👪

Inheritance

2

Autosomal recessive HP:0000007

The complete deficiency results from biallelic IFNAR1 loss-of-function variants. Reported genotypes include homozygosity in a consanguineous kindred, compound heterozygosity, and homozygosity for the Western Polynesian founder nonsense allele p.Glu386*.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:31270247 SUPPORT Human Clinical

"The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations."

Two independent biallelic genotypes in unrelated probands establish the recessive basis of the complete deficiency.

Autosomal dominant (negative dominance) HP:0000006

A separate, clinically distinct group of IFNAR1 alleles acts dominantly in the heterozygous state. The dominance is mediated by negative dominance rather than haploinsufficiency, and the resulting defect is partial and subtype-selective: responses to IFN-alpha and IFN-omega are impaired while responses to IFN-beta are preserved. This is recorded as a second inheritance mode rather than folded into the recessive entry, because both the mechanism and the severity differ.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:39680367 SUPPORT In Vitro

"Negative dominance, rather than haploinsufficiency, accounts for this dominance."

Names the specific dominance mechanism, which is what separates this arm from simple carrier status for a recessive null.

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Mechanistic Hypotheses

1

Type I interferon redundancy explains survival to adulthood with a complete signalling null

narrow_phenotype_ifn_redundancy EMERGING

Evidence balance 3 support

Complete IFNAR1 deficiency abolishes the type I interferon response in vitro, yet the reported patients were healthy until a specific viral challenge and some have reached their fifth and sixth decades. The proposed explanation is that human type I interferons are largely redundant for protective immunity under everyday conditions, with other cell-intrinsic antiviral mechanisms compensating, and become indispensable only on systemic challenge with a replicating attenuated virus or a particularly virulent one. The competing reading - that ascertainment favours the catastrophic presentations while milder susceptibility goes unrecorded - is not excluded, and the estimated homozygote frequency in Samoa is high enough that undiagnosed individuals are expected. Which reading is right determines whether population screening of the founder allele identifies people at risk or mostly people who will never present.

Show evidence (3 references)

PMID:39680367 SUPPORT Human Clinical

"Surprisingly, the patients concerned had managed to live to the age of 1–38 years without experiencing other unusually severe viral illnesses, and some are still alive at the age of 45–55 years."

The central observation the hypothesis rests on - a complete signalling defect without broad clinical susceptibility.

PMID:39680367 SUPPORT Human Clinical

"The frequency of homozygotes in these isolated populations has been estimated at 1/6,450 in Samoa and 1/1,539 in Greenland, and these individuals appear to be prone to only a few severe viral diseases."

The population-genetic side of the same argument, and the reason the ascertainment alternative cannot be dismissed.

PMID:33729549 SUPPORT Other

"A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated."

A review stating the redundancy reading directly, and framing it as an emerging picture rather than a settled one - which is why this entry records the hypothesis as EMERGING. The same review's human-versus-mouse comparison is the reason mouse type I interferon data cannot settle the question.

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Pathophysiology

9

IFNAR1 Loss of Function

Biallelic IFNAR1 variants abolish a functional low-affinity chain of the type I interferon receptor. Reported lesions include nonsense, frameshift and essential splice-site alleles that remove or truncate the protein, and the Western Polynesian founder nonsense allele c.1156G>T (p.Glu386*). Because IFNAR2 and the downstream JAK-STAT components are intact, the lesion is confined to assembly of a competent IFNAR1-IFNAR2 heterodimer.

Genetic context functional_impact_category: LOSS_OF_FUNCTION

Downstream

Absent Type I Interferon Receptor Signaling With no functional IFNAR1 chain there is no competent receptor to transduce an IFN-alpha/beta signal, so loss of the protein translates directly into loss of signalling.

Show evidence (2 references)

PMID:31270247 SUPPORT Human Clinical

"The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations."

Identifies loss-of-function IFNAR1 alleles as the molecular lesion in the index patients.

PMID:42116640 SUPPORT Human Clinical

"the regionally relevant pathogenic IFNAR1 variant c.1156G>T, p.Glu386*"

Names the founder nonsense allele that accounts for most disease in the Western Polynesian population.

Absent Type I Interferon Receptor Signaling

With no functional receptor, type I interferons cannot initiate JAK-STAT signalling. Patient fibroblasts are unresponsive to recombinant IFN-alpha2 and IFN-beta alike, so the block is complete rather than partial and is not specific to any one interferon subtype. The defect is cell-intrinsic and reversible: transduction with wild-type IFNAR1 restores responsiveness, which is what establishes the variant as causal rather than merely associated.

