Aicardi-Goutieres Syndrome

Mendelian MONDO:0018866 Pathograph 26 Type I interferonopathies Inborn errors of immunity Leukodystrophy Genetic encephalopathy

Aicardi-Goutieres syndrome is a genetically heterogeneous type I interferonopathy with antenatal, neonatal, or infantile onset. Pathogenic variants disrupt nucleic-acid clearance, nucleic-acid sensing, or histone pre-mRNA processing, leading to inappropriate innate immune activation, sustained type I interferon signaling, and inflammatory injury of the brain, skin, and other organs. The classical presentation resembles congenital infection and combines intracranial calcification, white matter disease, chronic CSF lymphocytosis, increased CSF interferon-alpha, severe early encephalopathy, spasticity, dystonia, developmental regression or delay, seizures, chilblains, hepatosplenomegaly, fevers, and autoimmunity. Supportive multidisciplinary care remains standard management, while JAK inhibition and reverse-transcriptase inhibition are mechanism-targeted investigational or emerging approaches with limited clinical evidence.

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2
Inheritance
7
Pathophys.
30
Phenotypes
1
Hypotheses
26
Pathograph
1
Genes
3
Treatments
9
Subtypes
16
References
1
Deep Research
1
Hyp. Reports
👪

Inheritance

2
Autosomal recessive HP:0000007
AGS is most often autosomal recessive, including biallelic disease caused by TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, LSM11, and RNU7-1.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for Aicardi-Goutieres syndrome.
PMID:20301648 SUPPORT Human Clinical
"AGS is most frequently inherited in an autosomal recessive"
GeneReviews states that AGS is most frequently inherited in an autosomal recessive manner.
Autosomal dominant HP:0000006
A smaller subset of AGS results from heterozygous dominant pathogenic variants, particularly IFIH1 gain-of-function variants and specific TREX1 or ADAR variants.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for a subset of Aicardi-Goutieres syndrome.
PMID:20301648 SUPPORT Human Clinical
"heterozygous autosomal dominant pathogenic variants in IFIH1"
GeneReviews supports IFIH1-associated autosomal dominant AGS and specific dominant TREX1 or ADAR variants.
◆

Subtypes

9
Aicardi-Goutieres syndrome 1 (TREX1) MONDO:0009165
TREX1 link
TREX1-related AGS subtype corresponding to the OMIM:225750 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:225750 | Broader"
Orphanet lists OMIM:225750 among the broader subtype cross-references for AGS.
Aicardi-Goutieres syndrome 2 (RNASEH2B) MONDO:0012429
RNASEH2B link
RNASEH2B-related AGS subtype corresponding to the OMIM:610181 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:610181 | Broader"
Orphanet lists OMIM:610181 among the broader subtype cross-references for AGS.
Aicardi-Goutieres syndrome 3 (RNASEH2C) MONDO:0012471
RNASEH2C link
RNASEH2C-related AGS subtype corresponding to the OMIM:610329 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:610329 | Broader"
Orphanet lists OMIM:610329 among the broader subtype cross-references for AGS.
Aicardi-Goutieres syndrome 4 (RNASEH2A) MONDO:0012472
RNASEH2A link
RNASEH2A-related AGS subtype corresponding to the OMIM:610333 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:610333 | Broader"
Orphanet lists OMIM:610333 among the broader subtype cross-references for AGS.
Aicardi-Goutieres syndrome 5 (SAMHD1) MONDO:0013059
SAMHD1 link
SAMHD1-related AGS subtype corresponding to the OMIM:612952 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:612952 | Broader"
Orphanet lists OMIM:612952 among the broader subtype cross-references for AGS.
Aicardi-Goutieres syndrome 6 (ADAR) MONDO:0014007
ADAR link
ADAR-related AGS subtype corresponding to the OMIM:615010 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:615010 | Broader"
Orphanet lists OMIM:615010 among the broader subtype cross-references for AGS.
Aicardi-Goutieres syndrome 7 (IFIH1) MONDO:0014367
IFIH1 link
IFIH1-related AGS subtype corresponding to the OMIM:615846 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:615846 | Broader"
Orphanet lists OMIM:615846 among the broader subtype cross-references for AGS.
Aicardi-Goutieres syndrome 8 (RNU7-1) MONDO:0030361
RNU7-1 link
RNU7-1-related histone pre-mRNA-processing AGS subtype corresponding to the OMIM:619486 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:619486 | Broader"
Orphanet lists OMIM:619486 among the broader subtype cross-references for AGS.
Aicardi-Goutieres syndrome 9 (LSM11) MONDO:0030362
LSM11 link
LSM11-related histone pre-mRNA-processing AGS subtype corresponding to the OMIM:619487 record that ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"OMIM:619487 | Broader"
Orphanet lists OMIM:619487 among the broader subtype cross-references for AGS.
◈

Mechanistic Hypotheses

1
Endogenous Nucleic Acid and Type I Interferon Model
ags_endogenous_nucleic_acid_interferon_model CANONICAL
AGS-causing variants perturb enzymes and sensors that normally clear, edit, process, or recognize nucleic acids and histone-associated chromatin. The resulting self nucleic-acid or chromatin stress activates innate immune pathways, including cGAS-STING in histone-processing subtypes, causing chronic type I interferon signaling and multi-organ inflammatory injury.
Retained as CANONICAL. The 2026 openscientist hypothesis-search report (kb/hypotheses/Aicardi_Goutieres_Syndrome/ags_endogenous_nucleic_acid_interferon_model) found the canonical IFN-centric mechanism strongly supported by definitive genetic epistasis (cGAS knockout fully rescues Trex1-/- lethal autoimmunity; MDA5 deletion rescues ADAR1 Zα-mutant encephalopathy), pharmacological STING inhibition, near-universal IFN biomarker positivity, and IFIH1 gain-of-function evidence. Four important qualifications refine the model: (1) RNASEH2-related neuropathology is driven primarily by p53/DNA-damage signaling, not by cGAS-mediated neuroinflammation — cerebellar defects in RNASEH2B-KO mice are rescued by p53 but NOT by cGAS deletion; (2) ~27% of RNASEH2B patients lack elevated IFN signatures, including asymptomatic homozygotes for the common p.Ala177Thr variant; (3) JAK inhibitors show limited neurological benefit despite reducing IFN scores, indicating IFN-independent CNS injury pathways; (4) ADAR1 Zα-mutant encephalopathy is fully reversed by blocking type I IFN, while PKR or ZBP1 deletion alone is insufficient, confirming type I IFN itself (not individual dsRNA effectors) is the central mediator in the RNA-sensing arm.
Deep research
OpenScientist citations 35 citations 2026-05-23T02:34:17.171483
Show evidence (10 references)
PMID:25604658 SUPPORT Human Clinical
"Patients with AGS consistently demonstrate increased levels of interferon activity"
Crow et al. connect the genotype spectrum to sustained interferon activity and an interferon-stimulated gene signature.
PMID:33230297 SUPPORT In Vitro
"cGAS-stimulator of interferon genes (STING) pathway in patient-derived"
Patient-derived fibroblast experiments connect LSM11/RNU7-1 histone-processing defects to cGAS-STING-mediated interferon signaling.
PMID:26223655 SUPPORT Model Organism
"cGAS−/−Trex1−/− mice were completely protected from lethality"
Definitive genetic-epistasis experiment: cGAS knockout completely rescues lethal autoimmune disease in Trex1-deficient mice, directly proving that cGAS is the obligate DNA sensor mediating TREX1-related AGS pathology.
+ 7 more references
⚙

