Introduction
STAT2
STAT2 Signaling
STAT2 Structure and Interactions
Viral Targeting of STAT2
Regulatory STAT2 Functions
Inborn Errors of Immunity Caused by Mutations in STAT2
Autosomal Recessive STAT2 Deficiency
Genetics
Variant | LAV dissemination | Severe/recurrent viral disease | Uncomplicated infections | Hyperinflammation | Ref |
---|---|---|---|---|---|
c.381 + 5 G > C (splicing defect) | P1—MMR pneumonitis/hepatitis P2—unvaccinated P3—vaccine history unknown P4—SNHL post-MMR* P5—unvaccinated | P1—HSV1 gingivostomatitis - IAV pneumonia P2—Fatal viral illness (10w) P3—none noted (childhood history unknown) P4—bronchiolitis P5—hospitalization with viral illness | P1—none reported P2—none reported P3—none reported P4—varicella P5—varicella | None reported | [19] |
c.1836 C > A, p.C617* | P1—acute febrile illness post-MMR* P2—acute febrile illness with MuV in CSF | P1—Opsoclonus-myoclonus syndrome post-MMR with CSF lymphocytosis Recurrent opsoclonus-myoclonus with meningoencephalitis P2—None reported | P1—not reported P2—not reported | P1—critical illness with pancytopenia in context of meningoencephalitis P2 – “septic shock,” organism not identified | [20] |
c.1528 C > T, p.R510* and c.1576 G > A, p.G526A (splicing defect) | P1—MMR rash and hepatitis* P2—MMR pneumonitis/hepatitis with coagulopathy | P1—severe RSV, EV, AdV - fatal febrile illness with DIC (7y), organism not identified (viruses not tested) P2—severe recurrent varicella - EV meningitis - prolonged primary EBV | P1—none reported P2—RSV, IAV, EV, AdV HPV molluscum | P1—recurrent severe febrile episodes P2 – “inflammatory” responses to viral infection with cytopenia and T cell activation | [21] |
c.1209 + 1delG (splicing defect) | P1—acute febrile illness with MuV in CSF | RSV, norovirus, EV leading to hospitalization | None reported | HLH secondary to MMR | [22] |
c.1999 C > T, p.667* | Acute febrile illness post-MMRV with probable post vVZV varicella* | Life-threatening IAV pneumonitis Febrile seizure with CoV HKU1 infection Rhinovirus pneumonia | Recurrent rhinovirus, PIV3, HMPV | HLH secondary to MMR | [23] |
Viral Susceptibility
Hyperinflammation
Diagnosis and Management
Autosomal Recessive STAT2-Associated Type I Interferonopathy (STAT2 Gain of Function)
Genetics
Gene/variant | Neurological features | Inflammatory features | Other features | Response to ruxolitinib | Outcome | Ref |
---|---|---|---|---|---|---|
STAT2 c.442 C > T p.R148W | P1—Seizures Intracranial calcification Hemorrhage White matter changes P2—Abnormal EEG Intracranial calcification Hemorrhage White matter changes Cerebellar hypoplasia BS atrophy | P1—Neonatal sepsis Recurrent HLH-like inflammation P2—None reported | P1—TCP TMA Proteinuria Preterm birth P2—TCP Preterm birth Recurrent apnoea | P1—Yes (2.5 mg b.d.) P2—Partial (1 mg b.d.—Improved ISG score but persistent neurodevelopmental abnormalities) | P1—Died in immediate post HSCT period (20 months) P2—Died (3 months) | [56] |
STAT2 c.443 G > A p.R148Q | Seizures Intracranial calcification | Fever | Adenitis Cardiomegaly ILD Respiratory failure | N/A | Died (5 months) | [57] |
USP18 P1–3: c.652C > T, p.Gln218* P4–5 c.652C > T (het) with large cryptic 3ʹ deletion (het) | P1—Microcephaly Intracranial calcification Cortical destruction P2—Abnormal EEG Hemorrhage P3—Seizures Hemorrhage Cortical necrosis White matter changes P4—Seizures Intracranial calcification Massive hemorrhage Enlarged lateral ventricles Cerebellar hypoplasia Malformation of BS and PF P5—Seizures Hemorrhage Abnormal cortical gyration Cysts | P1—NA P2—None reported P3—None reported P4—None reported P5—None reported | P1—NA P2—TCP PDA Liver dysfunction P3—Ascites Abn renal appearances ASD, PDA Liver dysfunction P4—TCP Dyserythropoiesis Ectopic calcifications P5—TCP Ectopic calcifications Hepatomegaly Pleural effusions | N/A | P1—TOP (22w) P2—Died (7d) P3—Died (17d) P4—Died (22d) P5—Died (12d) | [54] |
USP18 c.1073 + 1 G > A—leading to deletion of exon 10 | Seizures Hydrocephalus Intracranial calcification Intracerebral hemorrhage White matter changes | Fever Cellulitis | Shock with ARDS Necrotising cellulitis | Yes (5–10 mg b.d.) | Developmental delay but otherwise well (3 years) | [55] |