Type I interferon-mediated signaling GO:0060337 ↓ DECREASED Cellular response to type I interferon GO:0071357 ↓ DECREASED

Downstream

Failure of JAK-STAT ISGF3 Activation Signalling begins when ligand binding assembles a ternary complex that brings the receptor-associated kinases into proximity. With no competent receptor that assembly never happens, so the kinase step is never reached.

Show evidence (2 references)

PMID:32972995 SUPPORT In Vitro

"the patient’s SV40-transformed fibroblast (SV40-Fib) cells did not respond to IFN-α2 or IFN-β"

Establishes complete unresponsiveness to type I interferon in patient-derived fibroblasts.

PMID:35442418 SUPPORT In Vitro

"The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β)."

Independent confirmation in the Polynesian founder cohort, and it names all three interferon subtypes - which is what makes the block complete rather than subtype-selective, in contrast to the dominant allele class below.

Failure of JAK-STAT ISGF3 Activation

The step between the receptor and the genome. In a competent cell, ternary complex formation brings JAK1 and TYK2 together; they cross-phosphorylate each other, the receptor chains and STAT1/STAT2, and the phosphorylated STATs assemble with IRF9 into ISGF3, which binds interferon-stimulated response elements. None of this occurs without a receptor to nucleate it. The node is recorded separately because it is where the diagnostic assay reads out: phospho-STAT1 flow cytometry measures this step, not the one above or below it.

Type I interferon-mediated signaling GO:0060337 ↓ DECREASED

Downstream

Failure of Interferon-Stimulated Gene Induction ISGF3 is the transcription factor that induces interferon-stimulated genes, so an unassembled complex leaves them uninduced.

Show evidence (1 reference)

PMID:38608537 SUPPORT Other

"This results in close proximity of the intracellularly associated kinases JAK1 and TYK2, which cross phosphorylate each other, the associated receptor chains, and signal transducer and activator of transcriptions"

Describes the kinase and STAT steps this node represents. Graded OTHER because it is a structure-function review rather than primary patient or model data.

Failure of Interferon-Stimulated Gene Induction

Interferon-stimulated genes encode the effectors that make a cell hostile to viral replication. Because they are never induced, the cell-intrinsic antiviral state cannot be established at all rather than merely being blunted, leaving infected cells with no interferon-dependent restriction of incoming virus.

Antiviral defense response GO:0051607 ↓ DECREASED

Downstream

Unrestricted Viral Replication in Permissive Cells With no interferon-induced restriction factors, permissive cells support viral replication that an interferon-competent host would contain.

Unrestricted Viral Replication in Permissive Cells

Without an interferon-dependent brake, a replicating virus that would be contained in a healthy host expands unchecked. The causal direction is established by rescue rather than by correlation: transducing wild-type IFNAR1 into patient-genotype cells restores control of infection.

Downstream

Disseminated Viral Disease Uncontained replication in permissive cells is what converts a limited, immunising exposure into systemic viral disease.

Virus-Induced Systemic Hyperinflammation A large, uncontrolled viral burden drives the hyperinflammatory syndrome. The link is recorded as indirect because the intervening immune amplification is not itself characterised in IFNAR1-deficient patients.

Show evidence (2 references)

PMID:32972995 SUPPORT In Vitro

"SARS-CoV-2 infection levels were higher in mutant cells than in cells from healthy donors, and transduction of WT IRF7 or IFNAR1 rescued their defects"

Complementation rescue demonstrates that the excess viral replication is caused by the IFNAR1 lesion itself.

PMID:31270247 SUPPORT In Vitro

"The patients' fibroblast phenotypes are rescued with WT IFNAR1"

The same rescue result in the index patients' own cells.

Disseminated Viral Disease

The organism-level consequence: a replicating virus spreads beyond the tissue it would normally be confined to. In the index cases this was severe measles vaccine disease and yellow fever viscerotropic disease; in later cohorts it extends to naturally circulating viruses.

Show evidence (1 reference)

PMID:42116640 SUPPORT Human Clinical

"IFNAR1 deficiency confers an increased risk of severe and life-threatening infections caused by naturally circulating viruses including influenza, SARS-CoV-2, herpes simplex virus, respiratory syncytial virus (RSV), arboviruses and viruses in live attenuated vaccines (LAVs) including..."

The consensus statement of the disease's viral disease spectrum, covering both vaccine and wild-type viruses.

Virus-Induced Systemic Hyperinflammation

A hyperinflammatory syndrome overlapping haemophagocytic lymphohistiocytosis, described in the Oceania guideline under the name virus-induced systemic hyperinflammation. It is a major contributor to mortality and is a distinct clinical problem from the viral disease that triggers it, which is why it is modelled as its own node rather than as a severity grade of the one above.

Show evidence (2 references)

PMID:42116640 SUPPORT Human Clinical

"Complications including virus induced systemic hyperinflammation (VISH) are associated with significant mortality."

