Aicardi-Goutieres syndrome

Summary

Aicardi-Goutieres syndrome (MONDO:0018866) is a disease (an umbrella term covering 10 Mondo subtypes) with 8 cohort genes and 10 clinical trials. Top therapeutic interventions include abacavir and baricitinib.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 159
• Phenotypes (HPO): 72
• Clinical trials: 10

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Europe	Validated

Signs & symptoms

Clinical features (HPO)

72 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0002132	Porencephaly	Very frequent (80-99%)
HP:0002139	Arrhinencephaly	Very frequent (80-99%)
HP:0002187	Intellectual disability, profound	Very frequent (80-99%)
HP:0007052	Multifocal cerebral white matter abnormalities	Very frequent (80-99%)
HP:0000444	Convex nasal ridge	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000625	Eyelid coloboma	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001955	Unexplained fevers	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002371	Loss of speech	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002415	Leukodystrophy	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0002960	Autoimmunity	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004374	Hemiplegia/hemiparesis	Frequent (30-79%)
HP:0007076	Extrapyramidal muscular rigidity	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0009704	Chronic CSF lymphocytosis	Frequent (30-79%)
HP:0009709	Increased CSF interferon alpha	Frequent (30-79%)
HP:0009710	Chilblains	Frequent (30-79%)
HP:0012444	Brain atrophy	Frequent (30-79%)
HP:0030356	Increased serum interferon-gamma level	Frequent (30-79%)
HP:0000054	Micropenis	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000965	Cutis marmorata	Occasional (5-29%)
HP:0001063	Acrocyanosis	Occasional (5-29%)
HP:0001087	Developmental glaucoma	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0001609	Hoarse voice	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Aicardi-Goutieres syndrome
Mondo ID	MONDO:0018866
MeSH	C535607
OMIM	225750
Orphanet	51
DOID	DOID:0050629
SNOMED CT	230312006
UMLS	C0393591
MedGen	97953
GARD	0000575
NORD	111728
Is cancer (heuristic)	no

Also known as: AGS · Aicardi Goutieres syndrome · Aicardi-Goutières Syndrome · Cree encephalitis · encephalopathy with basal ganglia calcification · encephalopathy with intracranial calcification and chronic lymphocytosis of cerebrospinal fluid · encephalopathy, familial infantile, with calcification of basal ganglia and chronic cerebrospinal fluid lymphocytosis · pseudotoxoplasmosis syndrome

Data availability: 159 ClinVar variants · 7 GenCC gene-disease records · 40 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › Aicardi-Goutieres syndrome

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, hereditary hemophagocytic lymphohistiocytosis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

Subtypes (10): basal ganglia calcification, idiopathic, childhood-onset, Aicardi-Goutieres syndrome 1, Aicardi-Goutieres syndrome 2, Aicardi-Goutieres syndrome 3, Aicardi-Goutieres syndrome 4, Aicardi-Goutieres syndrome 5, Aicardi-Goutieres syndrome 6, Aicardi-Goutieres syndrome 7, Aicardi-Goutieres syndrome 8, Aicardi-Goutieres syndrome 9

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

159 retrieved; paginated sample, class counts are floors:

