IFIH1-related type 1 interferonopathy is an autosomal dominant autoinflammatory disease caused by heterozygous gain-of-function variants in IFIH1, which encodes MDA5, the cytosolic sensor of double-stranded RNA. The mutant receptor binds RNA more avidly and is slower to disassemble, so it signals without a viral trigger and drives constitutive type I interferon production. Nearly every carrier has a raised interferon signature in blood, but the clinical picture varies widely, even within one family. At one end is Aicardi-Goutieres syndrome type 7, an infantile encephalopathy, or a later rapid neuroregression or isolated spastic paraparesis. At the other is Singleton-Merten syndrome type 1, with early calcification of the aorta and heart valves, dental root resorption and tooth loss, osteopenia and acro-osteolysis, sometimes with psoriasis and glaucoma. Lupus-like disease also occurs, and about one carrier in eight is clinically unaffected. JAK inhibitors, which block signalling downstream of the interferon receptor, have been used off label with reported benefit in individual patients.
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name: IFIH1-Related Type 1 Interferonopathy
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
description: >-
IFIH1-related type 1 interferonopathy is an autosomal dominant
autoinflammatory disease caused by heterozygous gain-of-function variants in
IFIH1, which encodes MDA5, the cytosolic sensor of double-stranded RNA. The
mutant receptor binds RNA more avidly and is slower to disassemble, so it
signals without a viral trigger and drives constitutive type I interferon
production. Nearly every carrier has a raised interferon signature in blood,
but the clinical picture varies widely, even within one family. At one end
is Aicardi-Goutieres syndrome type 7, an infantile encephalopathy, or a later
rapid neuroregression or isolated spastic paraparesis. At the other is
Singleton-Merten syndrome type 1, with early calcification of the aorta and
heart valves, dental root resorption and tooth loss, osteopenia and
acro-osteolysis, sometimes with psoriasis and glaucoma. Lupus-like disease
also occurs, and about one carrier in eight is clinically unaffected. JAK
inhibitors, which block signalling downstream of the interferon receptor,
have been used off label with reported benefit in individual patients.
notes: >-
The entry is anchored on MONDO:0700262 and IFIH1 (hgnc:18873). It is a
gene-level disease whose two named phenotypes are recorded as subtypes:
Aicardi-Goutieres syndrome 7 (MONDO:0014367) and Singleton-Merten syndrome 1
(MONDO:0024535). AGS7 is also a subtype row on the Aicardi_Goutieres_Syndrome
entry, which groups the AGS series by phenotype across nine genes. The two
entries cut the same patients along different axes, by gene here and by
clinical syndrome there, and are not in conflict.
The deep-research report suggested several HPO identifiers that name other
findings: HP:0001171 (Split hand) for acro-osteolysis, HP:0032155 (Abdominal
cramps) for the interferon signature, and HP:0004382 (Mitral valve
calcification) for aortic valve calcification. None was used. HPO has no
generic acro-osteolysis term; OLS searches of HP for "acroosteolysis",
"acro-osteolysis" and "osteolysis" return only site-specific terms (foot,
clavicle, phalanges of one digit or of the hand), so the source's
distal-limb osteolysis is bound to HP:0002797 Osteolysis.
No frequency bands are recorded. The largest cohort (PMID:31898846) is
cached as abstract only and gives counts only for nonpenetrance.
No GeneReviews chapter is specific to IFIH1, and just check-genereviews
reports NO_CHAPTER against the 2026-09-10 Bookshelf index because no chapter
title matches this entry's names. The Aicardi-Goutieres Syndrome chapter
(PMID:20301648) does cover IFIH1 and is the baseline for the AGS7 subtype;
it does not cover Singleton-Merten syndrome.
Dystonia is described in Aicardi-Goutieres syndrome generally but no cached
source quotes it for IFIH1 carriers, so it is not curated. Chilblains are
recorded from the GeneReviews AGS summary, which is not IFIH1-specific.
disease_term:
preferred_term: IFIH1-related type 1 interferonopathy
term:
id: MONDO:0700262
label: IFIH1-related type 1 interferonopathy
synonyms:
- IFIH1 gain-of-function disease
- MDA5 gain-of-function interferonopathy
parents:
- Type 1 Interferonopathy
- Autoinflammatory Disease
has_subtypes:
- name: AGS7
display_name: Aicardi-Goutieres syndrome 7
subtype_term:
preferred_term: Aicardi-Goutieres syndrome 7
term:
id: MONDO:0014367
label: Aicardi-Goutieres syndrome 7
description: >-
Neurological presentation: neonatal or infantile Aicardi-Goutieres
syndrome, rapid neuroregression after normal early development, or
isolated spastic paraparesis.
evidence:
- 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: "The majority of IFIH1 mutation-positive probands (F102, F163, F259_1, F376 and F647) demonstrated a clinical picture typical of neonatal AGS (Supplementary Note, Supplementary Table 2)."
explanation: Most probands in the discovery cohort had typical neonatal AGS.
- reference: PMID:20301648
reference_title: "Aicardi-Goutières Syndrome."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "in a few instances the disease can result from specific de novo or inherited autosomal dominant pathogenic variants in ADAR or TREX1, and a variety of heterozygous autosomal dominant pathogenic variants in IFIH1."
explanation: The GeneReviews AGS chapter lists dominant IFIH1 variants as a genetic cause of AGS.
- name: SMS1
display_name: Singleton-Merten syndrome 1
subtype_term:
preferred_term: Singleton-Merten syndrome 1
term:
id: MONDO:0024535
label: Singleton-Merten syndrome 1
description: >-
Calcific, dental and skeletal presentation: aortic and valvular
calcification, early periodontitis and root resorption, osteopenia and
acro-osteolysis.
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption."
explanation: Establishes IFIH1 gain of function as the cause of SMS.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
description: >-
Heterozygous variants, often de novo. Penetrance is incomplete and
expressivity varies within families. Parental germline mosaicism has been
documented.
evidence:
- reference: PMID:31898846
reference_title: "Genetic and phenotypic spectrum associated with IFIH1 gain-of-function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years)."
explanation: About one carrier in eight is unaffected, so penetrance is incomplete.
- reference: PMID:31898846
reference_title: "Genetic and phenotypic spectrum associated with IFIH1 gain-of-function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate."
explanation: Variable expression and nonpenetrance across the cohort.
- reference: PMID:32042913
reference_title: "Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thus, both children inherited the R779H mutation through a germline mosaic from the father."
explanation: Parental germline mosaicism raises recurrence risk above the de novo baseline.
- reference: PMID:20301648
reference_title: "Aicardi-Goutières Syndrome."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "A variety of heterozygous autosomal dominant pathogenic variants in IFIH1."
explanation: GeneReviews diagnosis criteria for AGS include heterozygous dominant IFIH1 variants.
prevalence:
- population: Worldwide reported literature
measure_type: CASES_IN_LITERATURE
prevalence_class: RARE
notes: >-
The largest cohort identified 74 carriers in 51 families through a
European and North American collaboration. No population prevalence
estimate exists.
evidence:
- reference: PMID:31898846
reference_title: "Genetic and phenotypic spectrum associated with IFIH1 gain-of-function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1."
explanation: Size of the largest reported cohort.
pathophysiology:
- name: Heterozygous IFIH1 Gain-of-Function Variants
biological_scale: MOLECULAR
description: >-
Missense variants, and at least one in-frame deletion, cluster near the
ATP-binding region of the MDA5 helicase. The mutant protein binds
double-stranded RNA more avidly, hydrolyzes ATP less efficiently and
disassembles its filaments more slowly.
genes:
- preferred_term: IFIH1
term:
id: hgnc:18873
label: IFIH1
molecular_functions:
- preferred_term: double-stranded RNA binding
term:
id: GO:0003725
label: double-stranded RNA binding
modifier: INCREASED
- preferred_term: pattern recognition receptor activity
term:
id: GO:0038187
label: pattern recognition receptor activity
modifier: GAIN_OF_FUNCTION
genetic_context:
variant_origin: GERMLINE
functional_impact_category: GAIN_OF_FUNCTION
evidence:
- 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: IN_VITRO
snippet: "Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling."
explanation: Biochemical demonstration of gain of function.
- reference: PMID:31898846
reference_title: "Genetic and phenotypic spectrum associated with IFIH1 gain-of-function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The identified mutations cluster close to the ATP binding region of the protein."
explanation: Location of the disease variants in the protein.
downstream:
- target: Constitutive MDA5 Signaling and Type I Interferon Overproduction
causal_link_type: DIRECT
description: >-
The overactive sensor signals in response to endogenous RNA that does
not activate the wild-type receptor.
evidence:
- 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: IN_VITRO
snippet: "Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling."
explanation: Increased baseline signaling follows from tighter RNA binding.