Pathophysiology

7
Defective nucleic acid metabolism and sensing
TREX1, RNASEH2A/B/C, SAMHD1, ADAR, and IFIH1 encode proteins involved in nucleic-acid metabolism or sensing. Loss of nucleic-acid clearance/editing or gain of IFIH1 sensor activity causes abnormal detection of endogenous nucleic acids and activation of antiviral innate immune pathways.
RNA processing link ⚠ ABNORMAL innate immune response link ↑ INCREASED
Downstream
Endogenous nucleic acid-driven innate immune activation
Show evidence (3 references)
PMID:16845398 SUPPORT In Vitro
"mutations result in abrogation of TREX1 enzyme activity."
TREX1 discovery work shows loss of TREX1 exonuclease activity in AGS.
PMID:16845400 SUPPORT Human Clinical
"the genes encoding any one of its three subunits."
Crow et al. identify the RNASEH2A/B/C complex as a cause of AGS.
PMID:31130681 SUPPORT Human Clinical
"All these genes encode for proteins involved in nucleic acids metabolism and sensing."
The Italian AGS cohort review summarizes the shared nucleic-acid metabolism and sensing functions of the canonical AGS genes.
Histone pre-mRNA processing defect
LSM11 and RNU7-1 encode U7 snRNP/histone pre-mRNA processing components. Biallelic variants misprocess canonical histone transcripts, alter chromatin stoichiometry, and expose self chromatin to innate immune recognition.
RNA processing link ⚠ ABNORMAL DNA replication link ⚠ ABNORMAL
Downstream
Endogenous nucleic acid-driven innate immune activation
Show evidence (3 references)
PMID:33230297 SUPPORT Human Clinical
"biallelic mutations in LSM11 and RNU7-1"
Uggenti et al. identify LSM11 and RNU7-1 variants in genetically unexplained AGS cases.
PMID:33230297 SUPPORT In Vitro
"associated with the misprocessing of canonical histone transcripts"
Patient-cell and functional data support histone pre-mRNA misprocessing as the proximal mechanism.
PMID:35320431 SUPPORT Human Clinical
"Impairment of U7 snRNP function results in misprocessing"
RNU7-1-focused clinical and functional study supports U7 snRNP dysfunction and histone pre-mRNA misprocessing in AGS.
Endogenous nucleic acid-driven innate immune activation
Failure to clear, edit, or correctly process endogenous nucleic acids and chromatin causes innate immune receptors to activate antiviral inflammatory programs. In histone-processing AGS, patient-derived cells show enhanced cGAS-STING signaling; in canonical AGS, self nucleic acids are inferred to drive a type I interferon response.
innate immune response link ↑ INCREASED cGAS/STING signaling pathway link ↑ INCREASED
Downstream
Constitutive type I interferon signaling
Show evidence (2 references)
PMID:16845398 SUPPORT In Vitro
"abnormal innate immune response."
TREX1 loss is linked mechanistically to abnormal innate immune activation.
PMID:33230297 SUPPORT In Vitro
"cGAS-stimulator of interferon genes (STING) pathway in patient-derived"
Patient-derived fibroblast data support enhanced cGAS-STING signaling in LSM11/RNU7-1 AGS.
Constitutive type I interferon signaling
The shared downstream pathway is persistent type I interferon signaling, reflected by increased CSF and serum interferon activity and elevated interferon-stimulated gene expression in blood. This ongoing inflammatory signal is a biomarker and a treatment target.
type I interferon-mediated signaling pathway link ↑ INCREASED
Downstream
Neuroinflammatory encephalopathy and leukodystrophy
Systemic interferon-mediated inflammation and vasculopathy
Chronic CSF lymphocytosis
Increased CSF interferon alpha
Show evidence (2 references)
PMID:25604658 SUPPORT Human Clinical
"increased type I interferon activity in cerebrospinal fluid and serum"
The 374-patient cohort supports increased type I interferon activity across AGS genotypes.
PMID:31130681 SUPPORT Human Clinical
"Rice and colleagues proposed the IS as a possible biomarker of AGS."
The Italian cohort review supports peripheral interferon-stimulated gene expression as a diagnostic and monitoring biomarker, while noting genotype variability.
Neuroinflammatory encephalopathy and leukodystrophy
Inflammatory injury of the developing brain produces the classical congenital-infection-like AGS phenotype, including basal ganglia and white matter calcification, leukodystrophy, brain atrophy, spasticity, dystonia, seizures, developmental regression, profound intellectual disability, and other severe motor and communication impairments.
Downstream
Multifocal cerebral white matter abnormalities
Leukodystrophy
Cerebral calcification
Global developmental delay
Spasticity
Hypertonia
Seizure
Dystonia
Developmental regression
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"basal ganglia calcification, leukodystrophy, cerebrospinal fluid (CSF) lymphocytosis"
Orphanet definition identifies calcification, leukodystrophy, and CSF lymphocytosis as defining AGS features.
PMID:20301648 SUPPORT Human Clinical
"early-onset encephalopathy that usually, but not always,"
GeneReviews summarizes AGS as an early-onset encephalopathy often causing severe disability.
Systemic interferon-mediated inflammation and vasculopathy
Type I interferon overactivation extends beyond the CNS, causing recurrent chilblain lesions, fevers, hepatosplenomegaly, thrombocytopenia, elevated liver enzymes, glaucoma, autoimmunity, lupus-like disease, peripheral neuropathy, panniculitis, and SAMHD1-associated intracranial vasculopathy in subsets of patients.
Downstream
Chilblains
Unexplained fevers
Hepatosplenomegaly
Autoimmunity
Elevated circulating hepatic transaminase concentration
Panniculitis
Show evidence (2 references)
PMID:20301648 SUPPORT Human Clinical
"with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly,"
GeneReviews supports systemic inflammatory and congenital-infection-like manifestations.
PMID:36650407 SUPPORT Other
"chilblains, hepatosplenomegaly, and hematological"
This clinical-spectrum review supports non-neurologic inflammatory manifestations.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Aicardi-Goutieres Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

30
Cardiovascular 1
Hepatosplenomegaly FREQUENT Hepatosplenomegaly (HP:0001433)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"
Orphanet records hepatosplenomegaly as frequent in AGS.
PMID:20301648 SUPPORT Human Clinical
"with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly,"
GeneReviews supports hepatosplenomegaly in the congenital-infection-like presentation.
Head and Neck 1
Microcephaly FREQUENT Microcephaly (HP:0000252)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0000252 | Microcephaly | Frequent (79-30%)"
Orphanet records microcephaly as frequent in AGS.
PMID:20301648 SUPPORT Human Clinical
"loss of skills, and slowing of head growth"
GeneReviews describes slowing head growth during the subacute encephalopathic phase.
Immune 2
Autoimmunity FREQUENT Autoimmunity (HP:0002960)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0002960 | Autoimmunity | Frequent (79-30%)"
Orphanet records autoimmunity as frequent in AGS.
PMID:25604658 SUPPORT Human Clinical
"systemic lupus erythematosus were seen frequently enough"
The large cohort confirms lupus and related immune manifestations as real AGS associations.
Panniculitis OCCASIONAL Panniculitis (HP:0012490)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0012490 | Panniculitis | Occasional (29-5%)"
Orphanet records panniculitis as occasional in AGS.
Metabolism 1
Elevated circulating hepatic transaminase concentration FREQUENT Elevated circulating hepatic transaminase concentration (HP:0002910)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0002910 | Elevated circulating hepatic transaminase concentration | Frequent (79-30%)"
Orphanet records elevated transaminases as frequent in AGS.
Musculoskeletal 2
Spasticity VERY_FREQUENT Spasticity (HP:0001257)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0001257 | Spasticity | Very frequent (99-80%)"
Orphanet records spasticity as very frequent in AGS.
Hypertonia VERY_FREQUENT Hypertonia (HP:0001276)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0001276 | Hypertonia | Very frequent (99-80%)"
Orphanet records hypertonia as very frequent in AGS.
Nervous System 8
Global developmental delay VERY_FREQUENT Global developmental delay (HP:0001263)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0001263 | Global developmental delay | Very frequent (99-80%)"
Orphanet records global developmental delay as very frequent in AGS.
Irritability FREQUENT Irritability (HP:0000737)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0000737 | Irritability | Frequent (79-30%)"
Orphanet records irritability as frequent in AGS.
Seizure FREQUENT Seizure (HP:0001250)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0001250 | Seizure | Frequent (79-30%)"
Orphanet records seizures as frequent in AGS.
PMID:25604658 SUPPORT Human Clinical
"seizures (140 of 362 patients, 39%)"
The large genotype-phenotype cohort quantifies seizure frequency.
Dystonia FREQUENT Dystonia (HP:0001332)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0001332 | Dystonia | Frequent (79-30%)"
Orphanet records dystonia as frequent in AGS.
Hypoplasia of the corpus callosum FREQUENT Hypoplasia of the corpus callosum (HP:0002079)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0002079 | Hypoplasia of the corpus callosum | Frequent (79-30%)"
Orphanet records hypoplasia of the corpus callosum as frequent in AGS.
Ventriculomegaly FREQUENT Ventriculomegaly (HP:0002119)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0002119 | Ventriculomegaly | Frequent (79-30%)"
Orphanet records ventriculomegaly as frequent in AGS.
Developmental regression FREQUENT Developmental regression (HP:0002376)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0002376 | Developmental regression | Frequent (79-30%)"
Orphanet records developmental regression as frequent in AGS.
PMID:25604658 SUPPORT Human Clinical
"characterized by a sub-acute encephalopathy"
The large cohort supports regression as part of the postnatal presentation.
Leukodystrophy FREQUENT Leukodystrophy (HP:0002415)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0002415 | Leukodystrophy | Frequent (79-30%)"
Orphanet records leukodystrophy as frequent in AGS.
PMID:20301648 SUPPORT Human Clinical
"MRI (leukodystrophic changes)"
GeneReviews includes MRI leukodystrophic changes in AGS diagnosis.
Growth 1
Short stature FREQUENT Short stature (HP:0004322)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0004322 | Short stature | Frequent (79-30%)"
Orphanet records short stature as frequent in AGS.
Other 14
Porencephaly VERY_FREQUENT Porencephalic cyst (HP:0002132)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0002132 | Porencephaly | Very frequent (99-80%)"
Orphanet records porencephaly as very frequent in AGS.
Arrhinencephaly VERY_FREQUENT Arrhinencephaly (HP:0002139)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0002139 | Arrhinencephaly | Very frequent (99-80%)"
Orphanet records arrhinencephaly as very frequent in AGS.
Intellectual disability, profound VERY_FREQUENT Profound intellectual disability (HP:0002187)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0002187 | Intellectual disability, profound | Very frequent (99-80%)"
Orphanet records profound intellectual disability as very frequent in AGS.
PMID:25604658 SUPPORT Human Clinical
"210 (73.7%) were profoundly disabled"
The large genotype-phenotype cohort supports profound disability in most patients with available functional data.
Multifocal cerebral white matter abnormalities VERY_FREQUENT Multifocal cerebral white matter abnormalities (HP:0007052)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0007052 | Multifocal cerebral white matter abnormalities | Very frequent (99-80%)"
Orphanet records multifocal cerebral white matter abnormalities as very frequent in AGS.
Unexplained fevers FREQUENT Unexplained fevers (HP:0001955)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0001955 | Unexplained fevers | Frequent (79-30%)"
Orphanet records unexplained fevers as frequent in AGS.
Loss of speech FREQUENT Loss of speech (HP:0002371)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0002371 | Loss of speech | Frequent (79-30%)"
Orphanet records loss of speech as frequent in AGS.
Cerebral calcification FREQUENT Cerebral calcification (HP:0002514)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0002514 | Cerebral calcification | Frequent (79-30%)"
Orphanet records cerebral calcification as frequent in AGS.
PMID:20301648 SUPPORT Human Clinical
"of the basal ganglia and white matter)"
GeneReviews includes basal ganglia and white matter calcification in diagnostic CT findings.
Hemiplegia/hemiparesis FREQUENT Hemiplegia/hemiparesis (HP:0004374)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0004374 | Hemiplegia/hemiparesis | Frequent (79-30%)"
Orphanet records hemiplegia/hemiparesis as frequent in AGS.
Axial hypotonia FREQUENT Axial hypotonia (HP:0008936)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0008936 | Axial hypotonia | Frequent (79-30%)"
Orphanet records axial hypotonia as frequent in AGS.
Chronic CSF lymphocytosis FREQUENT Chronic CSF lymphocytosis (HP:0009704)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0009704 | Chronic CSF lymphocytosis | Frequent (79-30%)"
Orphanet records chronic CSF lymphocytosis as frequent in AGS.
PMID:8592332 SUPPORT Human Clinical
"cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid"
Early clinical description supports chronic CSF lymphocytosis as part of the defining syndrome.
Increased CSF interferon alpha FREQUENT Increased CSF interferon alpha (HP:0009709)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0009709 | Increased CSF interferon alpha | Frequent (79-30%)"
Orphanet records increased CSF interferon-alpha as frequent in AGS.
PMID:8592332 SUPPORT Human Clinical
"interferon-alpha (IFN-alpha)."
Early clinical description supports increased CSF interferon-alpha as a diagnostic feature.
Chilblains FREQUENT Chilblains (HP:0009710)
Show evidence (2 references)
ORPHA:51 SUPPORT Other
"HP:0009710 | Chilblains | Frequent (79-30%)"
Orphanet records chilblains as frequent in AGS.
PMID:25604658 SUPPORT Human Clinical
"Chilblains"
The large genotype-phenotype cohort supports chilblains across multiple AGS genotypes.
Brain atrophy FREQUENT Brain atrophy (HP:0012444)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0012444 | Brain atrophy | Frequent (79-30%)"
Orphanet records brain atrophy as frequent in AGS.
Increased serum interferon-gamma level FREQUENT Increased circulating interferon-gamma concentration (HP:0030356)
Show evidence (1 reference)
ORPHA:51 SUPPORT Other
"HP:0030356 | Increased serum interferon-gamma level | Frequent (79-30%)"
Orphanet records increased serum interferon-gamma as frequent in AGS.
🧬