78 uncertain significance, 25 pathogenic/likely pathogenic, 16 conflicting classifications of pathogenicity, 15 likely benign, 13 likely pathogenic, 9 pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
66067	NM_006397.3(RNASEH2A):c.69G>A (p.Val23=)	LOC117038795	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
445579	NM_006397.3(RNASEH2A):c.557G>A (p.Arg186Gln)	RNASEH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632305	NM_006397.3(RNASEH2A):c.206dup (p.Thr70fs)	RNASEH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66068	NM_006397.3(RNASEH2A):c.556C>T (p.Arg186Trp)	RNASEH2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1262	NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456507	NM_024570.4(RNASEH2B):c.331C>T (p.Gln111Ter)	RNASEH2B	Pathogenic	criteria provided, multiple submitters, no conflicts
2691643	NM_024570.4(RNASEH2B):c.737C>A (p.Ser246Ter)	RNASEH2B	Pathogenic	criteria provided, single submitter
3366699	NC_000013.10:g.(51519669_51522122)_(51523642_51528040)del	RNASEH2B	Pathogenic	criteria provided, single submitter
566198	NM_024570.4(RNASEH2B):c.136+1del	RNASEH2B	Pathogenic	criteria provided, multiple submitters, no conflicts
1260	NM_032193.4(RNASEH2C):c.205C>T (p.Arg69Trp)	RNASEH2C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4847627	NM_032193.4(RNASEH2C):c.215_218delinsTGGC (p.Glu72_Val73delinsValAla)	RNASEH2C	Pathogenic	criteria provided, single submitter
1076058	NM_015474.4(SAMHD1):c.68C>G (p.Ser23Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126413	NM_015474.4(SAMHD1):c.649_650insG (p.Phe217fs)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1384819	NM_015474.4(SAMHD1):c.316C>T (p.Arg106Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453299	NM_015474.4(SAMHD1):c.693G>A (p.Trp231Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453548	NM_015474.4(SAMHD1):c.703C>T (p.Gln235Ter)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1454961	NM_015474.4(SAMHD1):c.1584del (p.Ala529fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1500266	NM_015474.4(SAMHD1):c.626-1G>C	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1677234	NC_000020.10:g.(35575208_35579838)(35580247?)del	SAMHD1	Pathogenic	criteria provided, single submitter
1704574	NM_015474.4(SAMHD1):c.1436del (p.Glu479fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2099291	NM_015474.4(SAMHD1):c.1512_1513del (p.Met505fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30604	NM_015474.4(SAMHD1):c.427C>T (p.Arg143Cys)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30605	NM_015474.4(SAMHD1):c.602T>A (p.Ile201Asn)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4067	NM_015474.4(SAMHD1):c.433C>T (p.Arg145Ter)	SAMHD1	Pathogenic	criteria provided, multiple submitters, no conflicts
4069	NM_015474.4(SAMHD1):c.490C>T (p.Arg164Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
546088	NM_015474.4(SAMHD1):c.1343T>C (p.Ile448Thr)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
645045	NM_015474.4(SAMHD1):c.400C>T (p.Arg134Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
659536	NM_015474.4(SAMHD1):c.658C>T (p.Arg220Ter)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
659887	NM_015474.4(SAMHD1):c.1476del (p.Lys492fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800933	NM_015474.4(SAMHD1):c.646_647del (p.Met216fs)	SAMHD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 61 · Orphanet: 17 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ADAR	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 6	12
IFIH1	Definitive	Autosomal dominant	Aicardi-Goutieres syndrome 7	9
RNASEH2A	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 4	4
RNASEH2B	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 2	6
RNASEH2C	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 3	4
SAMHD1	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 5	9
TREX1	Definitive	Autosomal recessive	Aicardi-Goutieres syndrome 1	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TREX1	Orphanet:247691	Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
TREX1	Orphanet:481662	Familial Chilblain lupus
TREX1	Orphanet:51	Aicardi-Goutières syndrome
TREX1	Orphanet:536	Systemic lupus erythematosus
SAMHD1	Orphanet:481662	Familial Chilblain lupus
SAMHD1	Orphanet:51	Aicardi-Goutières syndrome
RNASEH2A	Orphanet:51	Aicardi-Goutières syndrome
IFIH1	Orphanet:51	Aicardi-Goutières syndrome
IFIH1	Orphanet:689231	IFIH1-related hereditary spastic paraplegia
IFIH1	Orphanet:85191	Singleton-Merten dysplasia
ADAR	Orphanet:225154	Familial infantile bilateral striatal necrosis
ADAR	Orphanet:41	Dyschromatosis symmetrica hereditaria
ADAR	Orphanet:51	Aicardi-Goutières syndrome
ADAR	Orphanet:694356	ADAR-related hereditary spastic paraplegia
RNASEH2C	Orphanet:51	Aicardi-Goutières syndrome
RNASEH2B	Orphanet:51	Aicardi-Goutières syndrome
RNASEH2B	Orphanet:689234	RNASEH2B-related hereditary spastic paraplegia

