, white matter alterations[37, 116]
PAHDNaseII deficiency (126350)ARDNASE2 (19p13.13)DeoxyribonucleaseDNA sensingLOF leading to constitutive activation of sensitivity to cytosolic nucleic acidsSevere neonatal anaemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies[34, 117]
ARDSUSP18 deficiency 617397ARUSP18 (22q11.21)ISG transcription inhibitionISG transcription inhibitionLOF in molecules responsible for limiting IFNAR1/2 signalling, leading to uncontrolled ISG productionPseudo-TORCH syndrome two with hydrocephalus, necrotising cellulitis, systemic inflammation and respiratory failure[56]

ILD, DAH and PAH as major patterns of lung manifestations variably observed the following monogenic interferonopathies: SAVI, CANDLE/ PRAAS syndrome, COPA syndrome, AGS-1, AGS7 and DNAse II deficiency. Acute respiratory distress syndrome (ARDS) was recently reported in inherited USP18 deficiency. IFN: interferonopathy; ILD: interstitial lung disease; PAH: pulmonary arterial hypertension; SAVI: STING-associated vasculopathy with onset in infancy; STING: stimulator of interferon genes; AD: autosomal dominant; GOF: gain-of-function; DAH: diffuse alveolar haemorrhage; CANDLE: chronic atypical dermatosis with lipodystrophy and elevated temperatures; PRASS: proteasome-associated auto-inflammatory syndrome; AR: autosomal recessive; LOF: loss-of-function; JMP: panniculitis-induced lipodystrophy; DN: dominant; COPA: coatomer protein complex, subunit-α; ER: endothelial reticulum; AGS: Aicardi–Goutières syndrome; dsRNA: double-stranded RNA; USP: ubiquitin-specific peptidase; ISG: IFN stimulated gene.