- name: Constitutive MDA5 Signaling and Type I Interferon Overproduction
biological_scale: CELLULAR
description: >-
Mutant MDA5 triggers type I interferon production without infection, so
interferon-stimulated genes are expressed constantly. Every variant tested
in the largest cohort raised interferon signaling, including variants that
prediction tools called benign.
biological_processes:
- preferred_term: positive regulation of type I interferon production
term:
id: GO:0032481
label: positive regulation of type I interferon production
modifier: INCREASED
evidence:
- reference: PMID:31898846
reference_title: "Genetic and phenotypic spectrum associated with IFIH1 gain-of-function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs."
explanation: Enhanced interferon signaling is common to all variants.
downstream:
- target: Chronic Type I Interferon Signaling in Tissues
causal_link_type: DIRECT
description: Excess interferon acts on its receptor throughout the body.
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Interferon signature genes were upregulated in SMS individuals' blood and dental cells."
explanation: Interferon-stimulated genes are raised in patient blood and dental cells.
- name: Chronic Type I Interferon Signaling in Tissues
conforms_to: "cgas_sting_pathway_activation#Chronic Type I Interferon-Driven Tissue Inflammation"
biological_scale: ORGANISM
description: >-
Sustained interferon receptor signaling in brain, vessels, bone, teeth and
skin. Why one carrier develops encephalopathy and another vascular and
dental calcification is not known; modifying genes and environmental
triggers are both proposed.
biological_processes:
- preferred_term: type I interferon-mediated signaling pathway
term:
id: GO:0060337
label: type I interferon-mediated signaling pathway
modifier: INCREASED
evidence:
- 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: "We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state."
explanation: An enhanced interferon state underlies the whole spectrum.
downstream:
- target: Developmental regression
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Interferon-driven neuroinflammation causes neurological regression.
evidence:
- 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: "In contrast, two patients (F237 and F626) were developmentally normal until the second year of life, at which point they experienced rapid neuro-regression."
explanation: Rapid neuroregression after normal early development.
- target: Spastic paraplegia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Corticospinal involvement presents as spastic paraparesis.
evidence:
- reference: PMID:25243380
reference_title: "Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "The patients with ADAR1 and IFIH1-related disease showed a robust interferon signature."
explanation: >-
The IFIH1 spastic paraplegia patient had a robust interferon signature.
This shows the two occur together, not that one causes the other.
- target: Calcification of the aorta
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Interferon-driven vascular calcification in Singleton-Merten syndrome.
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption."
explanation: Links IFIH1 gain of function to early arterial calcification.
- target: Periodontitis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Dental inflammation and root resorption in Singleton-Merten syndrome.
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption."
explanation: Links IFIH1 gain of function to dental inflammation and resorption.
- target: Psoriasiform dermatitis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Interferon-driven skin inflammation; psoriasis cleared within days of
starting a JAK inhibitor in one patient.
evidence:
- reference: PMID:35410415
reference_title: "Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "Within days of treatment, psoriatic skin lesions resolved completely and the IFN signature normalized."
explanation: >-
Psoriasis resolved together with the interferon signature when
interferon signaling was blocked, which supports interferon driving
the skin disease.
- target: Systemic lupus erythematosus
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: A minority of carriers develop lupus-like autoimmunity.
evidence:
- 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: "In keeping with this, two patients in our cohort (F376 and F524_1) experienced significant immunological disturbance consistent with lupus."
explanation: Lupus-like disease in two patients.
phenotypes:
- category: Neurological
name: Developmental regression
description: >-
Neonatal encephalopathy typical of Aicardi-Goutieres syndrome, or rapid
neuroregression after normal development in the first year.
subtype: AGS7
phenotype_term:
preferred_term: Neuroregression
term:
id: HP:0002376
label: Developmental regression
evidence:
- 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: "In contrast, two patients (F237 and F626) were developmentally normal until the second year of life, at which point they experienced rapid neuro-regression."
explanation: Rapid neuroregression in two patients.
- category: Neurological
name: Spastic paraplegia
description: >-
Isolated or predominant spastic paraparesis, sometimes dominantly inherited
and sometimes with normal intellect and neuroimaging.
subtype: AGS7
phenotype_term:
preferred_term: Spastic paraparesis
term:
id: HP:0001258
label: Spastic paraplegia
evidence:
- 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: "Of particular note, both affected individuals (F524_1 and F524_2) in family F524 present a distinct phenotype of (dominantly inherited) spastic paraparesis."
explanation: Dominantly inherited spastic paraparesis in one family.
- reference: PMID:32042913
reference_title: "Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both siblings were clinically diagnosed with hereditary spastic paraplegia."
explanation: Two brothers with an IFIH1 variant presented as spastic paraplegia.
- category: Neurological
name: Progressive microcephaly
description: Head growth slows after an initially normal head size.
subtype: AGS7
phenotype_term:
preferred_term: Progressive microcephaly
term:
id: HP:0000253
label: Progressive microcephaly
evidence:
- reference: PMID:32042913
reference_title: "Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "After a period of normal development, both brothers presented with gait disturbances and progressive microcephaly."
explanation: Progressive microcephaly in two IFIH1 brothers.
- category: Neurological
name: Cerebral calcification
description: Intracranial calcification, a hallmark of Aicardi-Goutieres syndrome.
subtype: AGS7
phenotype_term:
preferred_term: Intracranial calcification
term:
id: HP:0002514
label: Cerebral calcification
evidence:
- reference: PMID:40043752
reference_title: "Short-term efficacy of tofacitinib, a JAK inhibitor, in IFIH1-related Aicardi-Goutières syndrome."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "Aicardi-Goutières syndrome (AGS) is a genetically heterogeneous type-I interferonopathy presenting in infancy with intracranial calcifications, white matter lesions, and brain atrophy."
explanation: >-
Background statement about AGS in general, quoted in an IFIH1 report;
not an observation of IFIH1 carriers specifically.
- reference: PMID:20301648
reference_title: "Aicardi-Goutières Syndrome."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "The diagnosis of AGS is established in a proband with typical clinical findings and characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes)"
explanation: GeneReviews names basal ganglia and white matter calcification on CT as a diagnostic finding in AGS, the group that includes AGS7.
- category: Dermatological
name: Chilblains
description: >-
Chilblain lesions of the fingers, toes and ears, described across
Aicardi-Goutieres syndrome.
subtype: AGS7
phenotype_term:
preferred_term: Chilblains
term:
id: HP:0009710
label: Chilblains
evidence:
- reference: PMID:20301648
reference_title: "Aicardi-Goutières Syndrome."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears."
explanation: Chilblains in AGS overall; the chapter does not give a figure for IFIH1 carriers, so this is indirect for AGS7.
- category: Neurological
name: Leukodystrophy
description: White matter signal abnormality and delayed myelination on MRI.
subtype: AGS7
phenotype_term:
preferred_term: White matter abnormality
term:
id: HP:0002415
label: Leukodystrophy
evidence:
- reference: PMID:32042913
reference_title: "Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRI revealed symmetric hyperintensities within the periventricular white matter in both brothers, with hypomyelination more pronounced in the older sibling (figure, B)."
explanation: White matter changes in two IFIH1 brothers.
- category: Cardiovascular
name: Calcification of the aorta
description: Early and extreme calcification of the aorta.
subtype: SMS1
phenotype_term:
preferred_term: Aortic calcification
term:
id: HP:0004963
label: Calcification of the aorta
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis."
explanation: Aortic calcification is a defining SMS feature.
- category: Cardiovascular
name: Aortic valve calcification
description: Calcification of the aortic valve in childhood or puberty.
subtype: SMS1
phenotype_term:
preferred_term: Aortic valve calcification
term:
id: HP:0004380
label: Aortic valve calcification
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Calcifications of the aorta and aortic and mitral valves occur in childhood or puberty (Figures 1A and 1B and Movies S1 and S2) and can lead to early demise."
explanation: Aortic valve calcification beginning in childhood or puberty.
- category: Cardiovascular
name: Mitral valve calcification
description: Calcification of the mitral valve in childhood or puberty.
subtype: SMS1
phenotype_term:
preferred_term: Mitral valve calcification
term:
id: HP:0004382
label: Mitral valve calcification
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Calcifications of the aorta and aortic and mitral valves occur in childhood or puberty (Figures 1A and 1B and Movies S1 and S2) and can lead to early demise."
explanation: Mitral valve calcification beginning in childhood or puberty.
- category: Dental
name: Periodontitis
description: Early-onset periodontitis with root and alveolar bone resorption.
subtype: SMS1
phenotype_term:
preferred_term: Early-onset periodontitis
term:
id: HP:0000704
label: Periodontitis
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis."
explanation: Early-onset periodontitis is a defining SMS feature.
sequelae:
- target: Premature loss of teeth
description: Root and alveolar bone resorption lead to tooth loss.
