Table 1.

Human Molecular Defects of IFN-I Signalling and Their Associated Phenotypes^a, ^b

Gene	Protein expression	Severe/recurrent viral disease	Uncomplicated infection	Asymptomatic exposure	Other clinical manifestation	Refs
IFNAR1	Absent	P1: MMR encephalitis P2: disseminated 17D YFV (MMR without incident)	P1: none P2: none	P1: CMV P2: CMV, HSV1, HSV2	No	[35]
IFNAR2	Absent	P1: MMR encephalitis (fatal) P2: none (MMR withheld)	P1: HHV6 P2: none	P1: CMV, EBV P2: unknown (SCIG)	No	[33]
STAT1	Absent	P1: recurrent HSV encephalitis (fatal) P2: unknown viral pathogen (fatal)	Unknown	Unknown	Both: disseminated BCG	[43]
STAT1	Absent	Vaccine-strain polio virus shedding EBV-driven LPD post-HSCT	HRV, PIV2, polio vaccine	None	Disseminated BCG Severe hepatitis Multiorgan failure post-HSCT (fatal)	[45]
STAT1	Reduced expression of truncated nonfunctional protein (∆Ex3)	Recurrent CMV pneumonitis Encephalitis (cause not identified)	Viral GI infections and RTIs Cutaneous HSV1	Unknown	Pulmonary NTM infection Sepsis Recurrent pneumonia (BCG naïve)	[44]
STAT1	Absent	HLH, possibly related to MMR and/or HHV6	Nil stated	Unknown	(BCG naïve)	[41]
STAT1	Splicing defect (∆Ex23) with low-level expression of WT protein	P1: None noted P2: HSV1 gingivostomatitis, hospitalisation for CMV and VZV infection	Unknown	Unknown	P1: recurrent NTS infection (BCG naïve) P2: Salmonella meningitis (BCG naïve)	[46]
STAT1	Splicing defect (∆Ex8) with low-level expression of WT protein	P1: severe varicella P2: none noted	Unknown	P1: CMV, EBV P2: unknown	P1: disseminated NTM infection (BCG naïve), Candida line infection P2: disseminated BCG Septic shock (fatal)	[47]
STAT2	Absent (multiple splicing defects)	P1: MMR pneumonitis/hepatitis HSV1 gingivostomatitis IAV pneumonia P2: fatal viral illness (10 weeks) P3: none noted (childhood history unknown) P4: bronchiolitis MMR encephalitis (SNHL) P5: hospitalisation with viral illness	P1: none P2: N/A P3: unknown P4: varicella P5: varicella	P1: EBV P2: N/A P3: MMR, VZV, CMV P4: Unknown P5: Unknown	None	[31]
STAT2	Absent	P1: opsoclonus–myoclonus syndrome post-MMR with late recurrence P2: MMR encephalitis (MuV)	P1: unknown P2: unknown	P1: Unknown P2: Unknown	Mild renal tubulopathy Defect of mitochondrial fission	[48]
STAT2	Absent (premature stop/splicing defect)	P1: MMR hepatitis Severe RSV, EV, AdV Fatal febrile illness (7 years) P2: severe varicella MMR pneumonitis/hepatitis EV meningitis Prolonged primary EBV	P1: unknown P2: RSV, IAV, EV, AdV	P1: Unknown P2: Unknown	‘Inflammatory’ responses to viral infection	[49]
STAT2	Absent	HLH post-MMR	Unknown	HHV6, CMV, VZV, RSV, AdV, PIV1–3	No	[50]
IRF9	Reduced expression of truncated product (∆Ex7)	Severe IAV pneumonitis Biliary perforation post-MMR Recurrent bronchiolitis	HMPV, RSV, AdV, PIV1-4	HSV1, CMV, HRV, EV	(i) Periodic fever (ii) C1q autoantibody	[52]
IRF9	Absent	P1: disseminated VZV post vaccination Severe dengue fever and Zika virus disease EV encephalitis IAV pneumonia RSV bronchiolitis P2: none (on SCIG)	P1: dengue, IBV pneumonia P2: none	P1: Unknown P2: Unknown	P1: recurrent pneumonia and bronchitis, septic shock with purpura fulminans P2: none	[53]
JAK1	Unaffected	None	VZV (shingles), HPV	Unknown	Recurrent mycobacterial infection Metastatic bladder carcinoma (fatal)	[57]
TYK2	Absent	P1: PIV3 pneumonia, recurrent oropharyngeal HSV1 P2: none P3: none P4: none P5: none P6: unspecified viral infection of skin P7: none P8: recurrent herpes gingivostomatitis and aseptic meningitis	P1: molluscum contagiosum P2: shingles	Unknown	P1: eosinophilia, elevated IgE Disseminated BCG NTS infection Candidiasis Ocular sarcoidosis P2: disseminated BCG Recurrent Brucella meningitis P3: TB, bacterial meningitis (fatal) P4: meningitis, otitis media, UTI, asthma P5: disseminated BCG P6: disseminated BCG P7: TB P8: none	[60]
TYK2	Absent	None	Unknown	HHV6, IAV, parvo-B19 MMR vaccinated	Recurrent bronchopneumonia Duodenal perforation Anal/skin abscesses	[61]
TYK2	Absent	Recurrent herpes gingivostomatitis and aseptic meningitis	VZV	Unknown	Disseminated BCG	[62]

^aAll of the variants included above are pathogenic in homozygosity or compound heterozygosity.

^bAdV, adenovirus; CNS, central nervous system; ECMO, extracorporeal membrane oxygenation; EV, enterovirus; HHV6, human herpesvirus 6; HPV, human papillomavirus; HRV, human rhinovirus; IAV/IBV, influenza A/B virus; LPD, lymphoproliferative disease; MuV, mumps virus; NTM, nontuberculous mycobacteria; NTS, non-typhoidal Salmonella; PIV, parainfluenza virus; RTI, respiratory tract infection; SCIG, subcutaneous immunoglobulin; SNHL, sensorineural hearing loss; TB, tuberculosis.