Genetic Associations

1
AGS-related germline variant spectrum (Disease-causing germline variants in multiple AGS genes)
Autosomal recessive Autosomal dominant
Show evidence (2 references)
PMID:25604658 SUPPORT Human Clinical
"genetic and clinical data on 374 mutation-positive patients"
Large mutation-positive cohort supports the canonical seven-gene AGS spectrum and genotype-phenotype correlations.
PMID:33230297 SUPPORT Human Clinical
"biallelic mutations in LSM11 and RNU7-1"
This identifies LSM11 and RNU7-1 as additional AGS genes.
💊

Treatments

3
Supportive multidisciplinary management
Action: supportive care MAXO:0000950
Standard care is supportive and symptom-directed, including respiratory management, feeding and aspiration prevention, seizure management, rehabilitation, and surveillance for glaucoma, endocrine disease, scoliosis, and other complications.
Show evidence (2 references)
PMID:20301648 SUPPORT Other
"MANAGEMENT: Treatment of manifestations: Chest physiotherapy and treatment of"
GeneReviews supports symptomatic supportive management for AGS.
PMID:20301648 SUPPORT Other
"management of seizures using"
GeneReviews supports standard seizure management as part of AGS care.
Janus kinase inhibitor therapy
Action: Pharmacotherapy NCIT:C15986
Agent: JAK inhibitor ↗ baricitinib ↗ ruxolitinib ↗
JAK inhibition is a mechanism-targeted approach intended to block signaling downstream of interferon receptors. Baricitinib open-label data and case reports show improved interferon biomarkers, skin inflammation, and some developmental milestones, but treatment requires monitoring for infection, cytopenias, thrombosis, and other adverse events.
Mechanism Target:
INHIBITS Constitutive type I interferon signaling
Show evidence (4 references)
PMID:32877590 SUPPORT Human Clinical
"The patients received baricitinib, an oral JAK1 and JAK2 inhibitor."
Expanded-access open-label data directly support baricitinib as a JAK inhibitor treatment studied in genetically confirmed AGS.
PMID:32877590 SUPPORT Human Clinical
"A biomarker for interferon signaling, the interferon-signaling gene-expression score, indicated a response to treatment"
The study reports interferon biomarker response during baricitinib treatment.
PMID:30666809 SUPPORT Human Clinical
"After 6 weeks of treatment, the lesions completely resolved."
Case evidence supports baricitinib benefit for AGS-associated chilblains.
+ 1 more reference
Investigational reverse-transcriptase inhibitor therapy
Action: Pharmacotherapy NCIT:C15986
Reverse-transcriptase inhibition has been tested to reduce type I interferon signaling, based on the hypothesis that endogenous retroelements contribute to nucleic-acid-driven inflammation. Evidence remains mixed and insufficient for routine efficacy claims.
Mechanism Target:
INHIBITS Endogenous nucleic acid-driven innate immune activation
INHIBITS Constitutive type I interferon signaling
Show evidence (2 references)
PMID:39630935 PARTIAL Human Clinical
"There is insufficient evidence that ABC or 3TC is either"
The crossover trial found insufficient evidence for individual ABC or 3TC efficacy over six weeks.
PMID:39630935 PARTIAL Human Clinical
"reduction of ISG expression was recorded after 3"
The same trial found a short-term ISG reduction signal for combined ABC, 3TC, and AZT, but not sustained at six weeks.
{ }