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dental findings include a delay in primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, and severe root and alveolar bone resorption associated with dysregulated mineralization3 leading to tooth loss (Figure 1C)."
explanation: Resorption leads to tooth loss.
- category: Dental
name: Premature loss of teeth
description: Loss of permanent teeth after root and alveolar bone resorption.
subtype: SMS1
phenotype_term:
preferred_term: Premature loss of permanent teeth
term:
id: HP:0006480
label: Premature loss of teeth
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dental findings include a delay in primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, and severe root and alveolar bone resorption associated with dysregulated mineralization3 leading to tooth loss (Figure 1C)."
explanation: Tooth loss in SMS.
- category: Dental
name: Delayed eruption of permanent teeth
description: Delayed loss of primary teeth and eruption of permanent teeth.
subtype: SMS1
phenotype_term:
preferred_term: Delayed eruption of permanent teeth
term:
id: HP:0000696
label: Delayed eruption of permanent teeth
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Dental findings include a delay in primary tooth exfoliation and permanent tooth eruption, truncated tooth root formation, early-onset periodontal disease, and severe root and alveolar bone resorption associated with dysregulated mineralization3 leading to tooth loss (Figure 1C)."
explanation: Delayed permanent tooth eruption in SMS.
- category: Musculoskeletal
name: Osteopenia
description: Osteopenia or osteoporosis, generalized or limited to the distal limbs.
subtype: SMS1
phenotype_term:
preferred_term: Osteopenia
term:
id: HP:0000938
label: Osteopenia
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis."
explanation: Osteopenia is a defining SMS feature.
- category: Musculoskeletal
name: Osteolysis
description: >-
Acro-osteolysis of the distal limbs. HPO has no generic acro-osteolysis
term, so Osteolysis is bound and the distal site is carried in
preferred_term.
subtype: SMS1
phenotype_term:
preferred_term: Acro-osteolysis
term:
id: HP:0002797
label: Osteolysis
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis."
explanation: Acro-osteolysis is a defining SMS feature.
- category: Dermatological
name: Psoriasiform dermatitis
description: Psoriasis, a less common feature that can be severe.
phenotype_term:
preferred_term: Psoriasis
term:
id: HP:0003765
label: Psoriasiform dermatitis
evidence:
- reference: PMID:35410415
reference_title: "Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At the age of five years, he developed osteoporosis, acro-osteolysis, alveolar bone loss and severe psoriasis."
explanation: Severe psoriasis in a child with SMS1.
- category: Ophthalmological
name: Glaucoma
description: Early-onset glaucoma, a less common feature.
phenotype_term:
preferred_term: Early-onset glaucoma
term:
id: HP:0000501
label: Glaucoma
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
quote_role: BACKGROUND
evidence_source: HUMAN_CLINICAL
snippet: "Less common features are an unusual face (high anterior hair line, broad forehead, smooth philtrum, and thin upper vermillion), generalized muscle weakness, psoriasis, early-onset glaucoma, and recurrent infections."
explanation: The paper's background summary of less common SMS features.
- category: Immunological
name: Systemic lupus erythematosus
description: Lupus-like immunological disease in a minority of carriers.
phenotype_term:
preferred_term: Lupus-like disease
term:
id: HP:0002725
label: Systemic lupus erythematosus
evidence:
- 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: "In keeping with this, two patients in our cohort (F376 and F524_1) experienced significant immunological disturbance consistent with lupus."
explanation: Lupus-like disease in two patients.
- reference: PMID:40043752
reference_title: "Short-term efficacy of tofacitinib, a JAK inhibitor, in IFIH1-related Aicardi-Goutières syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In 2014, she presented with multiple joint swelling, facial rash, and hair loss, and received a diagnosis of juvenile idiopathic arthritis and systemic lupus erythematosus."
explanation: A patient with an IFIH1 variant first diagnosed with lupus.
biochemical:
- name: Interferon-stimulated gene expression
presence: INCREASED
notes: >-
The blood interferon signature is raised in nearly all carriers,
including clinically unaffected ones, so it supports the diagnosis but
does not predict disease.
evidence:
- reference: PMID:31898846
reference_title: "Genetic and phenotypic spectrum associated with IFIH1 gain-of-function."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs."
explanation: Interferon signaling is raised with every variant.
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Interferon signature genes were upregulated in SMS individuals' blood and dental cells."
explanation: Raised interferon signature in SMS patients.
genetic:
- name: IFIH1
gene_term:
preferred_term: IFIH1
term:
id: hgnc:18873
label: IFIH1
association: Causative
relationship_type: CAUSATIVE
variant_origin: GERMLINE
features: >-
IFIH1 (2q24.2) encodes MDA5, a RIG-I-like receptor that senses cytosolic
double-stranded RNA and signals through MAVS to induce type I interferon.
Heterozygous gain-of-function variants cause this disease. Common IFIH1
polymorphisms that modify autoimmune risk, and loss-of-function variants
that predispose to viral infection, are different mechanisms and are not
part of this entry. The variant is usually germline, but one AGS7 patient
with lupus-like disease carried a somatic gain-of-function variant
(PMID:40043752).
evidence:
- 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: "We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state."
explanation: Discovery of heterozygous IFIH1 variants as the cause.
variants:
- name: NM_022168:c.2465G>A (p.Arg822Gln)
type: MISSENSE
clinical_significance: PATHOGENIC
description: Recurrent Singleton-Merten allele.
evidence:
- reference: PMID:25620204
reference_title: "A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1"
explanation: The allele in five SMS patients from three families.
- name: NM_022168:c.2336G>A (p.Arg779His)
type: MISSENSE
description: >-
Inherited by two brothers with spastic paraplegia from their
asymptomatic father, who was mosaic.
evidence:
- reference: PMID:32042913
reference_title: "Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thus, both children inherited the R779H mutation through a germline mosaic from the father."
explanation: Paternal germline mosaicism for the allele.
treatments:
- name: Ruxolitinib
description: >-
The JAK1/2 inhibitor ruxolitinib, which blocks signaling from the type I
interferon receptor, has been given off label to three patients in two
reports. In a child with SMS1, psoriasis cleared and the interferon
signature normalized within days, and weakness, osteopenia and growth
improved. Two brothers with AGS7 presenting as spastic paraplegia had a
significant fall in the interferon signature, better quality of life, and
maintained or slightly improved motor function.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: JAK inhibitor pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ruxolitinib
term:
id: CHEBI:66919
label: ruxolitinib
target_mechanisms:
- target: Chronic Type I Interferon Signaling in Tissues
description: Blocks JAK signaling downstream of the interferon receptor.
evidence:
- reference: PMID:35410415
reference_title: "Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Within days of treatment, psoriatic skin lesions resolved completely and the IFN signature normalized."
explanation: Rapid response of skin disease and interferon signature.
- reference: PMID:35410415
reference_title: "Precision treatment of Singleton Merten syndrome with ruxolitinib: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Therapeutic efficacy was sustained and over the course muscular weakness, osteopenia and growth also improved."
explanation: Sustained benefit on systemic features.
- reference: PMID:32042913
reference_title: "Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both children responded with a significant reduction of the IFN signature"
explanation: Interferon signature response in two brothers with AGS7.
- reference: PMID:32042913
reference_title: "Aicardi-Goutières syndrome due to a paternal mosaic IFIH1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both children were able to maintain and even moderately improve their motor abilities, with a progress more noticeable in the younger brother, whose gait using orthoses improved by 40% after 8 months of treatment"
explanation: Clinical benefit on motor function in the same two patients.
- name: Tofacitinib
description: >-
The JAK inhibitor tofacitinib, with oral methylprednisolone, controlled
disease activity for about a year in a young woman with an IFIH1 variant
and lupus-like disease. The variant was somatic. Single case; off label.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: JAK inhibitor pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: tofacitinib
term:
id: CHEBI:71200
label: tofacitinib
target_mechanisms:
- target: Chronic Type I Interferon Signaling in Tissues
description: Blocks JAK signaling downstream of the interferon receptor.
evidence:
- reference: PMID:40043752
reference_title: "Short-term efficacy of tofacitinib, a JAK inhibitor, in IFIH1-related Aicardi-Goutières syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "After nearly one year, the patient showed no significant disease activity and normal hair growth, with no notable changes in thyroid function."
explanation: Disease control on tofacitinib in one patient.