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TREX1	HGNC:12269	ENSG00000213689	Q9NSU2	Three-prime repair exonuclease 1	gencc,clinvar
SAMHD1	HGNC:15925	ENSG00000101347	Q9Y3Z3	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	gencc,clinvar
RNASEH2A	HGNC:18518	ENSG00000104889	O75792	Ribonuclease H2 subunit A	gencc,clinvar
IFIH1	HGNC:18873	ENSG00000115267	Q9BYX4	Interferon-induced helicase C domain-containing protein 1	gencc,clinvar
ADAR	HGNC:225	ENSG00000160710	P55265	Double-stranded RNA-specific adenosine deaminase	gencc,clinvar
RNASEH2C	HGNC:24116	ENSG00000172922	Q8TDP1	Ribonuclease H2 subunit C	gencc,clinvar
RNASEH2B	HGNC:25671	ENSG00000136104	Q5TBB1	Ribonuclease H2 subunit B	gencc,clinvar
TLDC2	HGNC:16112	ENSG00000101342	A0PJX2	TLD domain-containing protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TREX1	Three-prime repair exonuclease 1	Major cellular 3’-to-5’ DNA exonuclease which digests single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) with mismatched 3’ termini.
SAMHD1	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks.
RNASEH2A	Ribonuclease H2 subunit A	Catalytic subunit of RNase HII, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.
IFIH1	Interferon-induced helicase C domain-containing protein 1	Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and…
ADAR	Double-stranded RNA-specific adenosine deaminase	Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing.
RNASEH2C	Ribonuclease H2 subunit C	Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.
RNASEH2B	Ribonuclease H2 subunit B	Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.
TLDC2	TLD domain-containing protein 2	Inhibits the activity of the vacuolar-type ATPase (V-ATPase) by inducing disassembly of the V-ATPase complex.

Protein-family classification

Druggable: 5 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.62

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	5	7.5×	5e-04
Transcription factor	1	1.0×	0.966
Other/Unknown	2	0.5×	0.984

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TREX1	Enzyme (other)	yes	3.1.11.2	RNaseH-like_sf, Ribonucl_H, RNaseH_sf
SAMHD1	Transcription factor	no	3.1.5.B1	SAM, HD/PDEase_dom, HD_domain
RNASEH2A	Enzyme (other)	yes	3.1.26.4	RNase_HII/HIII, RNase_H2_suA, RNaseH-like_sf
IFIH1	Other/Unknown	no		Helicase_C-like, Helicase/UvrB_N, DEATH-like_dom_sf
ADAR	Enzyme (other)	yes	3.5.4.37	A_deamin, dsRBD_dom, WH-like_DNA-bd_sf
RNASEH2C	Enzyme (other)	yes	3.1.26.4	RNase_H2_suC, RNase_H2_subunit_C
RNASEH2B	Enzyme (other)	yes	3.1.26.4	RNase_H2_suB_wHTH, RNase_H2_suB, Rnh202_N
TLDC2	Other/Unknown	no		TLDc_dom

Expression context

Cohort genes with no expression data: 0.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	2
ventricular zone	2
granulocyte	1
leukocyte	1
olfactory segment of nasal mucosa	1
monocyte	1
mononuclear cell	1
pericardium	1
embryo	1
jejunal mucosa	1
palpebral conjunctiva	1
parotid gland	1
endothelial cell	1
middle temporal gyrus	1
visceral pleura	1
apex of heart	1
pancreatic ductal cell	1
tendon of biceps brachii	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TREX1	134	ubiquitous	yes	olfactory segment of nasal mucosa, granulocyte, leukocyte
SAMHD1	291	ubiquitous	marker	monocyte, mononuclear cell, pericardium
RNASEH2A	140	ubiquitous	marker	ganglionic eminence, embryo, ventricular zone
IFIH1	276	ubiquitous	marker	palpebral conjunctiva, parotid gland, jejunal mucosa
ADAR	295	ubiquitous	marker	endothelial cell, middle temporal gyrus, visceral pleura
RNASEH2C	259	ubiquitous	marker	pancreatic ductal cell, tendon of biceps brachii, apex of heart
RNASEH2B	242	ubiquitous	marker	calcaneal tendon, ganglionic eminence, ventricular zone
TLDC2	160	tissue_specific	marker	sural nerve, mucosa of transverse colon, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 19.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFIH1	3,706
ADAR	3,166
RNASEH2A	3,129
SAMHD1	2,186
RNASEH2B	1,306
TREX1	1,214
RNASEH2C	806
TLDC2	254