Source YAML

click to show 
name: Aicardi-Goutieres Syndrome
creation_date: '2026-05-04T08:35:00Z'
updated_date: '2026-05-04T08:35:00Z'
category: Mendelian
description: >
  Aicardi-Goutieres syndrome is a genetically heterogeneous type I
  interferonopathy with antenatal, neonatal, or infantile onset. Pathogenic
  variants disrupt nucleic-acid clearance, nucleic-acid sensing, or histone
  pre-mRNA processing, leading to inappropriate innate immune activation,
  sustained type I interferon signaling, and inflammatory injury of the brain,
  skin, and other organs. The classical presentation resembles congenital
  infection and combines intracranial calcification, white matter disease,
  chronic CSF lymphocytosis, increased CSF interferon-alpha, severe early
  encephalopathy, spasticity, dystonia, developmental regression or delay,
  seizures, chilblains, hepatosplenomegaly, fevers, and autoimmunity. Supportive
  multidisciplinary care remains standard management, while JAK inhibition and
  reverse-transcriptase inhibition are mechanism-targeted investigational or
  emerging approaches with limited clinical evidence.
disease_term:
  preferred_term: Aicardi-Goutieres syndrome
  term:
    id: MONDO:0018866
    label: Aicardi-Goutieres syndrome
notes: >-
  ORPHA:51 cross-references Aicardi-Goutieres syndrome to MONDO:0018866 with an
  Exact mapping and also lists ICD-10:G31.8, ICD-11:5C55.2, MeSH:C535607,
  MedDRA:10083189, multiple OMIM subtype records, and UMLS:C0393591.
synonyms:
- Encephalopathy with basal ganglia calcification
- Encephalopathy with intracranial calcification and chronic lymphocytosis of cerebrospinal fluid
- AGS
parents:
- Type I interferonopathies
- Inborn errors of immunity
- Leukodystrophy
- Genetic encephalopathy
has_subtypes:
- name: Aicardi-Goutieres syndrome 1
  display_name: Aicardi-Goutieres syndrome 1 (TREX1)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 1
    term:
      id: MONDO:0009165
      label: Aicardi-Goutieres syndrome 1
  description: >
    TREX1-related AGS subtype corresponding to the OMIM:225750 record that
    ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: TREX1
    term:
      id: hgnc:12269
      label: TREX1
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:225750 | Broader"
    explanation: Orphanet lists OMIM:225750 among the broader subtype cross-references for AGS.
- name: Aicardi-Goutieres syndrome 2
  display_name: Aicardi-Goutieres syndrome 2 (RNASEH2B)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 2
    term:
      id: MONDO:0012429
      label: Aicardi-Goutieres syndrome 2
  description: >
    RNASEH2B-related AGS subtype corresponding to the OMIM:610181 record that
    ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: RNASEH2B
    term:
      id: hgnc:25671
      label: RNASEH2B
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:610181 | Broader"
    explanation: Orphanet lists OMIM:610181 among the broader subtype cross-references for AGS.
- name: Aicardi-Goutieres syndrome 3
  display_name: Aicardi-Goutieres syndrome 3 (RNASEH2C)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 3
    term:
      id: MONDO:0012471
      label: Aicardi-Goutieres syndrome 3
  description: >
    RNASEH2C-related AGS subtype corresponding to the OMIM:610329 record that
    ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: RNASEH2C
    term:
      id: hgnc:24116
      label: RNASEH2C
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:610329 | Broader"
    explanation: Orphanet lists OMIM:610329 among the broader subtype cross-references for AGS.
- name: Aicardi-Goutieres syndrome 4
  display_name: Aicardi-Goutieres syndrome 4 (RNASEH2A)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 4
    term:
      id: MONDO:0012472
      label: Aicardi-Goutieres syndrome 4
  description: >
    RNASEH2A-related AGS subtype corresponding to the OMIM:610333 record that
    ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: RNASEH2A
    term:
      id: hgnc:18518
      label: RNASEH2A
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:610333 | Broader"
    explanation: Orphanet lists OMIM:610333 among the broader subtype cross-references for AGS.
- name: Aicardi-Goutieres syndrome 5
  display_name: Aicardi-Goutieres syndrome 5 (SAMHD1)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 5
    term:
      id: MONDO:0013059
      label: Aicardi-Goutieres syndrome 5
  description: >
    SAMHD1-related AGS subtype corresponding to the OMIM:612952 record that
    ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: SAMHD1
    term:
      id: hgnc:15925
      label: SAMHD1
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:612952 | Broader"
    explanation: Orphanet lists OMIM:612952 among the broader subtype cross-references for AGS.
- name: Aicardi-Goutieres syndrome 6
  display_name: Aicardi-Goutieres syndrome 6 (ADAR)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 6
    term:
      id: MONDO:0014007
      label: Aicardi-Goutieres syndrome 6
  description: >
    ADAR-related AGS subtype corresponding to the OMIM:615010 record that
    ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: ADAR
    term:
      id: hgnc:225
      label: ADAR
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:615010 | Broader"
    explanation: Orphanet lists OMIM:615010 among the broader subtype cross-references for AGS.
- name: Aicardi-Goutieres syndrome 7
  display_name: Aicardi-Goutieres syndrome 7 (IFIH1)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 7
    term:
      id: MONDO:0014367
      label: Aicardi-Goutieres syndrome 7
  description: >
    IFIH1-related AGS subtype corresponding to the OMIM:615846 record that
    ORPHA:51 lists as a broader cross-reference for Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: IFIH1
    term:
      id: hgnc:18873
      label: IFIH1
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:615846 | Broader"
    explanation: Orphanet lists OMIM:615846 among the broader subtype cross-references for AGS.
- name: Aicardi-Goutieres syndrome 8
  display_name: Aicardi-Goutieres syndrome 8 (RNU7-1)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 8
    term:
      id: MONDO:0030361
      label: Aicardi-Goutieres syndrome 8
  description: >
    RNU7-1-related histone pre-mRNA-processing AGS subtype corresponding to the
    OMIM:619486 record that ORPHA:51 lists as a broader cross-reference for
    Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: RNU7-1
    term:
      id: hgnc:34033
      label: RNU7-1
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:619486 | Broader"
    explanation: Orphanet lists OMIM:619486 among the broader subtype cross-references for AGS.
- name: Aicardi-Goutieres syndrome 9
  display_name: Aicardi-Goutieres syndrome 9 (LSM11)
  classification: molecular
  subtype_term:
    preferred_term: Aicardi-Goutieres syndrome 9
    term:
      id: MONDO:0030362
      label: Aicardi-Goutieres syndrome 9
  description: >
    LSM11-related histone pre-mRNA-processing AGS subtype corresponding to the
    OMIM:619487 record that ORPHA:51 lists as a broader cross-reference for
    Aicardi-Goutieres syndrome.
  genes:
  - preferred_term: LSM11
    term:
      id: hgnc:30860
      label: LSM11
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:619487 | Broader"
    explanation: Orphanet lists OMIM:619487 among the broader subtype cross-references for AGS.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    AGS is most often autosomal recessive, including biallelic disease caused
    by TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, LSM11, and RNU7-1.
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for Aicardi-Goutieres syndrome.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AGS is most frequently inherited in an autosomal recessive"
    explanation: GeneReviews states that AGS is most frequently inherited in an autosomal recessive manner.
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >
    A smaller subset of AGS results from heterozygous dominant pathogenic
    variants, particularly IFIH1 gain-of-function variants and specific TREX1 or
    ADAR variants.
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for a subset of Aicardi-Goutieres syndrome.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heterozygous autosomal dominant pathogenic variants in IFIH1"
    explanation: GeneReviews supports IFIH1-associated autosomal dominant AGS and specific dominant TREX1 or ADAR variants.
prevalence:
- population: Europe
  percentage: 1-5 per 10,000
  notes: Orphanet records a European point prevalence estimate of 1-5 per 10,000.
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-5 / 10 000 | Europe | Point prevalence | PMID:2015"
    explanation: Orphanet provides a European point-prevalence estimate.
progression:
- phase: Onset
  age_range: Antenatal to infancy
  notes: >
    ORPHA lists antenatal, neonatal, and infantile onset categories. Large
    clinical series show either in utero disease or a postnatal subacute
    encephalopathy, usually within the first year of life.
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Antenatal"
    explanation: Orphanet records antenatal onset as an AGS onset category.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset as an AGS onset category.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infantile onset as an AGS onset category.
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "post-natal presentation, usually within the first"
    explanation: A 374-patient genotype-phenotype cohort supports postnatal presentation, usually in the first year, in most affected children.
- phase: Long-term neurologic outcome
  age_range: Childhood to adulthood
  notes: >
    Severe motor, communication, and intellectual disability is common, but
    neurologic severity varies by genotype and ascertainment. Some affected
    people live into adulthood.
  evidence:
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "210 (73.7%) were profoundly disabled"
    explanation: A large mutation-positive cohort found profound disability in most patients with available functional data.
  - reference: PMID:31559893
    reference_title: "Developmental Outcomes of Aicardi Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all identified individuals affected by AGS exhibit some degree of neurologic impairment"
    explanation: A 100-child international developmental cohort supports near-universal neurologic involvement, with variable severity.
mechanistic_hypotheses:
- hypothesis_group_id: ags_endogenous_nucleic_acid_interferon_model
  hypothesis_label: Endogenous Nucleic Acid and Type I Interferon Model
  status: CANONICAL
  description: >
    AGS-causing variants perturb enzymes and sensors that normally clear, edit,
    process, or recognize nucleic acids and histone-associated chromatin. The
    resulting self nucleic-acid or chromatin stress activates innate immune
    pathways, including cGAS-STING in histone-processing subtypes, causing
    chronic type I interferon signaling and multi-organ inflammatory injury.
  notes: >-
    Retained as CANONICAL. The 2026 openscientist hypothesis-search report
    (kb/hypotheses/Aicardi_Goutieres_Syndrome/ags_endogenous_nucleic_acid_interferon_model)
    found the canonical IFN-centric mechanism strongly supported by
    definitive genetic epistasis (cGAS knockout fully rescues Trex1-/-
    lethal autoimmunity; MDA5 deletion rescues ADAR1 Zα-mutant
    encephalopathy), pharmacological STING inhibition, near-universal IFN
    biomarker positivity, and IFIH1 gain-of-function evidence. Four
    important qualifications refine the model: (1) RNASEH2-related
    neuropathology is driven primarily by p53/DNA-damage signaling, not by
    cGAS-mediated neuroinflammation — cerebellar defects in RNASEH2B-KO
    mice are rescued by p53 but NOT by cGAS deletion; (2) ~27% of RNASEH2B
    patients lack elevated IFN signatures, including asymptomatic
    homozygotes for the common p.Ala177Thr variant; (3) JAK inhibitors show
    limited neurological benefit despite reducing IFN scores, indicating
    IFN-independent CNS injury pathways; (4) ADAR1 Zα-mutant encephalopathy
    is fully reversed by blocking type I IFN, while PKR or ZBP1 deletion
    alone is insufficient, confirming type I IFN itself (not individual
    dsRNA effectors) is the central mediator in the RNA-sensing arm.
  evidence:
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with AGS consistently demonstrate increased levels of interferon activity"
    explanation: Crow et al. connect the genotype spectrum to sustained interferon activity and an interferon-stimulated gene signature.
  - reference: PMID:33230297
    reference_title: "cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cGAS-stimulator of interferon genes (STING) pathway in patient-derived"
    explanation: Patient-derived fibroblast experiments connect LSM11/RNU7-1 histone-processing defects to cGAS-STING-mediated interferon signaling.
  - reference: PMID:26223655
    reference_title: "Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "cGAS−/−Trex1−/− mice were completely protected from lethality"
    explanation: >
      Definitive genetic-epistasis experiment: cGAS knockout completely
      rescues lethal autoimmune disease in Trex1-deficient mice, directly
      proving that cGAS is the obligate DNA sensor mediating TREX1-related
      AGS pathology.