- name: Baricitinib
description: >-
The JAK1/2 inhibitor baricitinib was given in an open-label expanded-access
study of 35 patients with genetically confirmed Aicardi-Goutieres
syndrome. The interferon signature fell, symptom diaries improved and many
children gained new developmental milestones. The cohort mixed AGS
genotypes and the cached report does not give results by gene, so the
evidence applies to AGS7 only as part of AGS.
action_category: THERAPEUTIC
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: JAK inhibitor pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: baricitinib
term:
id: CHEBI:95341
label: baricitinib
target_mechanisms:
- target: Chronic Type I Interferon Signaling in Tissues
description: Blocks JAK signaling downstream of the interferon receptor.
evidence:
- 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: >-
Interferon biomarker response on baricitinib. The 35 patients had AGS of
several genotypes, not only IFIH1.
- reference: PMID:32877590
reference_title: "Janus Kinase Inhibition in the Aicardi-Goutières Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "During the study, 20 patients met new milestones, and 12 patients gained two to seven new skills."
explanation: >-
Developmental gains on baricitinib in a genetically heterogeneous AGS
cohort; results are not broken down by gene.
- name: Supportive care
description: >-
Management of AGS is otherwise supportive: chest physiotherapy, feeding
support to maintain intake and avoid aspiration, standard seizure
management, and surveillance for glaucoma, scoliosis, diabetes and
hypothyroidism.
action_category: THERAPEUTIC
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:20301648
reference_title: "Aicardi-Goutières Syndrome."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "Treatment of manifestations: Chest physiotherapy and treatment of respiratory complications; attention to diet and feeding methods to assure adequate caloric intake and avoid aspiration; management of seizures using standard protocols."
explanation: GeneReviews management of AGS, which includes AGS7.
clinical_trials:
- name: NCT03921554
phase: PHASE_II
status: COMPLETED
description: >-
Study of the safety and efficacy of baricitinib in Aicardi-Goutieres
syndrome. Enrolment was not restricted to IFIH1.
evidence:
- reference: clinicaltrials:NCT03921554
reference_title: "Janus Kinase Inhibitor (Baricitinib) for Aicardi Goutières Syndrome"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The primary objective of this study is to assess safety as well as efficacy of baricitinib, a Janus Kinase (JAK) inhibitor, in patients with Aicardi Goutières Syndrome (AGS)"
explanation: Registered trial of baricitinib in AGS, which includes AGS7.
references:
- reference: PMID:20301648
title: "Aicardi-Goutières Syndrome."
tags:
- GeneReviews
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Record notes
The entry is anchored on MONDO:0700262 and IFIH1 (hgnc:18873). It is a gene-level disease whose two named phenotypes are recorded as subtypes: Aicardi-Goutieres syndrome 7 (MONDO:0014367) and Singleton-Merten syndrome 1 (MONDO:0024535). AGS7 is also a subtype row on the Aicardi_Goutieres_Syndrome entry, which groups the AGS series by phenotype across nine genes. The two entries cut the same patients along different axes, by gene here and by clinical syndrome there, and are not in conflict. The deep-research report suggested several HPO identifiers that name other findings: HP:0001171 (Split hand) for acro-osteolysis, HP:0032155 (Abdominal cramps) for the interferon signature, and HP:0004382 (Mitral valve calcification) for aortic valve calcification. None was used. HPO has no generic acro-osteolysis term; OLS searches of HP for "acroosteolysis", "acro-osteolysis" and "osteolysis" return only site-specific terms (foot, clavicle, phalanges of one digit or of the hand), so the source's distal-limb osteolysis is bound to HP:0002797 Osteolysis. No frequency bands are recorded. The largest cohort (PMID:31898846) is cached as abstract only and gives counts only for nonpenetrance. No GeneReviews chapter is specific to IFIH1, and just check-genereviews reports NO_CHAPTER against the 2026-09-10 Bookshelf index because no chapter title matches this entry's names. The Aicardi-Goutieres Syndrome chapter (PMID:20301648) does cover IFIH1 and is the baseline for the AGS7 subtype; it does not cover Singleton-Merten syndrome. Dystonia is described in Aicardi-Goutieres syndrome generally but no cached source quotes it for IFIH1 carriers, so it is not curated. Chilblains are recorded from the GeneReviews AGS summary, which is not IFIH1-specific.
Create: IFIH1-Related Type 1 Interferonopathy · 2026-10-15T09:27:36Z · View source
New entry for IFIH1-related type 1 interferonopathy (MONDO:0700262), curated as a gene-level disease with AGS7 and SMS1 as subtypes. Source report: research/IFIH1-Related_Type_1_Interferonopathy-deep-research-perplexity.md, generated with Perplexity sonar-deep-research at reasoning_effort=low, because two runs at the default effort were disconnected at about 300 seconds. Reference validation resolved 25/25 references and 1/1 quotes, with one off-topic DOI not cited. preflight-dr returned WARN because its heuristic lexicon counted the disease abbreviation AGS as a gene. Three of the report's HPO suggestions named other findings (HP:0001171 Split hand for acro-osteolysis, HP:0032155 Abdominal cramps for the interferon signature, HP:0004382 Mitral valve calcification for aortic valve calcification) and were not used; acro-osteolysis is bound to HP:0002797 Osteolysis because HPO has no generic term. Primary papers fetched from a PubMed search: PMID:24686847, 25620204, 31898846, 32042913, 25243380, 35410415, 40043752. Validated with just validate, count-verified-snippets (45/45), validate-terms, check-genereviews (NO_CHAPTER), check-causal-targets and the gene-grounding gate.
Disease-knowledge-base research report — evidence reviewed through 15 October 2026
IFIH1-related type 1 interferonopathy (MONDO:0700262) is a rare, autosomal-dominant Mendelian immune-dysregulation disorder caused principally by heterozygous germline gain-of-function (GOF) variants in IFIH1, encoding the cytosolic double-stranded-RNA sensor MDA5. It is best understood as one continuous, variably penetrant disease spectrum encompassing Aicardi–Goutières syndrome type 7 (AGS7), neuroregression/spastic-dystonic and spastic-paraparetic phenotypes, Singleton–Merten syndrome type 1 (SMS1), lupus-like or organ-predominant inflammation, and clinically asymptomatic carriers with an elevated interferon signature. The ClinGen/GenCC-style 2024 evaluation classifies the IFIH1–disease relationship as definitive and deliberately “lumps” AGS7 and SMS1 under MONDO:0700262. GenCC submission, 23 August 2024, URL [64][69]
The largest dedicated cohort comprised 74 variant-positive people from 51 families with 27 likely pathogenic variants. Ten carriers (13.5%) were clinically asymptomatic, including seven older than 50 years, demonstrating incomplete penetrance; nevertheless, nearly all tested variants or carriers showed elevated type-I-interferon signaling. Rice et al., Human Mutation, published online 14 January 2020, PMID: 31898846 [31][39]
Key primary-literature quote: “We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1.” [PMID: 31898846] [31]
There is no approved disease-specific curative therapy. Off-label JAK1/2 inhibition—particularly baricitinib or ruxolitinib—is the leading targeted strategy. It can suppress the interferon signature and improve inflammatory, skin, systemic, and sometimes developmental outcomes, but reversal of established brain injury is uncertain and infections and cytopenias are important risks. Vanderver et al., NEJM, 3 September 2020 [155]
IFIH1-related type 1 interferonopathy is a monogenic autoinflammatory/autoimmune disorder of innate nucleic-acid sensing. Constitutively or excessively active MDA5 produces inappropriate type-I-interferon signaling in the absence of an adequate viral threat. The resulting phenotype ranges from prenatal or infantile encephalopathy to later spastic paraparesis, vascular/dental/skeletal calcific disease, isolated inflammatory manifestations, or biochemical nonpenetrance.
The umbrella concept is preferable to treating AGS7 and SMS1 as unrelated disorders because:
| Resource | Identifier/name | Interpretation or URL |
|---|---|---|
| MONDO | MONDO:0700262 — IFIH1-related type 1 interferonopathy | Umbrella disease entity; GenCC [64] |
| MONDO | MONDO:0014367 — Aicardi–Goutières syndrome 7 | Neurological subphenotype [65] |
| OMIM disease | 615846 — Aicardi–Goutières syndrome 7 | AD IFIH1 GOF disease; OMIM [61] |
| OMIM disease | 182250 — Singleton–Merten syndrome 1 | AD IFIH1 GOF disease; OMIM [62] |
| OMIM gene | 606951 — IFIH1 | Gene record [10] |
| Orphanet | ORPHA:51 — Aicardi–Goutières syndrome | Genetically heterogeneous umbrella AGS entry [73] |
| Orphanet | ORPHA:85191 — Singleton–Merten dysplasia | Calcific/dental/skeletal presentation [62][63] |
| ICD-10 | No unique IFIH1 code; AGS generally coded under rare/other specified neurological or genetic disease; SMS may map to Q78.8 | Q78.8 = other specified osteochondrodysplasias [63] |
| ICD-11 | No uniquely specific IFIH1 code identified; SMS mapping LD24.KY | “Other specified osteochondrodysplasias” mapping reported by Orphanet [63] |
| MeSH | No dedicated IFIH1-interferonopathy descriptor | Use Aicardi-Goutières Syndrome, Interferon Type I, IFIH1 protein, human, and relevant phenotype headings |
| MedGen | C3888244 — AGS7 | NCBI MedGen [65] |
Synonyms: IFIH1 gain-of-function disease; MDA5 gain-of-function disease; MDA5-associated interferonopathy; IFIH1-associated autoinflammation; AGS7; Aicardi–Goutières syndrome due to IFIH1; Singleton–Merten syndrome 1; IFIH1-related Singleton–Merten dysplasia.
