Pulmonary features | IFNopathy (OMIM#) | Inheritance | Gene (location) | Protein function | Putative disease mechanism | Mutation effect | Clinical picture | [Reference] |
ILD/PAH | SAVI (615934) | AD | TMEM173 (5q31.2) | Cytosolic DNA signal transduction | DNA sensing | GOF leading to constitutive activation of sensitivity to cytosolic nucleic acids | Systemic 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/PAH | CANDLE/PRASS (256040, 177045, 602177 176843 613386) | AR | PSMB8 (6p21.32), PSMB9 (6p21.32), PSMB4 (1q21.3), PSMA3 (14q23.1), POMP (13q12.3 | Proteasome | Proteasome | LOF causing proteasomal dysfunction leading to increased IFN signalling through an unknown mechanism | Recurrent 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/DAH | COPA (601924) | DN (dominant) | COPA (1q23.2) | Vesicle transport | ER–Golgi | Unclear | Inflammatory arthritis, ILD with alveolar haemorrhages, PAH, glomerulonefritis | [65, 105–115] |
PAH | AGS1 (225750) | AR or DN (AD?) | TREX1 (3p21.31) | Deoxyribonuclease | DNA sensing | LOF leading to increased DNA sensing | Progressive familial encephalopathy, basal ganglia calcifications, white matter alterations | [10, 17–19, 116] |
PAH | AGS7 (615846) | AD | MDA5/ IFIH1 (2q24.2) | dsRNA sensing | RNA sensing | GOF leading to constitutive activation of sensitivity to cytosolic RNA nucleic acids | Progressive familial encephalopathy, basal ganglia calcifications, white matter alterations | [37, 116] |
PAH | DNaseII deficiency (126350) | AR | DNASE2 (19p13.13) | Deoxyribonuclease | DNA sensing | LOF leading to constitutive activation of sensitivity to cytosolic nucleic acids | Severe neonatal anaemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies | [34, 117] |
ARDS | USP18 deficiency 617397 | AR | USP18 (22q11.21) | ISG transcription inhibition | ISG transcription inhibition | LOF in molecules responsible for limiting IFNAR1/2 signalling, leading to uncontrolled ISG production | Pseudo-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.