  - reference: PMID:34380029
    reference_title: "ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "MDA5/MAVS-mediated type I interferon response and leads to the development of lethal autoinflammation in mice"
    explanation: >
      ADAR1 Zα-domain mutations reduce A-to-I editing of endogenous dsRNA,
      activating the MDA5/MAVS sensor and triggering an MDA5-dependent
      type I IFN response and lethal autoinflammation, validating the
      RNA-sensing arm of the canonical model.
  - reference: PMID:41855203
    reference_title: "Aberrant multicellular type I interferon signaling drives Aicardi-Goutières syndrome-like encephalopathy in ADAR1 Zα-mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Blocking type I IFN signaling fully reversed these abnormalities"
    explanation: >
      In ADAR1 Zα-mutant mice, blocking type I IFN signaling fully reverses
      encephalopathy, whereas deletion of downstream PKR or ZBP1 alone does
      not — confirming type I IFN itself is the central pathogenic mediator
      in ADAR1-related AGS rather than individual dsRNA effectors.
  - reference: PMID:24686847
    reference_title: "Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes"
    explanation: >
      Heterozygous IFIH1 (MDA5) gain-of-function mutations cause AGS-like
      phenotypes with elevated IFN signaling. This "converse genetic proof"
      shows that sensor hyperactivation alone is sufficient to recapitulate
      AGS, validating the endogenous nucleic-acid sensing model.
  - reference: PMID:24183309
    reference_title: "Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "74 (90%) of 82 patients had a positive interferon score"
    explanation: >
      90% of AGS patients have positive interferon scores, but 7/8
      IFN-negative patients carried RNASEH2B mutations (27% of all
      RNASEH2B cases), qualifying the canonical model by showing a
      substantial RNASEH2B subgroup with IFN-independent disease.
  - reference: PMID:34655526
    reference_title: "Differential cGAS and p53 signaling underlie RNASEH2B-associated neurodegeneration."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Cerebellar defects after RNASEH2B inactivation are rescued by p53 but not cGAS deletion"
    explanation: >
      Qualifies the canonical model by demonstrating that RNASEH2B
      neuropathology is driven primarily by p53/DNA-damage signaling rather
      than cGAS-mediated neuroinflammation — a critical IFN-independent
      branch with direct therapeutic implications.
  - reference: PMID:41871482
    reference_title: "Janus kinase 1/2 inhibition in Aicardi-Goutières syndrome: a multicenter retrospective study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "impact on neurological manifestations was limited and heterogeneous"
    explanation: >
      Multicenter retrospective JAK1/2 inhibitor study (12 treated vs 20
      untreated) shows that IFN blockade improves immunological and
      dermatological features but neurological benefit is limited and
      heterogeneous, supporting IFN-independent contributions to CNS
      injury.
  - reference: PMID:40812004
    reference_title: "Clinical Characterization of a Multicenter International Cohort of Patients With Aicardi-Goutières Syndrome Homozygous for the RNASEH2B:p.Ala177Thr Variant: Early Clinical Markers of Disease Severity."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "have been described, with recent finding of asymptomatic homozygous individuals."
    explanation: >
      The most common AGS variant worldwide, RNASEH2B:p.Ala177Thr, displays
      a phenotypic spectrum from severe neonatal encephalopathy to
      asymptomatic homozygotes, qualifying any deterministic
      loss-of-function-to-IFN model and implicating modifiers, threshold
      effects, or environmental factors.
pathophysiology:
- name: AGS-related pathogenic variants
  description: >
    Pathogenic germline variants in AGS genes initiate disease by altering
    nucleic-acid clearance, nucleic-acid editing, nucleic-acid sensing, or
    histone pre-mRNA processing. ORPHA:51 currently lists ADAR, IFIH1, LSM11,
    RNASEH2A, RNASEH2B, RNASEH2C, RNU7-1, SAMHD1, and TREX1 as disease-causing
    genes.
  genes:
  - preferred_term: ADAR
    term:
      id: hgnc:225
      label: ADAR
  - preferred_term: IFIH1
    term:
      id: hgnc:18873
      label: IFIH1
  - preferred_term: LSM11
    term:
      id: hgnc:30860
      label: LSM11
  - preferred_term: RNASEH2A
    term:
      id: hgnc:18518
      label: RNASEH2A
  - preferred_term: RNASEH2B
    term:
      id: hgnc:25671
      label: RNASEH2B
  - preferred_term: RNASEH2C
    term:
      id: hgnc:24116
      label: RNASEH2C
  - preferred_term: RNU7-1
    term:
      id: hgnc:34033
      label: RNU7-1
  - preferred_term: SAMHD1
    term:
      id: hgnc:15925
      label: SAMHD1
  - preferred_term: TREX1
    term:
      id: hgnc:12269
      label: TREX1
  downstream:
  - target: Defective nucleic acid metabolism and sensing
    causal_link_type: DIRECT
  - target: Histone pre-mRNA processing defect
    causal_link_type: DIRECT
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ADAR | adenosine deaminase RNA specific | hgnc:225 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records ADAR as an AGS disease-causing gene.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IFIH1 | interferon induced with helicase C domain 1 | hgnc:18873 | Disease-causing germline mutation(s) (gain of function) in"
    explanation: Orphanet records gain-of-function IFIH1 variants as disease-causing in AGS.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LSM11 | LSM11, U7 small nuclear RNA associated | hgnc:30860 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records LSM11 as an AGS disease-causing gene.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RNASEH2A | ribonuclease H2 subunit A | hgnc:18518 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records RNASEH2A as an AGS disease-causing gene.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RNASEH2B | ribonuclease H2 subunit B | hgnc:25671 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records RNASEH2B as an AGS disease-causing gene.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RNASEH2C | ribonuclease H2 subunit C | hgnc:24116 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records RNASEH2C as an AGS disease-causing gene.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RNU7-1 | RNA, U7 small nuclear 1 | hgnc:34033 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records RNU7-1 as an AGS disease-causing gene.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SAMHD1 | SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 | hgnc:15925 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records SAMHD1 as an AGS disease-causing gene.
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TREX1 | three prime repair exonuclease 1 | hgnc:12269 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records TREX1 as an AGS disease-causing gene.
- name: Defective nucleic acid metabolism and sensing
  description: >
    TREX1, RNASEH2A/B/C, SAMHD1, ADAR, and IFIH1 encode proteins involved in
    nucleic-acid metabolism or sensing. Loss of nucleic-acid clearance/editing
    or gain of IFIH1 sensor activity causes abnormal detection of endogenous
    nucleic acids and activation of antiviral innate immune pathways.
  biological_processes:
  - preferred_term: RNA processing
    term:
      id: GO:0006396
      label: RNA processing
    modifier: ABNORMAL
  - preferred_term: innate immune response
    term:
      id: GO:0045087
      label: innate immune response
    modifier: INCREASED
  downstream:
  - target: Endogenous nucleic acid-driven innate immune activation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:16845398
    reference_title: "Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "mutations result in abrogation of TREX1 enzyme activity."
    explanation: TREX1 discovery work shows loss of TREX1 exonuclease activity in AGS.
  - reference: PMID:16845400
    reference_title: "Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the genes encoding any one of its three subunits."
    explanation: Crow et al. identify the RNASEH2A/B/C complex as a cause of AGS.
  - reference: PMID:31130681
    reference_title: "Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All these genes encode for proteins involved in nucleic acids metabolism and sensing."
    explanation: The Italian AGS cohort review summarizes the shared nucleic-acid metabolism and sensing functions of the canonical AGS genes.
- name: Histone pre-mRNA processing defect
  description: >
    LSM11 and RNU7-1 encode U7 snRNP/histone pre-mRNA processing components.
    Biallelic variants misprocess canonical histone transcripts, alter chromatin
    stoichiometry, and expose self chromatin to innate immune recognition.
  biological_processes:
  - preferred_term: RNA processing
    term:
      id: GO:0006396
      label: RNA processing
    modifier: ABNORMAL
  - preferred_term: DNA replication
    term:
      id: GO:0006260
      label: DNA replication
    modifier: ABNORMAL
  downstream:
  - target: Endogenous nucleic acid-driven innate immune activation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33230297
    reference_title: "cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic mutations in LSM11 and RNU7-1"
    explanation: Uggenti et al. identify LSM11 and RNU7-1 variants in genetically unexplained AGS cases.
  - reference: PMID:33230297
    reference_title: "cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "associated with the misprocessing of canonical histone transcripts"
    explanation: Patient-cell and functional data support histone pre-mRNA misprocessing as the proximal mechanism.
  - reference: PMID:35320431
    reference_title: "Mutations in RNU7-1 Weaken Secondary RNA Structure, Induce MCP-1 and CXCL10 in CSF, and Result in Aicardi-Goutières Syndrome with Severe End-Organ Involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impairment of U7 snRNP function results in misprocessing"
    explanation: RNU7-1-focused clinical and functional study supports U7 snRNP dysfunction and histone pre-mRNA misprocessing in AGS.
- name: Endogenous nucleic acid-driven innate immune activation
  description: >
    Failure to clear, edit, or correctly process endogenous nucleic acids and
    chromatin causes innate immune receptors to activate antiviral inflammatory
    programs. In histone-processing AGS, patient-derived cells show enhanced
    cGAS-STING signaling; in canonical AGS, self nucleic acids are inferred to
    drive a type I interferon response.
  biological_processes:
  - preferred_term: innate immune response
    term:
      id: GO:0045087
      label: innate immune response
    modifier: INCREASED
  - preferred_term: cGAS/STING signaling pathway
    term:
      id: GO:0140896
      label: cGAS/STING signaling pathway
    modifier: INCREASED
  downstream:
  - target: Constitutive type I interferon signaling
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:16845398
    reference_title: "Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "abnormal innate immune response."
    explanation: TREX1 loss is linked mechanistically to abnormal innate immune activation.
  - reference: PMID:33230297
    reference_title: "cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cGAS-stimulator of interferon genes (STING) pathway in patient-derived"
    explanation: Patient-derived fibroblast data support enhanced cGAS-STING signaling in LSM11/RNU7-1 AGS.
- name: Constitutive type I interferon signaling
  description: >
    The shared downstream pathway is persistent type I interferon signaling,
    reflected by increased CSF and serum interferon activity and elevated
    interferon-stimulated gene expression in blood. This ongoing inflammatory
    signal is a biomarker and a treatment target.
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: INCREASED
  downstream:
  - target: Neuroinflammatory encephalopathy and leukodystrophy
    causal_link_type: DIRECT
  - target: Systemic interferon-mediated inflammation and vasculopathy
    causal_link_type: DIRECT
  - target: Chronic CSF lymphocytosis
    causal_link_type: DIRECT
  - target: Increased CSF interferon alpha
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased type I interferon activity in cerebrospinal fluid and serum"
    explanation: The 374-patient cohort supports increased type I interferon activity across AGS genotypes.
  - reference: PMID:31130681
    reference_title: "Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rice and colleagues proposed the IS as a possible biomarker of AGS."
    explanation: The Italian cohort review supports peripheral interferon-stimulated gene expression as a diagnostic and monitoring biomarker, while noting genotype variability.
- name: Neuroinflammatory encephalopathy and leukodystrophy
  description: >
    Inflammatory injury of the developing brain produces the classical
    congenital-infection-like AGS phenotype, including basal ganglia and white
    matter calcification, leukodystrophy, brain atrophy, spasticity, dystonia,
    seizures, developmental regression, profound intellectual disability, and
    other severe motor and communication impairments.
  downstream:
  - target: Multifocal cerebral white matter abnormalities