This report is based primarily on aggregated disease-level resources and published cohorts, supplemented by individual case reports and pedigrees. It is not derived from a single patient’s EHR. A 2024 real-world/natural-history analysis included 19 IFIH1-positive patients among 167 molecularly diagnosed AGS patients, but those data concern genetically heterogeneous AGS and should not automatically be generalized to every IFIH1 carrier. [138]
The established cause is a heterozygous constitutional GOF variant in IFIH1. Most confirmed variants are missense substitutions in or near the MDA5 helicase/ATP- and RNA-interacting regions. A 2024 report expanded the mechanism to an in-frame deletion, p.Glu794del, showing that not every pathogenic GOF allele is missense. MDA5 p.Glu794del report, 2 October 2024 [76]
GOF can result from:
| Factor | Evidence and interpretation |
|---|---|
| Pathogenic IFIH1 GOF allele | Necessary primary causal factor in established cases |
| De novo occurrence | Common in severe infantile AGS-like disease; 22 of the 27 cohort variants occurred de novo in at least one patient [39] |
| Familial AD inheritance | Produces a 50% transmission risk per conception, but not a 50% certainty of clinical disease because penetrance is incomplete |
| Variant location/function | Most disease alleles cluster around helicase ATP/RNA-binding structures; functional assay evidence is more reliable than in-silico prediction |
| Modifier alleles | Suspected, not established; implied by severe intrafamilial variability and unaffected carriers |
| Parental mosaicism | Documented: paternal mosaic IFIH1 mutation caused affected siblings, supporting recurrence risk above the usual de novo baseline Neurology Genetics, 19 December 2019 [29] |
Common IFIH1 polymorphisms influence polygenic autoimmunity and antiviral responses, but these susceptibility associations are not equivalent to monogenic GOF interferonopathy. Conversely, monoallelic or biallelic loss-of-function can predispose to viral disease/immunodeficiency and should not be classified as the same mechanism. [44]
No toxin, diet, occupation, smoking exposure, alcohol exposure, or lifestyle behavior is established as a primary cause.
Infection or dsRNA exposure is a biologically plausible disease modifier. In an MDA5-R822Q mouse model, poly(I:C), a synthetic dsRNA analogue, sharply exacerbated inflammation and mortality; deleting MAVS or IFNAR prevented this enhancement. This is strong model-organism evidence for gene–immune-trigger interaction but not proof that a particular human virus initiates disease. [121][126]
Clinical neuroregression can occur after apparently normal development and may appear temporally associated with febrile illness, but published evidence does not establish one infectious agent as necessary or sufficient.
No validated environmental protective factor exists.
Potential genetic/biological protection is inferred from:
These are mechanistic hypotheses, not clinically actionable protective genotypes. Routine deliberate infection avoidance beyond standard care, special diets, or supplements have not been proven to prevent onset.
Phenotypic frequency estimates are limited by ascertainment bias toward pediatric neurological disease. In the 74-person cohort, at least 20 had unequivocal rapid neuroregression, ten were clinically asymptomatic, and six symptomatic patients had died. Imaging findings were not systematically recorded, so precise percentages are unavailable. [39]
| Phenotype type | Manifestation and suggested HPO term | Onset/course/frequency | Functional and quality-of-life effect |
|---|---|---|---|
| Symptom/sign | Developmental delay — HP:0001263 | Congenital or infantile; common in AGS-like cases; variable severity | Dependence for mobility, feeding, communication and self-care |
| Symptom/sign | Developmental regression — HP:0002376 | Acute/subacute, usually infancy; at least 20/74 carriers had unequivocal rapid regression; seven regressed after age 1 following normal development [39] | Loss of motor, language and adaptive skills |
| Sign | Spasticity — HP:0001257; spastic paraparesis — HP:0002313 | Infantile through adolescent onset; may progress slowly; one cohort patient began at 13 years | Gait impairment, contractures, wheelchair need |
| Sign | Dystonia — HP:0001332 | Often follows neuroregression; variable | Pain, abnormal posture, impaired hand use and ambulation |
| Sign | Axial hypotonia — HP:0008936 | Usually infantile, often preceding later spasticity | Poor head/trunk control |
| Symptom | Irritability — HP:0000737 | Often prominent during active infantile encephalopathy | Sleep and feeding disruption; caregiver burden |
| Sign | Acquired/progressive microcephaly — HP:0000252/HP:0000253 | Slowing of head growth after inflammatory neurological injury | Correlates with severe neurodevelopmental morbidity |
| Imaging | Intracranial/basal-ganglia calcification — HP:0002514 | Congenital or childhood; sometimes present without neurological signs | Diagnostic clue; direct daily-life impact depends on associated injury |
| Imaging | Cerebral white-matter abnormality/leukodystrophy — HP:0002500 | Variable; unilateral disease has occurred | Motor, cognitive or visual consequences; may be clinically silent |
| Imaging | Cerebral atrophy — HP:0002059 | Often develops after encephalopathic phase | Usually indicates irreversible structural injury |
| Laboratory | Elevated interferon-stimulated gene expression — HP:0032155 (type-I IFN signature; confirm current HPO label) | Persistent or fluctuating; present even in many asymptomatic carriers | Biomarker, not itself a patient-reported symptom |
| Laboratory | CSF lymphocytosis — HP:0200149 | More likely during early active disease | Indicates neuroinflammation |
| Laboratory | Elevated CSF interferon-α / neopterin | Often early, not universal | Diagnostic rather than direct functional impact |
| Skin | Chilblains/perniosis — HP:0009710 | Episodic, cold-sensitive; AGS-wide estimate up to 40%, but IFIH1-specific rate unavailable [166] | Pain, ulceration and reduced hand/foot use |
| Skin | Psoriasiform dermatitis — HP:0003765 | Chronic or fluctuating; uncommon | Pruritus, pain and psychosocial burden |
| Immune | Sterile fever — HP:0001945 | Episodic, particularly active phase | Fatigue, discomfort and hospitalization |
| Immune | Lupus-like disease/autoimmunity — HP:0002725 | Uncommon but established within spectrum | Organ-specific morbidity, medication burden |
| Hepatic | Elevated transaminases/hepatitis — HP:0002910/HP:0012115 | Congenital systemic disease or isolated childhood liver presentation | Ranges from laboratory finding to hepatic dysfunction |
| Dental | Delayed tooth eruption — HP:0000684 | Childhood; core SMS feature | Feeding, speech, appearance and dental-prosthetic burden |
| Dental | Premature loss of permanent teeth — HP:0006480 | Childhood/adolescence; progressive | Major chewing, speech and psychosocial effects |
| Skeletal | Osteopenia/osteoporosis — HP:0000938/HP:0000939 | Childhood onward in SMS | Fracture risk, pain, reduced activity |
| Skeletal | Acro-osteolysis — HP:0001171 | Progressive | Hand/foot deformity and reduced dexterity |
| Skeletal | Widened medullary cavities of phalanges | Childhood | Radiographic hallmark; variable functional effect |
| Cardiovascular | Aortic calcification — HP:0004963 | Childhood or puberty; progressive | Stenosis, surgery risk, potentially early death |
| Cardiovascular | Aortic/mitral-valve calcification — HP:0004382 or appropriate valve-specific HPO term | Progressive SMS manifestation | Heart failure, arrhythmia or intervention risk |
| Cardiopulmonary | Pulmonary hypertension — HP:0002092 | Rare but serious; found postmortem in one cohort death | Exercise limitation and mortality risk |
| Eye | Glaucoma — HP:0000501 | Less frequent SMS manifestation | Progressive visual loss |
| Endocrine | Hypothyroidism — HP:0000821 | Uncommon | Fatigue, growth and developmental effects |
| Carrier state | Clinical nonpenetrance — HP:0003828 | 10/74 carriers (13.5%); seven older than 50 years [31] | No overt impairment despite genotype; biomarker may remain abnormal |
The core SMS phenotype comprises aortic/valvular calcification, delayed eruption and abnormal root formation, early permanent-tooth loss, osteoporosis and acro-osteolysis; glaucoma, psoriasis, muscle weakness and joint laxity are less consistent. [167][179]
No disease-specific validated EQ-5D, SF-36 or PROMIS dataset was found. Quality-of-life effects must therefore be inferred from neurological dependence, communication impairment, recurrent inflammatory symptoms, dental loss, cardiopulmonary disease and caregiver burden.