Intra-cohort edges

A	B	Sources
ADAR	IFIH1	string_interaction
ADAR	RNASEH2A	string_interaction
ADAR	RNASEH2B	string_interaction
ADAR	RNASEH2C	string_interaction
ADAR	SAMHD1	string_interaction
ADAR	TREX1	string_interaction
IFIH1	RNASEH2A	string_interaction
IFIH1	RNASEH2B	string_interaction
IFIH1	RNASEH2C	string_interaction
RNASEH2A	RNASEH2B	biogrid_interaction, intact, string_interaction
RNASEH2A	RNASEH2C	biogrid_interaction, intact, string_interaction
RNASEH2A	SAMHD1	string_interaction
RNASEH2A	TREX1	string_interaction
RNASEH2B	RNASEH2C	biogrid_interaction, intact, string_interaction
RNASEH2B	SAMHD1	string_interaction
RNASEH2B	TREX1	string_interaction
RNASEH2C	SAMHD1	string_interaction
RNASEH2C	TREX1	string_interaction
SAMHD1	TREX1	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SAMHD1	Q9Y3Z3	76
ADAR	P55265	24
TREX1	Q9NSU2	12
IFIH1	Q9BYX4	9
RNASEH2B	Q5TBB1	4
RNASEH2A	O75792	3
RNASEH2C	Q8TDP1	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TLDC2	A0PJX2	85.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 8 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation by TREX1	1	2855.0×	0.004	TREX1
C6 deamination of adenosine	1	1427.5×	0.004	ADAR
Formation of editosomes by ADAR proteins	1	1427.5×	0.004	ADAR
Interferon alpha/beta signaling	2	76.1×	0.004	SAMHD1, ADAR
Nucleotide catabolism	1	317.2×	0.016	SAMHD1
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	219.6×	0.016	IFIH1
IRF3-mediated induction of type I IFN	1	203.9×	0.016	TREX1
TRAF3-dependent IRF activation pathway	1	190.3×	0.016	IFIH1
Modulation of host responses by IFN-stimulated genes	1	150.3×	0.018	IFIH1
TRAF6 mediated NF-kB activation	1	114.2×	0.022	IFIH1
TRAF6 mediated IRF7 activation	1	95.2×	0.022	IFIH1
Dengue virus activates/modulates innate and adaptive immune responses	1	84.0×	0.022	IFIH1
Negative regulators of DDX58/IFIH1 signaling	1	81.6×	0.022	IFIH1
Evasion by RSV of host interferon responses	1	81.6×	0.022	IFIH1
Metabolism of nucleotides	1	75.1×	0.022	SAMHD1
Ovarian tumor domain proteases	1	69.6×	0.022	IFIH1
SARS-CoV-1 activates/modulates innate immune responses	1	68.0×	0.022	IFIH1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1	63.4×	0.022	IFIH1
PKR-mediated signaling	1	35.2×	0.037	ADAR
Interferon Signaling	1	30.1×	0.041	SAMHD1
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	22.3×	0.052	IFIH1
Ub-specific processing proteases	1	13.3×	0.083	IFIH1
Cytokine Signaling in Immune system	1	10.2×	0.103	SAMHD1
Immune System	1	3.2×	0.286	SAMHD1
Metabolism	1	2.9×	0.302	SAMHD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mismatch repair	4	324.1×	3e-08	TREX1, RNASEH2A, RNASEH2C, RNASEH2B
negative regulation of type I interferon-mediated signaling pathway	3	287.2×	6e-06	TREX1, SAMHD1, ADAR
RNA catabolic process	3	170.8×	2e-05	RNASEH2A, RNASEH2C, RNASEH2B
defense response to virus	4	34.7×	8e-05	TREX1, SAMHD1, IFIH1, ADAR
type I interferon-mediated signaling pathway	2	86.0×	0.005	TREX1, IFIH1
immune response in brain or nervous system	1	2106.5×	0.005	TREX1
somatic diversification of immune receptors via somatic mutation	1	2106.5×	0.005	ADAR
ribonucleotide metabolic process	1	2106.5×	0.005	RNASEH2B
immune complex formation	1	2106.5×	0.005	TREX1
negative regulation of post-transcriptional gene silencing by regulatory ncRNA	1	2106.5×	0.005	ADAR
activation of immune response	1	1053.2×	0.006	TREX1
dGTP catabolic process	1	1053.2×	0.006	SAMHD1
DNA modification	1	1053.2×	0.006	TREX1
deoxyribonucleotide catabolic process	1	1053.2×	0.006	SAMHD1
regulation of type III interferon production	1	1053.2×	0.006	IFIH1
dATP catabolic process	1	1053.2×	0.006	SAMHD1
DNA synthesis involved in UV-damage excision repair	1	1053.2×	0.006	TREX1
cellular response to virus	2	50.1×	0.006	IFIH1, ADAR
DNA replication	2	41.3×	0.006	TREX1, RNASEH2A
response to virus	2	36.0×	0.007	IFIH1, ADAR
innate immune response	3	12.6×	0.007	SAMHD1, IFIH1, ADAR
retrotransposition	1	702.2×	0.007	TREX1
atrial cardiac muscle tissue development	1	526.6×	0.008	TREX1
detection of virus	1	526.6×	0.008	IFIH1
base conversion or substitution editing	1	526.6×	0.008	ADAR
MDA-5 signaling pathway	1	526.6×	0.008	IFIH1
DNA replication, removal of RNA primer	1	526.6×	0.008	RNASEH2A
T cell antigen processing and presentation	1	421.3×	0.008	TREX1
adenosine to inosine editing	1	421.3×	0.008	ADAR
negative regulation of protein kinase activity by regulation of protein phosphorylation	1	421.3×	0.008	ADAR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 8