    causal_link_type: DIRECT
  - target: Leukodystrophy
    causal_link_type: DIRECT
  - target: Cerebral calcification
    causal_link_type: DIRECT
  - target: Global developmental delay
    causal_link_type: DIRECT
  - target: Spasticity
    causal_link_type: DIRECT
  - target: Hypertonia
    causal_link_type: DIRECT
  - target: Seizure
    causal_link_type: DIRECT
  - target: Dystonia
    causal_link_type: DIRECT
  - target: Developmental regression
    causal_link_type: DIRECT
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "basal ganglia calcification, leukodystrophy, cerebrospinal fluid (CSF) lymphocytosis"
    explanation: Orphanet definition identifies calcification, leukodystrophy, and CSF lymphocytosis as defining AGS features.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early-onset encephalopathy that usually, but not always,"
    explanation: GeneReviews summarizes AGS as an early-onset encephalopathy often causing severe disability.
- name: Systemic interferon-mediated inflammation and vasculopathy
  description: >
    Type I interferon overactivation extends beyond the CNS, causing recurrent
    chilblain lesions, fevers, hepatosplenomegaly, thrombocytopenia, elevated
    liver enzymes, glaucoma, autoimmunity, lupus-like disease, peripheral
    neuropathy, panniculitis, and SAMHD1-associated intracranial vasculopathy in
    subsets of patients.
  downstream:
  - target: Chilblains
    causal_link_type: DIRECT
  - target: Unexplained fevers
    causal_link_type: DIRECT
  - target: Hepatosplenomegaly
    causal_link_type: DIRECT
  - target: Autoimmunity
    causal_link_type: DIRECT
  - target: Elevated circulating hepatic transaminase concentration
    causal_link_type: DIRECT
  - target: Panniculitis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly,"
    explanation: GeneReviews supports systemic inflammatory and congenital-infection-like manifestations.
  - reference: PMID:36650407
    reference_title: "Clinical spectrum and currently available treatment of type I interferonopathy Aicardi-Goutières syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "chilblains, hepatosplenomegaly, and hematological"
    explanation: This clinical-spectrum review supports non-neurologic inflammatory manifestations.
genetic:
- name: AGS-related germline variant spectrum
  association: Disease-causing germline variants in multiple AGS genes
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    ORPHA:51 lists nine disease-causing genes: ADAR, IFIH1, LSM11, RNASEH2A,
    RNASEH2B, RNASEH2C, RNU7-1, SAMHD1, and TREX1. The classical seven-gene
    spectrum involves nucleic-acid metabolism or sensing, while LSM11 and RNU7-1
    affect histone pre-mRNA processing. Most cases are autosomal recessive, with
    dominant IFIH1 gain-of-function and specific TREX1/ADAR variants accounting
    for dominant disease.
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:20301648
      reference_title: "Aicardi-Goutières Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Biallelic pathogenic variants in"
      explanation: GeneReviews supports biallelic pathogenic variants in multiple AGS genes as diagnostic.
  - name: Autosomal dominant
    evidence:
    - reference: PMID:25604658
      reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "mutations in IFIH1 are all heterozygous gain-of-function"
      explanation: Crow et al. support dominant IFIH1 gain-of-function disease in AGS.
  evidence:
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genetic and clinical data on 374 mutation-positive patients"
    explanation: Large mutation-positive cohort supports the canonical seven-gene AGS spectrum and genotype-phenotype correlations.
  - reference: PMID:33230297
    reference_title: "cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biallelic mutations in LSM11 and RNU7-1"
    explanation: This identifies LSM11 and RNU7-1 as additional AGS genes.
phenotypes:
- name: Spasticity
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Spasticity is a very frequent motor manifestation of AGS.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001257 | Spasticity | Very frequent (99-80%)"
    explanation: Orphanet records spasticity as very frequent in AGS.
- name: Global developmental delay
  category: Neurodevelopmental
  frequency: VERY_FREQUENT
  description: Global developmental delay is a very frequent consequence of early AGS encephalopathy.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
    explanation: Orphanet records global developmental delay as very frequent in AGS.
- name: Hypertonia
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Increased tone is very frequent.
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001276 | Hypertonia | Very frequent (99-80%)"
    explanation: Orphanet records hypertonia as very frequent in AGS.
- name: Porencephaly
  category: Neuroimaging
  frequency: VERY_FREQUENT
  description: Porencephaly is listed as a very frequent structural brain phenotype.
  phenotype_term:
    preferred_term: Porencephalic cyst
    term:
      id: HP:0002132
      label: Porencephalic cyst
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002132 | Porencephaly | Very frequent (99-80%)"
    explanation: Orphanet records porencephaly as very frequent in AGS.
- name: Arrhinencephaly
  category: Neuroimaging
  frequency: VERY_FREQUENT
  description: Arrhinencephaly is listed as a very frequent structural brain phenotype.
  phenotype_term:
    preferred_term: Arrhinencephaly
    term:
      id: HP:0002139
      label: Arrhinencephaly
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002139 | Arrhinencephaly | Very frequent (99-80%)"
    explanation: Orphanet records arrhinencephaly as very frequent in AGS.
- name: Intellectual disability, profound
  category: Neurodevelopmental
  frequency: VERY_FREQUENT
  description: Profound intellectual disability is common in the severe classical phenotype.
  phenotype_term:
    preferred_term: Profound intellectual disability
    term:
      id: HP:0002187
      label: Profound intellectual disability
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002187 | Intellectual disability, profound | Very frequent (99-80%)"
    explanation: Orphanet records profound intellectual disability as very frequent in AGS.
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "210 (73.7%) were profoundly disabled"
    explanation: The large genotype-phenotype cohort supports profound disability in most patients with available functional data.
- name: Multifocal cerebral white matter abnormalities
  category: Neuroimaging
  frequency: VERY_FREQUENT
  description: Multifocal cerebral white matter disease is a hallmark imaging abnormality.
  phenotype_term:
    preferred_term: Multifocal cerebral white matter abnormalities
    term:
      id: HP:0007052
      label: Multifocal cerebral white matter abnormalities
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007052 | Multifocal cerebral white matter abnormalities | Very frequent (99-80%)"
    explanation: Orphanet records multifocal cerebral white matter abnormalities as very frequent in AGS.
- name: Microcephaly
  category: Neurologic
  frequency: FREQUENT
  description: Microcephaly and slowing of head growth are frequent in classical AGS.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000252 | Microcephaly | Frequent (79-30%)"
    explanation: Orphanet records microcephaly as frequent in AGS.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "loss of skills, and slowing of head growth"
    explanation: GeneReviews describes slowing head growth during the subacute encephalopathic phase.
- name: Irritability
  category: Neurologic
  frequency: FREQUENT
  description: Extreme irritability is a frequent early encephalopathic symptom.
  phenotype_term:
    preferred_term: Irritability
    term:
      id: HP:0000737
      label: Irritability
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000737 | Irritability | Frequent (79-30%)"
    explanation: Orphanet records irritability as frequent in AGS.
- name: Seizure
  category: Neurologic
  frequency: FREQUENT
  description: Seizures occur in a substantial subset of affected individuals.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Frequent (79-30%)"
    explanation: Orphanet records seizures as frequent in AGS.
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "seizures (140 of 362 patients, 39%)"
    explanation: The large genotype-phenotype cohort quantifies seizure frequency.
- name: Dystonia
  category: Neurologic
  frequency: FREQUENT
  description: Dystonia is a frequent movement disorder in AGS and can be prominent in ADAR-associated striatal necrosis.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001332 | Dystonia | Frequent (79-30%)"
    explanation: Orphanet records dystonia as frequent in AGS.
- name: Hepatosplenomegaly
  category: Systemic
  frequency: FREQUENT
  description: Hepatosplenomegaly can occur in the congenital-infection-like systemic presentation.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"
    explanation: Orphanet records hepatosplenomegaly as frequent in AGS.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly,"
    explanation: GeneReviews supports hepatosplenomegaly in the congenital-infection-like presentation.
- name: Unexplained fevers
  category: Systemic
  frequency: FREQUENT
  description: Sterile pyrexias and recurrent fevers reflect systemic interferon-mediated inflammation.
  phenotype_term:
    preferred_term: Unexplained fevers
    term:
      id: HP:0001955
      label: Unexplained fevers
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001955 | Unexplained fevers | Frequent (79-30%)"
    explanation: Orphanet records unexplained fevers as frequent in AGS.
- name: Hypoplasia of the corpus callosum
  category: Neuroimaging
  frequency: FREQUENT
  description: Corpus callosum hypoplasia is a frequent structural brain finding.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002079 | Hypoplasia of the corpus callosum | Frequent (79-30%)"
    explanation: Orphanet records hypoplasia of the corpus callosum as frequent in AGS.
- name: Ventriculomegaly
  category: Neuroimaging
  frequency: FREQUENT
  description: Ventriculomegaly is a frequent brain imaging phenotype.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002119 | Ventriculomegaly | Frequent (79-30%)"
    explanation: Orphanet records ventriculomegaly as frequent in AGS.
- name: Developmental regression
  category: Neurodevelopmental
  frequency: FREQUENT
  description: Loss of previously acquired skills is part of the typical subacute presentation.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002376 | Developmental regression | Frequent (79-30%)"
    explanation: Orphanet records developmental regression as frequent in AGS.
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by a sub-acute encephalopathy"
    explanation: The large cohort supports regression as part of the postnatal presentation.
- name: Loss of speech
  category: Neurodevelopmental
  frequency: FREQUENT
  description: Loss of speech is a frequent communication phenotype and is distinct from global developmental regression.
  phenotype_term:
    preferred_term: Loss of speech
    term:
      id: HP:0002371
      label: Loss of speech
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002371 | Loss of speech | Frequent (79-30%)"
    explanation: Orphanet records loss of speech as frequent in AGS.
- name: Leukodystrophy
  category: Neuroimaging
  frequency: FREQUENT
  description: Leukodystrophic white matter changes are central to AGS diagnosis.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002415 | Leukodystrophy | Frequent (79-30%)"
    explanation: Orphanet records leukodystrophy as frequent in AGS.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI (leukodystrophic changes)"
    explanation: GeneReviews includes MRI leukodystrophic changes in AGS diagnosis.
- name: Cerebral calcification
  category: Neuroimaging
  frequency: FREQUENT
  description: Cerebral and basal ganglia calcification are characteristic diagnostic imaging findings.
  phenotype_term:
    preferred_term: Cerebral calcification
    term:
      id: HP:0002514
      label: Cerebral calcification
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002514 | Cerebral calcification | Frequent (79-30%)"
    explanation: Orphanet records cerebral calcification as frequent in AGS.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "of the basal ganglia and white matter)"
    explanation: GeneReviews includes basal ganglia and white matter calcification in diagnostic CT findings.
- name: Elevated circulating hepatic transaminase concentration
  category: Biochemical
  frequency: FREQUENT
  description: Elevated liver enzymes are part of the congenital-infection-like systemic presentation.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002910 | Elevated circulating hepatic transaminase concentration | Frequent (79-30%)"
    explanation: Orphanet records elevated transaminases as frequent in AGS.
- name: Autoimmunity
  category: Immunologic
  frequency: FREQUENT
  description: Lupus-like and other autoimmune manifestations occur in subsets of AGS.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002960 | Autoimmunity | Frequent (79-30%)"
    explanation: Orphanet records autoimmunity as frequent in AGS.