| Attribute | Value |
|---|---|
| Gene | IFIH1, interferon induced with helicase C domain 1 |
| HGNC | HGNC:18873 |
| NCBI Gene | 64135 |
| Ensembl | ENSG00000115267 |
| OMIM | 606951 |
| Locus | 2q24.2 |
| GRCh38 interval | chr2:162,267,074–162,318,684, reverse strand |
| Protein | MDA5; interferon-induced helicase C-domain-containing protein 1 |
| UniProt | Q9BYX4 |
| Principal transcript used in 2020 cohort | NM_022168.2; current clinical reporting should use the laboratory-specified current MANE transcript |
| Main compartments | Cytosol; signaling complex associated with mitochondrial MAVS; reported nuclear localization during apoptosis |
These identifiers are supported by NCBI Gene and UniProt. [46][47][49]
All variants in the landmark cohort were germline/constitutional and heterozygous. Population frequencies were absent or ultra-rare. Do not infer benignity solely from computational prediction: six of 27 variants, 22%, were called benign by multiple in-silico tools despite functional/biomarker evidence of GOF. [31]
| Variant (NM_022168.2) | Protein | Reported population frequency in cohort paper | Principal reported phenotype(s) |
|---|---|---|---|
| c.992C>G | p.Thr331Arg | Absent | AGS–SMS overlap; SMS |
| c.992C>T | p.Thr331Ile | Absent | SMS |
| c.1009A>G | p.Arg337Gly | Absent | Neuroregression |
| c.1165G>A | p.Gly389Arg | Absent | AGS, spastic paraparesis, nonpenetrance |
| c.1178A>T | p.Asp393Val | Absent | Neuroregression |
| c.1178A>C | p.Asp393Ala | Absent | AGS |
| c.1331A>G | p.Glu444Gly | Absent | Severe AGS |
| c.1347C>G | p.Asn449Lys | Absent | Spastic paraparesis |
| c.1465G>A | p.Ala489Thr | Absent | Chilblains, AGS–SMS, SMS |
| c.1483G>A | p.Gly495Arg | Absent | Spastic paraparesis, lupus-like disease |
| c.1747A>G | p.Ile583Val | Absent | AGS |
| c.2156C>T | p.Ala719Val | Absent | AGS |
| c.2159G>A | p.Arg720Gln | Absent | AGS or spastic paraparesis |
| c.2317G>C | p.Glu773Gln | Absent | Neuroregression |
| c.2335C>T | p.Arg779Cys | Absent | AGS, lupus-like disease, paraparesis, nonpenetrance |
| c.2336G>A | p.Arg779His | 1/244,230 alleles | AGS, neuroregression, paraparesis, nonpenetrance |
| c.2336G>T | p.Arg779Leu | Absent | AGS |
| c.2342G>A | p.Gly781Glu | Absent | Neuroregression or paraparesis |
| c.2404A>G | p.Asn802Asp | Absent | Neuroregression |
| c.2407A>T | p.Ile803Phe | Absent | AGS |
| c.2465G>A | p.Arg822Gln | 6/244,096 alleles | SMS; spastic-dystonic/calcification phenotype |
| c.2471G>A | p.Arg824Lys | Absent | Neuroregression or isolated liver disease |
| c.2486C>G | p.Thr829Ser | Absent | AGS |
| c.2544T>G | p.Asp848Glu | Absent | Paraparesis/calcification or nonpenetrance |
| c.2561T>A | p.Met854Lys | Absent | AGS–SMS overlap |
| c.2866A>G | p.Ile956Val | Absent | Paraparesis/calcification or nonpenetrance |
| c.2936T>G | p.Leu979Trp | Absent | Severe AGS |
| Later expansion | p.Glu794del | Ultra-rare/novel | AGS-like disease; first reported in-frame-deletion GOF mechanism [76] |
Full cohort source: Rice et al., PMID: 31898846 [39].
ACMG interpretation: classifications vary by ClinVar submitter and date. A rare missense or in-frame variant should generally require segregation/de novo evidence, a compatible phenotype, blood interferon signature and preferably a validated IFNβ reporter, RNA-binding, ATPase or filament assay. A negative family history is weak counter-evidence because both de novo disease and nonpenetrance are common.
| Domain | Current evidence |
|---|---|
| Toxins/radiation/pollution | No established causal association |
| Smoking/alcohol/diet/exercise | No demonstrated effect on penetrance or progression |
| Temperature | Cold can precipitate or worsen chilblains but does not cause the genetic disorder |
| Viral infection | Wild-type MDA5 is a viral-dsRNA sensor; infection is a plausible flare trigger, but no specific pathogen is required |
| Vaccination | No evidence that routine vaccination causes IFIH1 disease; individual risk assessment is appropriate during immunosuppression |
| Synthetic dsRNA | Poly(I:C) markedly exacerbates disease in MDA5-GOF models, supporting trigger sensitivity [81][121] |
The correct knowledge-base representation is therefore genetic cause with possible infection/innate-immune-stimulation modifiers, not a communicable or environmentally acquired disease.
Upstream: MDA5 RNA recognition, ATP binding/hydrolysis and filament dynamics.
Intermediate: MAVS, TBK1/IKKε, IRF3/7, NF-κB, IFN secretion.
Downstream: IFNAR–JAK1/TYK2–STAT1/2–IRF9, ISG expression, chronic inflammation and tissue injury.
Suggested GO biological-process terms:
Suggested GO cellular-component terms:
| Cell type | Suggested CL term | Evidence/status |
|---|---|---|
| Microglial cell | CL:0000129 | Likely CNS effector of interferon-mediated inflammation; partly inferred from AGS biology |
| Astrocyte | CL:0000127 | Likely contributes to white-matter and cytokine responses; human IFIH1-specific evidence limited |
| Neuron | CL:0000540 | Injured downstream; degree of cell-autonomous MDA5 toxicity uncertain |
| Oligodendrocyte | CL:0000128 | Relevant to white-matter injury; mechanism incompletely demonstrated |
| Monocyte | CL:0000576 | Peripheral innate immune/ISG-signature source |
| Macrophage | CL:0000235 | Model evidence of expansion and inflammatory infiltration |
| Dendritic cell | CL:0000451 | Expanded in MDA5-GOF mouse models; type-I-IFN amplification |
| T cell | CL:0000084 | Downstream adaptive immune activation |
| Regulatory T cell | CL:0000815 | Cell-specific MDA5-G821S expression can cause Treg loss and lethal autoimmunity in mice [130] |
| Vascular endothelial cell | CL:0000115 | Plausible vascular-injury target; direct causal hierarchy not fully established |
| Osteoblast/osteoclast | CL:0000062 / CL:0000092 | Likely altered in skeletal remodeling; definitive human cell-level data limited |
The validated clinical transcriptomic feature is the whole-blood ISG signature. In the 2020 cohort, 109/117 measurements from 51 mutation-positive people were elevated; 16 samples from seven clinically unaffected carriers were also positive. The six-gene score used IFI27, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1. [39]
No validated disease-specific human:
was identified. The absence of these data should be encoded as “not established,” rather than as a negative finding.
| Scale | Structure | Suggested ontology term | Typical disease |
|---|---|---|---|
| Organ | Brain | UBERON:0000955 | AGS-like neuroinflammation |
| Region | Basal ganglia | UBERON:0002420 | Calcification |
| Tissue | Cerebral white matter | UBERON:0002437 | Leukodystrophy/white-matter lesions |
| Organ | Spinal cord/corticospinal tracts | UBERON:0002240 | Spastic paraparesis, sometimes normal MRI |
| Organ | Skin | UBERON:0002097 | Chilblains, psoriasiform lesions |
| Organ | Liver | UBERON:0002107 | Hepatitis, transaminitis or isolated disease |
| Structure | Aorta | UBERON:0000947 | Progressive calcification/stenosis |
| Structure | Aortic and mitral valves | UBERON:0002137 and valve-specific child terms | Calcification |
| Organ | Heart | UBERON:0000948 | Valvular disease, model myocarditis/fibrosis |
| Organ | Lung/pulmonary vasculature | UBERON:0002048 | Rare pulmonary hypertension |
| Tissue | Bone | UBERON:0002481 | Osteopenia, acro-osteolysis |
| Structure | Phalanges | UBERON:0001435 or specific digit-bone terms | Acro-osteolysis, widened marrow cavities |
| Organ | Tooth/periodontium | UBERON:0001091 | Delayed eruption, short roots, resorption and tooth loss |
| Organ | Eye/anterior chamber | UBERON:0000970 | Glaucoma in SMS |
| Organ | Thyroid gland | UBERON:0002046 | Occasional hypothyroidism |
Neurological disease is generally bilateral/diffuse, but unilateral white-matter disease is documented; therefore lateralization is variable rather than defining. [39]
The active encephalopathic phase may be followed by relative neurological stabilization, but fixed disability remains. Spastic paraparesis and vascular/skeletal disease may continue to progress. Spontaneous molecular remission is not characterized. Earlier suppression of interferon signaling is biologically more likely to prevent injury than to reverse calcification, atrophy or established leukodystrophy.