Druggability breadth: 3 of 8 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TREX1	0	0
SAMHD1	0	0
RNASEH2A	0	0
IFIH1	0	0
ADAR	0	0
RNASEH2C	0	0
RNASEH2B	0	0
TLDC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SAMHD1	4	Binding:3, Functional:1
ADAR	2	Binding:2
IFIH1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TREX1	3.1.11.2	exodeoxyribonuclease III
SAMHD1	3.1.5.B1
RNASEH2A	3.1.26.4	ribonuclease H
ADAR	3.5.4.37	double-stranded RNA adenine deaminase
RNASEH2C	3.1.26.4	ribonuclease H
RNASEH2B	3.1.26.4	ribonuclease H

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	5	TREX1, RNASEH2A, ADAR, RNASEH2C, RNASEH2B
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SAMHD1, IFIH1, TLDC2

Undrugged target profiles

8 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TREX1	0	—
SAMHD1	4	—
RNASEH2A	0	—
IFIH1	1	—
ADAR	2	—
RNASEH2C	0	—
RNASEH2B	0	—
TLDC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	4
Not specified	4
PHASE2/PHASE3	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04517253	PHASE2/PHASE3	TERMINATED	A Study of Baricitinib (LY3009104) in Adult and Pediatric Japanese Participants With NNS/CANDLE, SAVI, and AGS
NCT02363452	PHASE2	COMPLETED	Reverse Transcriptase Inhibitors in AGS
NCT03304717	PHASE1/PHASE2	WITHDRAWN	Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome
NCT03921554	PHASE2	COMPLETED	JAK Inhibitor Treatment in AGS
NCT04731103	PHASE2	COMPLETED	Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome
NCT05613868	PHASE2	TERMINATED	TPN-101 in Aicardi-Goutières Syndrome (AGS)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT01724580	Not specified	APPROVED_FOR_MARKETING	Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT06898372	Not specified	COMPLETED	Evaluate the Efficacy of Anti-Jak1 Inhibitors as Treatment for Patients With Aicardi-Goutières Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ABACAVIR	4	3
BARICITINIB	4	3
CHEMBL5427854	0	2