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "systemic lupus erythematosus were seen frequently enough"
    explanation: The large cohort confirms lupus and related immune manifestations as real AGS associations.
- name: Short stature
  category: Growth
  frequency: FREQUENT
  description: Short stature is a frequent ORPHA-recorded phenotype.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004322 | Short stature | Frequent (79-30%)"
    explanation: Orphanet records short stature as frequent in AGS.
- name: Hemiplegia/hemiparesis
  category: Neurologic
  frequency: FREQUENT
  description: Focal motor weakness or hemiparesis can occur in AGS.
  phenotype_term:
    preferred_term: Hemiplegia/hemiparesis
    term:
      id: HP:0004374
      label: Hemiplegia/hemiparesis
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004374 | Hemiplegia/hemiparesis | Frequent (79-30%)"
    explanation: Orphanet records hemiplegia/hemiparesis as frequent in AGS.
- name: Axial hypotonia
  category: Neurologic
  frequency: FREQUENT
  description: Axial hypotonia is frequent despite limb spasticity and hypertonia.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008936 | Axial hypotonia | Frequent (79-30%)"
    explanation: Orphanet records axial hypotonia as frequent in AGS.
- name: Chronic CSF lymphocytosis
  category: Laboratory
  frequency: FREQUENT
  description: Chronic lymphocytosis of cerebrospinal fluid is a classical diagnostic biomarker.
  phenotype_term:
    preferred_term: Chronic CSF lymphocytosis
    term:
      id: HP:0009704
      label: Chronic CSF lymphocytosis
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009704 | Chronic CSF lymphocytosis | Frequent (79-30%)"
    explanation: Orphanet records chronic CSF lymphocytosis as frequent in AGS.
  - reference: PMID:8592332
    reference_title: "The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid"
    explanation: Early clinical description supports chronic CSF lymphocytosis as part of the defining syndrome.
- name: Increased CSF interferon alpha
  category: Laboratory
  frequency: FREQUENT
  description: Increased CSF interferon-alpha reflects the central type I interferonopathy.
  phenotype_term:
    preferred_term: Increased CSF interferon alpha
    term:
      id: HP:0009709
      label: Increased CSF interferon alpha
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009709 | Increased CSF interferon alpha | Frequent (79-30%)"
    explanation: Orphanet records increased CSF interferon-alpha as frequent in AGS.
  - reference: PMID:8592332
    reference_title: "The Aicardi-Goutières syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "interferon-alpha (IFN-alpha)."
    explanation: Early clinical description supports increased CSF interferon-alpha as a diagnostic feature.
- name: Chilblains
  category: Dermatologic
  frequency: FREQUENT
  description: Chilblain lesions affect fingers, toes, and ears in many patients and are often cold-sensitive.
  phenotype_term:
    preferred_term: Chilblains
    term:
      id: HP:0009710
      label: Chilblains
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009710 | Chilblains | Frequent (79-30%)"
    explanation: Orphanet records chilblains as frequent in AGS.
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chilblains"
    explanation: The large genotype-phenotype cohort supports chilblains across multiple AGS genotypes.
- name: Brain atrophy
  category: Neuroimaging
  frequency: FREQUENT
  description: Brain atrophy is a frequent imaging feature.
  phenotype_term:
    preferred_term: Brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012444 | Brain atrophy | Frequent (79-30%)"
    explanation: Orphanet records brain atrophy as frequent in AGS.
- name: Panniculitis
  category: Dermatologic
  frequency: OCCASIONAL
  description: Panniculitis occurs in a subset of patients.
  phenotype_term:
    preferred_term: Panniculitis
    term:
      id: HP:0012490
      label: Panniculitis
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012490 | Panniculitis | Occasional (29-5%)"
    explanation: Orphanet records panniculitis as occasional in AGS.
- name: Increased serum interferon-gamma level
  category: Laboratory
  frequency: FREQUENT
  description: Orphanet records increased serum interferon-gamma as frequent; this entry is retained as an ORPHA phenotype.
  phenotype_term:
    preferred_term: Increased circulating interferon-gamma concentration
    term:
      id: HP:0030356
      label: Increased circulating interferon-gamma concentration
  evidence:
  - reference: ORPHA:51
    reference_title: "Aicardi-Goutières syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030356 | Increased serum interferon-gamma level | Frequent (79-30%)"
    explanation: Orphanet records increased serum interferon-gamma as frequent in AGS.
treatments:
- name: Supportive multidisciplinary management
  description: >
    Standard care is supportive and symptom-directed, including respiratory
    management, feeding and aspiration prevention, seizure management,
    rehabilitation, and surveillance for glaucoma, endocrine disease, scoliosis,
    and other complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MANAGEMENT: Treatment of manifestations: Chest physiotherapy and treatment of"
    explanation: GeneReviews supports symptomatic supportive management for AGS.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "management of seizures using"
    explanation: GeneReviews supports standard seizure management as part of AGS care.
- name: Janus kinase inhibitor therapy
  description: >
    JAK inhibition is a mechanism-targeted approach intended to block signaling
    downstream of interferon receptors. Baricitinib open-label data and case
    reports show improved interferon biomarkers, skin inflammation, and some
    developmental milestones, but treatment requires monitoring for infection,
    cytopenias, thrombosis, and other adverse events.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: JAK inhibitor
      term:
        id: NCIT:C172200
        label: JAK Inhibitor
    - preferred_term: baricitinib
      term:
        id: CHEBI:95341
        label: baricitinib
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
  target_mechanisms:
  - target: Constitutive type I interferon signaling
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:32877590
    reference_title: "Janus Kinase Inhibition in the Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients received baricitinib, an oral JAK1 and JAK2 inhibitor."
    explanation: Expanded-access open-label data directly support baricitinib as a JAK inhibitor treatment studied in genetically confirmed AGS.
  - reference: PMID:32877590
    reference_title: "Janus Kinase Inhibition in the Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A biomarker for interferon signaling, the interferon-signaling gene-expression score, indicated a response to treatment"
    explanation: The study reports interferon biomarker response during baricitinib treatment.
  - reference: PMID:30666809
    reference_title: "Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi-Goutières Syndrome, a Type I Interferonopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 6 weeks of treatment, the lesions completely resolved."
    explanation: Case evidence supports baricitinib benefit for AGS-associated chilblains.
  - reference: PMID:33721182
    reference_title: "Ruxolitinib in Aicardi-Goutières syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Janus Kinase inhibitors (JAKIs) have"
    explanation: Ruxolitinib case follow-up supports possible JAK inhibitor benefit but remains limited by sparse case-level evidence.
- name: Investigational reverse-transcriptase inhibitor therapy
  description: >
    Reverse-transcriptase inhibition has been tested to reduce type I interferon
    signaling, based on the hypothesis that endogenous retroelements contribute
    to nucleic-acid-driven inflammation. Evidence remains mixed and insufficient
    for routine efficacy claims.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Endogenous nucleic acid-driven innate immune activation
    treatment_effect: INHIBITS
  - target: Constitutive type I interferon signaling
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:39630935
    reference_title: "Reverse transcriptase inhibitors in Aicardi-Goutières syndrome: A crossover clinical trial."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "There is insufficient evidence that ABC or 3TC is either"
    explanation: The crossover trial found insufficient evidence for individual ABC or 3TC efficacy over six weeks.
  - reference: PMID:39630935
    reference_title: "Reverse transcriptase inhibitors in Aicardi-Goutières syndrome: A crossover clinical trial."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "reduction of ISG expression was recorded after 3"
    explanation: The same trial found a short-term ISG reduction signal for combined ABC, 3TC, and AZT, but not sustained at six weeks.
diagnosis:
- name: Molecular genetic testing for AGS genes
  presence: Pathogenic variants in AGS-associated genes confirm the molecular diagnosis.
  description: >
    Molecular genetic testing establishes AGS by identifying biallelic or
    specific heterozygous pathogenic variants in AGS genes.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of AGS is established in a proband with typical"
    explanation: GeneReviews supports clinical findings plus molecular testing for diagnosis.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "by identification of one of the following: Biallelic pathogenic variants in"
    explanation: GeneReviews supports biallelic pathogenic variants in AGS genes as diagnostic.
- name: Brain CT and MRI for AGS pattern recognition
  presence: Basal ganglia and white matter calcification plus leukodystrophic MRI changes support diagnosis.
  description: >
    Cranial CT and MRI identify the characteristic congenital-infection-like
    pattern of basal ganglia or white matter calcification and leukodystrophic
    white matter changes.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  evidence:
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic abnormalities on cranial CT"
    explanation: GeneReviews supports cranial CT abnormalities as part of AGS diagnosis.
  - reference: PMID:20301648
    reference_title: "Aicardi-Goutières Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI (leukodystrophic changes)"
    explanation: GeneReviews supports MRI leukodystrophic changes as part of AGS diagnosis.
- name: Interferon signature and CSF inflammatory biomarkers
  presence: Elevated CSF interferon-alpha, CSF lymphocytosis, or peripheral interferon-stimulated gene expression supports diagnosis and monitoring.
  description: >
    Increased CSF interferon-alpha, chronic CSF lymphocytosis, and peripheral
    interferon-stimulated gene expression are useful biomarkers, although
    interferon signature sensitivity varies by genotype and timing.
  diagnosis_term:
    preferred_term: biomarker analysis
    term:
      id: MAXO:0000018
      label: biomarker analysis
  evidence:
  - reference: PMID:25604658
    reference_title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased expression of interferon-stimulated gene transcripts in peripheral"
    explanation: The large cohort supports peripheral interferon-stimulated gene expression as a biomarker.
  - reference: PMID:31130681
    reference_title: "Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genetic analysis of AGS-related genes continues to be essential for the diagnosis"
    explanation: The Italian cohort cautions that interferon signature varies and molecular testing remains essential.
references:
- reference: ORPHA:51
  title: "Aicardi-Goutières syndrome"
- reference: PMID:16845398
  title: "Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus."
- reference: PMID:16845400
  title: "Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection."
- reference: PMID:17846997
  title: "Clinical and molecular phenotype of Aicardi-Goutieres syndrome."
- reference: PMID:20301648
  title: "Aicardi-Goutières Syndrome."
  tags:
  - GeneReviews
- reference: PMID:25604658
  title: "Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1."
- reference: PMID:30566312
  title: "Reverse-Transcriptase Inhibitors in the Aicardi-Goutières Syndrome."
- reference: PMID:30666809
  title: "Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi-Goutières Syndrome, a Type I Interferonopathy."
- reference: PMID:31130681
  title: "Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review."
- reference: PMID:31559893
  title: "Developmental Outcomes of Aicardi Goutières Syndrome."
- reference: PMID:32877590
  title: "Janus Kinase Inhibition in the Aicardi-Goutières Syndrome."
- reference: PMID:33230297
  title: "cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing."
- reference: PMID:33721182
  title: "Ruxolitinib in Aicardi-Goutières syndrome."
- reference: PMID:35320431
  title: "Mutations in RNU7-1 Weaken Secondary RNA Structure, Induce MCP-1 and CXCL10 in CSF, and Result in Aicardi-Goutières Syndrome with Severe End-Organ Involvement."
- reference: PMID:36650407
  title: "Clinical spectrum and currently available treatment of type I interferonopathy Aicardi-Goutières syndrome."
- reference: PMID:39630935
  title: "Reverse transcriptase inhibitors in Aicardi-Goutières syndrome: A crossover clinical trial."
📚