| Characteristic | Current knowledge |
|---|---|
| Inheritance | Autosomal dominant, monoallelic GOF |
| Recurrence if a parent is heterozygous | 50% transmission probability per pregnancy |
| De novo disease | Common, particularly severe AGS presentations |
| Penetrance | Incomplete: 10/74 carriers, 13.5%, asymptomatic in the largest cohort [31] |
| Expressivity | Extremely variable, including within the same family |
| Sex ratio | No reliable sex bias established |
| Anticipation | Not demonstrated |
| Germline mosaicism | Possible; paternal somatic/germline mosaicism documented [29] |
| Founder effects | None established |
| Carrier frequency | Not reliably measurable; pathogenic alleles individually ultra-rare |
| Consanguinity | Not etiologically relevant to dominant GOF, except in differential diagnoses |
| Prevalence/incidence | Unknown; no robust cases-per-100,000 estimate |
| Geography/ethnicity | Worldwide cases; no confirmed high-risk ancestry |
More than 500 AGS patients of all molecular subtypes have been described, but this is not an IFIH1 prevalence estimate. [136] In one Italian molecular cohort IFIH1 accounted for 11–12% of AGS, versus approximately 3% in an earlier international cohort; this variation likely reflects ascertainment and small samples rather than true geographic prevalence. [141]
| Test | Expected finding/use |
|---|---|
| Blood six-gene ISG panel | Elevated IFI27, IFI44L, IFIT1, ISG15, RSAD2 and SIGLEC1; highly useful but not perfectly sensitive or specific |
| CSF cell count | Lymphocytosis, especially early |
| CSF IFN-α and neopterin | May be elevated; normal values do not exclude disease [22] |
| CBC | Thrombocytopenia in congenital disease; cytopenias may also reflect treatment |
| Liver enzymes/thyroid tests/urinalysis | Screen systemic involvement and differential diagnoses |
| Autoantibodies/complement | Indicated where lupus-like disease is suspected |
| Brain CT | Most sensitive routine test for intracranial/basal-ganglia calcification |
| Brain MRI | White-matter disease, atrophy, developmental abnormalities; may be normal in spastic paraparesis |
| Echocardiography | Valve calcification/stenosis, ventricular function, pulmonary pressure |
| ECG | Baseline and cardiac surveillance |
| CT or vascular imaging | Define aortic calcification when SMS phenotype suspected |
| Dental panoramic imaging | Eruption, roots, alveolar bone and resorption |
| Skeletal radiography/DXA | Acro-osteolysis, marrow-cavity widening, osteopenia |
| Ophthalmology | Glaucoma screening |
| EEG | If seizures or episodic altered awareness; no disease-specific electrophysiological signature |
| Skin biopsy | Nonspecific inflammatory/vasculopathic findings; not diagnostic |
| Brain biopsy | Not recommended for routine diagnosis |
| Modality | Utility |
|---|---|
| Interferonopathy/AGS panel | Preferred when phenotype and IFN signature are suggestive; include IFIH1, TREX1, RNASEH2A/B/C, SAMHD1, ADAR, RNU7-1, LSM11 and relevant phenocopy genes |
| Single-gene IFIH1 sequencing | Appropriate for a highly characteristic familial phenotype or known family variant |
| Trio WES | Effective for detecting de novo coding GOF variants |
| WGS | Useful after negative panel/WES, for noncoding, mosaic and structural possibilities; still requires functional interpretation |
| CNV analysis/CMA | Low expected yield for the canonical disorder but useful in unexplained developmental disease |
| Karyotype/FISH | Not routine |
| mtDNA testing | Only if mitochondrial differential remains |
| Repeat-expansion testing | Not indicated for the canonical disorder |
| RNA sequencing | Research/adjunctive utility; blood ISG qPCR/NanoString is presently more established |
| Prenatal/PGT testing | Feasible when a familial pathogenic variant is known |
A normal parental phenotype does not establish that a familial variant is benign. Test both parents molecularly and, if indicated, assess their interferon signatures.
| Differential | Distinguishing considerations |
|---|---|
| Other genetic AGS subtypes | Usually TREX1, RNASEH2A/B/C, SAMHD1, ADAR, RNU7-1 or LSM11; often recessive except selected TREX1/ADAR mechanisms |
| DDX58-related atypical Singleton–Merten syndrome | RIG-I rather than MDA5; overlapping calcific/dental phenotype |
| STING-associated vasculopathy (SAVI) | Severe early vasculitic skin and lung disease; TMEM173 variants |
| CANDLE/PRAAS | Lipodystrophy, panniculitis, proteasome-gene defects |
| Congenital infection/TORCH | Positive pathogen testing; AGS often mimics infection but cultures/PCR are negative |
| Genetic leukodystrophies | Usually no persistent type-I-IFN signature |
| Cerebral palsy | Nonprogressive injury; does not explain IFN signature, chilblains or familial calcification |
| Hereditary spastic paraplegia | Can closely mimic IFIH1 paraparesis; test interferon signature and IFIH1 |
| Familial brain calcification | Calcification without typical inflammatory signature or systemic AGS/SMS manifestations |
| Monogenic SLE | Overlap is genuine; IFIH1 GOF can itself produce lupus-like disease |
| Primary immunodeficiency from IFIH1 loss of function | Recurrent/severe RNA-virus infection rather than GOF interferonopathy |
No universally accepted stand-alone clinical diagnostic criteria exist; diagnosis is clinicomolecular.
No reliable 5- or 10-year survival statistic is available.
In the largest IFIH1 cohort, six symptomatic patients died: five had severe disease apparent at or soon after birth, and one developed regression at 15 months and died at age 16 from sudden cardiorespiratory arrest with pulmonary hypertension found at autopsy. [39][143]
Important morbidity includes:
Poor prognostic indicators: prenatal/congenital presentation, early rapid regression, severe microcephaly, extensive atrophy/white-matter disease, cardiopulmonary disease, and delayed control of active inflammation.
Relatively favorable indicators: later isolated paraparesis, preserved cognition, absence of structural CNS injury and sustained response to pathway-directed therapy. These are descriptive rather than validated predictors.
The blood ISG score is a pharmacodynamic biomarker, but its quantitative value as a long-term prognostic marker is not established; asymptomatic carriers may have persistently high scores.
There is no approved IFIH1-corrective treatment and no evidence-based surgical cure. A reasonable expert pathway is:
| Intervention | Mechanism/use | Evidence and outcomes | Suggested NCIT term |
|---|---|---|---|
| Baricitinib | Oral JAK1/JAK2 inhibitor; blocks signaling downstream of IFNAR | In an open-label expanded-access AGS cohort of 35, doses were 0.1–0.6 mg/kg/day; reduced skin inflammation and some patients gained milestones. Risks included thrombocytosis, leukopenia and infection. Cohort was genetically heterogeneous and included eight IFIH1 cases in one review summary. [18][155] | NCIT:C127012, Baricitinib |
| Ruxolitinib | JAK1/JAK2 inhibitor | Individual IFIH1 cases showed reduced blood/CSF inflammatory markers, improved motor scores or developmental gains; two siblings with paternal mosaic disease had marked ISG-score reduction on 0.5–0.75 mg/kg. Evidence remains uncontrolled. [18][29] | NCIT:C77861, Ruxolitinib |
| Tofacitinib | JAK1/JAK3-predominant inhibitor | Case-level interferonopathy evidence; little IFIH1-specific outcome evidence | NCIT:C95829, Tofacitinib |
| Corticosteroids | Broad anti-inflammatory therapy | May transiently improve fever/irritability; chronic neurological efficacy poor and toxicity substantial | NCIT:C211, Corticosteroid |
| IV immunoglobulin | Immunomodulation | Temporary benefit reported in an IFIH1 child before/around JAK therapy; not established disease modification | NCIT:C270, Intravenous Immunoglobulin |
| Antispasticity therapy | Baclofen, botulinum toxin, benzodiazepines as clinically indicated | Symptomatic; no IFIH1-specific trials | NCIT intervention terms for individual agents |
| Antidystonia/antiepileptic therapy | Individualized | Symptom control only | Drug-specific NCIT term |
| Bisphosphonate/bone-health therapy | Osteoporosis/fracture management | No controlled SMS1 evidence; specialist-directed | NCIT:C1599, Bisphosphonate |
| Dental rehabilitation | Periodontal treatment, prosthetics/implants where feasible | Essential for function; progressive alveolar/root loss complicates management | NCIT:C15329, Dental Procedure |
| Cardiac/vascular intervention | Valve replacement or treatment of stenosis where indicated | Organ-directed; no standardized IFIH1 outcome series | NCIT:C80473 or procedure-specific term |
| PT/OT/speech/feeding therapy | Prevent contracture, preserve mobility and communication; augmentative communication | Standard supportive care, although disease-specific trials absent | NCIT:C15311 Rehabilitation Therapy; NCIT:C15903 Physical Therapy |
Before and during JAK inhibition, screen for tuberculosis and hepatitis as locally recommended, update non-live vaccines where possible, and monitor infection, CBC, hepatic/renal function and thrombosis risk. Live-vaccine decisions require specialist assessment.
| Trial | Intervention and population | Status/relevance |
|---|---|---|
| NCT03921554 | Baricitinib in AGS; primary outcome change/stability on AGS scale at 52 weeks; secondary ISG and GMFM-88 outcomes | Directly relevant, genetically heterogeneous AGS [153] |
| NCT01724580 | Compassionate-use baricitinib for interferonopathies including AGS | Generated expanded-access experience [162] |
| NCT04517253 | Japanese adults/children with NNS/CANDLE, SAVI or AGS; individualized baricitinib, approximately 6–8 mg daily in AGS arm | Long-term, multi-disease study [151] |
| NCT06898372 | Retrospective Italian multicenter comparison of JAK1/2-treated and untreated AGS/related interferonopathy patients | Began 2025; planned approximately 24 participants [152] |
No IFIH1-directed gene replacement, CRISPR editing, ASO, siRNA or cell therapy is in established clinical use. Because disease is dominant GOF, successful genetic therapy would likely require allele-specific silencing or correction rather than simple gene addition.
The occurrence of a de novo mutation cannot currently be prevented by lifestyle modification. For known familial disease:
can reduce recurrence according to family preferences.
Routine vaccination remains important, particularly before immunosuppression. There is no IFIH1-specific vaccine or antimicrobial prophylaxis. Live vaccines may be contraindicated or deferred during significant JAK inhibition according to local guidance.
No well-validated naturally occurring companion-animal or livestock equivalent caused by spontaneous IFIH1 GOF was identified in OMIA. The disorder is not infectious and has no zoonotic or cross-species transmission risk.
| Species | Taxon | Orthologue/resource | Relevance |
|---|---|---|---|
| Human | NCBI Taxon 9606 | IFIH1, NCBI Gene 64135 | Natural disease |
| Mouse, Mus musculus | 10090 | Ifih1, NCBI Gene 71586, MGI:1918836 | Experimental GOF and knockout models [91] |
| Zebrafish, Danio rerio | 7955 | ifih1, ZFIN-linked orthologue | Transgenic p.Arg742His model corresponding to human p.Arg779His |
| Rat, Rattus norvegicus | 10116 | Ifih1 orthologue | Conserved antiviral sensing; no established natural IFIH1 syndrome |
| Pig, Sus scrofa | 9823 | IFIH1, NCBI Gene 100101927 | Conserved innate antiviral sensor [48] |
MDA5-dependent dsRNA sensing is evolutionarily conserved among jawed vertebrates, but species differ in interferon development, ligand exposure and tissue response. Consequently, animal models often reproduce systemic inflammation better than human neurological disability.
| Model | Construction | Recapitulated features | Limitations and applications |
|---|---|---|---|
| Ifih1 G821S/+ mouse | ENU-induced constitutively active MDA5 missense variant | Systemic IFN signature, growth retardation, early death, lupus-like nephritis, dermatitis, autoantibodies, liver/skin inflammation and skeletal abnormalities [127][128] | CNS phenotype is subtle relative to severe human AGS; useful for systemic autoimmunity, bone disease and pathway dissection |
| Human MDA5-R822Q BAC-transgenic mouse | Human SMS-associated p.Arg822Gln transgene | Cardiac inflammation/fibrosis, enlarged aortic valve, aortic calcification, mild skeletal abnormalities and adaptive immune activation [121][126] | Transgene dosage may not reproduce human heterozygosity; limited neurophenotype |
| R822Q plus poly(I:C) mouse | Synthetic dsRNA challenge | Exacerbated inflammation and mortality; rescue on Mavs-null or Ifnar-null backgrounds | Strong trigger may exceed physiological viral exposure; excellent causal test of MDA5→MAVS→IFNAR dependence |
| MDA5-G821S Treg-specific mouse | Conditional GOF in regulatory T cells | Treg apoptosis/loss and lethal systemic autoimmunity | Cell-restricted model, not full human disease; identifies immune-cell contribution [130] |
| Tg(ifih1 p.Arg742His) zebrafish | Overexpressed zebrafish mutant corresponding to human p.Arg779His | Systemic inflammation and enhanced IFN signature after suboptimal poly(I:C); visible nfkb:eGFP and isg15:eGFP reporter activation [106][112] | Overexpression rather than endogenous knock-in; fish neuroanatomy and adaptive immunity differ |
| Zebrafish drug-screening model | Same model treated with compounds | Baricitinib reduced inflammation and ISG expression | Preclinical pharmacodynamic evidence, not proof of human clinical efficacy [107] |
| HEK293T IFNβ-reporter system | Expression of wild-type or mutant IFIH1, ± poly(I:C) | Measures basal and ligand-induced IFNβ promoter activation | Artificial expression and non-native cell context; useful for VUS functional classification |
| Purified-protein/structural systems | RNA binding, ATPase and filament assays | Tests increased RNA affinity, reduced ATP hydrolysis or slower disassembly | Does not reproduce tissue-level disease |
| Patient-derived cells/iPSCs | Fibroblasts, blood cells or neural progenitor systems | Can assess endogenous ISG response and drug suppression | Few IFIH1-specific standardized lines; cellular phenotype may depend on differentiation and baseline IFN state |
2023 model-paper quote: RNA sequencing of mutant zebrafish “revealed a systemic inflammation and IFN signature upon a suboptimal poly I:C induction compared with wild-type larvae.” [Bernal-Bermúdez et al., Frontiers in Immunology, 24 November 2023, PMID: 38077314] [106]
Model resources include MGI/IMSR/MMRRC for mouse alleles—mouse Ifih1 is MGI:1918836 and an Ifih1 resource is listed by MMRRC—and ZFIN for zebrafish lines and publications. [56][96][120]
The most important practical interpretation is that a rare IFIH1 variant must be evaluated in the joint context of phenotype, inheritance, interferon signature and functional signaling—not by computational pathogenicity prediction alone.
Checked with linkml-reference-validator 0.3.0.
| Outcome | Count |
|---|---|
| References checked | 25 |
| Resolved | 25 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 1 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 0 |
| References weighed for topical relevance | 25 |
| On topic | 9 |
| Off topic | 1 |
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
DOI:10.1007/s12688-026-00957-1 (1 mention) - Januskinase-Inhibitoren bei InterferonopathienWeighed against this report's own most characteristic terms: disease, ifih1, gof, established, ags, variant, mda5, dental, phenotype, inflammation, cohort, signaling, interferon, gene, signature, ifn, calcification, inflammatory, infection, skeletal.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 89 |
| Resolved | 84 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 1 |
| Unverifiable | 4 |
| Terms whose name was checked | 25 |
| Terms named correctly | 16 |
| Terms named as a different term | 2 |
| Terms whose name is worth a second look | 7 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
UBERON:0002048 (1 mention) - the report calls it "Lung/pulmonary vasculature"; UBERON calls it lungUBERON:0000970 (1 mention) - the report calls it "Eye/anterior chamber"; UBERON calls it eyeThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0039528 (GO_0039528) (1 mention) - replaced by GO:0002753The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
MONDO:0014367 (1 mention) - the report calls it "Aicardi–Goutières syndrome 7"; MONDO calls it Aicardi-Goutieres syndrome 7CL:0000115 (1 mention) - the report calls it "Vascular endothelial cell"; CL calls it endothelial cellUBERON:0002420 (1 mention) - the report calls it "Basal ganglia"; UBERON calls it basal ganglion, and lists "basal ganglia" among its other namesUBERON:0002240 (1 mention) - the report calls it "Spinal cord/corticospinal tracts"; UBERON calls it spinal cord, and lists "spinal cord structure" among its other namesUBERON:0002097 (1 mention) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other namesUBERON:0002481 (1 mention) - the report calls it "Bone"; UBERON calls it bone tissue, and lists "bone" among its other namesUBERON:0001091 (1 mention) - the report calls it "Tooth/periodontium"; UBERON calls it calcareous tooth, and lists "tooth" among its other namesTerms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.