References & Deep Research

References

16
ORPHA:51
Aicardi-Goutières syndrome
No top-level findings curated for this source.
PMID:16845398
Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.
No top-level findings curated for this source.
PMID:16845400
Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection.
No top-level findings curated for this source.
PMID:17846997
Clinical and molecular phenotype of Aicardi-Goutieres syndrome.
No top-level findings curated for this source.
PMID:20301648
Aicardi-Goutières Syndrome.
No top-level findings curated for this source.
PMID:25604658
Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.
No top-level findings curated for this source.
PMID:30566312
Reverse-Transcriptase Inhibitors in the Aicardi-Goutières Syndrome.
No top-level findings curated for this source.
PMID:30666809
Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi-Goutières Syndrome, a Type I Interferonopathy.
No top-level findings curated for this source.
PMID:31130681
Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review.
No top-level findings curated for this source.
PMID:31559893
Developmental Outcomes of Aicardi Goutières Syndrome.
No top-level findings curated for this source.
PMID:32877590
Janus Kinase Inhibition in the Aicardi-Goutières Syndrome.
No top-level findings curated for this source.
PMID:33230297
cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.
No top-level findings curated for this source.
PMID:33721182
Ruxolitinib in Aicardi-Goutières syndrome.
No top-level findings curated for this source.
PMID:35320431
Mutations in RNU7-1 Weaken Secondary RNA Structure, Induce MCP-1 and CXCL10 in CSF, and Result in Aicardi-Goutières Syndrome with Severe End-Organ Involvement.
No top-level findings curated for this source.
PMID:36650407
Clinical spectrum and currently available treatment of type I interferonopathy Aicardi-Goutières syndrome.
No top-level findings curated for this source.
PMID:39630935
Reverse transcriptase inhibitors in Aicardi-Goutières syndrome: A crossover clinical trial.
No top-level findings curated for this source.

Deep Research

1
Aicardi-Goutieres Syndrome Deep Research Fallback ▸

Aicardi-Goutieres Syndrome Deep Research Fallback

Provider Attempts

  • timeout 120 just research-disorder falcon Aicardi_Goutieres_Syndrome timed out and was terminated by timeout with exit code 124.
  • timeout 120 just research-disorder openai Aicardi_Goutieres_Syndrome timed out and was terminated by timeout with exit code 124.

Evidence Scope Integrated

The curation proceeded from generated ORPHA:51 structured data and targeted PubMed evidence cached with just fetch-reference. The YAML integrates:

  • ORPHA:51 disease identity, MONDO exact mapping, autosomal dominant/recessive inheritance, current AGS genes, onset categories, and HPO frequency rows.
  • GeneReviews PMID:20301648 for clinical characteristics, diagnosis/testing, genetic counseling, supportive management, and surveillance.
  • Discovery and cohort papers for TREX1, RNASEH2A/B/C, SAMHD1, ADAR, IFIH1, LSM11, and RNU7-1 mechanisms: PMID:16845398, PMID:16845400, PMID:17846997, PMID:25604658, PMID:31130681, PMID:31559893, PMID:33230297, and PMID:35320431.
  • Human treatment evidence for JAK inhibition and reverse-transcriptase inhibitor trials: PMID:32877590, PMID:30666809, PMID:33721182, PMID:30566312, PMID:39630935, and the clinical-spectrum treatment review PMID:36650407.

Curation Notes

No provider-generated deep-research narrative was available within the bounded runtime. The YAML therefore uses only exact snippets from ORPHA/PubMed reference caches and avoids unsupported treatment claims. JAK inhibition is represented as emerging mechanism-targeted therapy with human open-label/case evidence, while reverse-transcriptase inhibition is represented as investigational with mixed trial evidence.