Establishes the syndrome as a recognised and lethal complication of the disease.

PMID:42097348 SUPPORT Human Clinical

"A novel homozygous IFNAR1 copy number variation (CNV Δ3-4-5) in the proband (heterozygous in five of 11 unaffected relatives) caused receptor dysfunction, suppressing baseline IFN responses but triggering inflammasome-driven innate cell activation upon YFV-17D exposure."

Supplies a candidate mechanism for the hyperinflammation rather than only its existence - the same receptor defect that removes the baseline interferon response permits inflammasome-driven innate activation when the vaccine virus is encountered. This is a single family, so it is a lead rather than an established mechanism.

IFNAR1 Negative Dominance

A mechanistically separate arm. Certain in-frame IFNAR1 alleles are expressed and interfere with the wild-type product, so heterozygotes show a defect rather than being silent carriers. The dominance is by negative dominance and not by haploinsufficiency, and the resulting lesion is partial and subtype-selective rather than a complete signalling null.

Genetic context functional_impact_category: DOMINANT_NEGATIVE

Downstream

Subtype-Selective Loss of IFN-alpha and IFN-omega Responsiveness The interfering allele impairs signalling through the receptor for the leukocyte-derived interferons while leaving the IFN-beta response intact.

Show evidence (1 reference)

PMID:39680367 SUPPORT In Vitro

"Negative dominance, rather than haploinsufficiency, accounts for this dominance."

Identifies the molecular basis of dominance for this allele class.

Subtype-Selective Loss of IFN-alpha and IFN-omega Responsiveness

A partial cellular defect, distinct from the complete block of the recessive disease. Responses to IFN-alpha and IFN-omega - the abundant, leukocyte-derived type I interferons - are impaired or abolished, while the IFN-beta response is preserved. Carriers of these alleles are prone to viral disease, which is what makes the residual IFN-beta arm insufficient on its own.

Type I interferon-mediated signaling GO:0060337 ↓ DECREASED

Downstream

Unrestricted Viral Replication in Permissive Cells The partial signalling defect still leaves permissive cells unable to restrict some viruses, converging on the same downstream node as the complete block.

Show evidence (1 reference)

PMID:39680367 SUPPORT In Vitro

"We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β."

Defines the allele class and the exact shape of the signalling defect it produces.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

5

Blood 1

Virus-induced systemic hyperinflammation Hemophagocytosis HP:0012156

Show evidence (1 reference)

PMID:42116640 SUPPORT Human Clinical

"Complications including virus induced systemic hyperinflammation (VISH) are associated with significant mortality."

Establishes the hyperinflammatory complication. The binding to Hemophagocytosis is the closest available HPO term for the syndrome the guideline names; HPO has no term for virus-induced systemic hyperinflammation as such.

Immune 4

Disseminated infection with live vaccine virus HP:0031697

Show evidence (1 reference)

PMID:31270247 SUPPORT Human Clinical

"We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr."

The two index presentations, both after live attenuated viral vaccination in previously healthy children.

Severe viral infection HP:0031691

Show evidence (1 reference)

PMID:42116640 SUPPORT Human Clinical

"IFNAR1 deficiency confers an increased risk of severe and life-threatening infections caused by naturally circulating viruses including influenza, SARS-CoV-2, herpes simplex virus, respiratory syncytial virus (RSV), arboviruses and viruses in live attenuated vaccines (LAVs) including..."

The consensus statement of the natural-virus susceptibility spectrum.

Life-threatening COVID-19 pneumonia HP:0002090

Show evidence (3 references)

PMID:32972995 SUPPORT Human Clinical

"Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection."

Places IFNAR1 deficiency, one of the 13 loci tested, among the inborn errors underlying critical COVID-19 in previously healthy people. The snippet names the class rather than the gene, so the gene-specific attribution rests on the same paper's finding of homozygous IFNAR1 among the four biallelic patients.

PMID:35708626 SUPPORT Human Clinical

"X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies"

Names IFNAR1 deficiency explicitly among children hospitalised with COVID-19 pneumonia, which the class-level snippet above does not.

PMID:35708626 SUPPORT In Vitro

"Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2."

The cellular counterpart of the clinical finding, in the same cohort's cells.

Multisystem inflammatory syndrome in children Increased inflammatory response HP:0012649

Show evidence (2 references)

PMID:35091979 SUPPORT Human Clinical

"We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C."

The single case establishing this presentation, together with the fatal outcome. HPO has no term for multisystem inflammatory syndrome in children, so the binding is to the closest available concept and the specificity is carried by the name and description.

PMID:35091979 SUPPORT Human Clinical

"Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C."

The authors distinguish what they confirm from what they suggest, and that distinction is preserved here rather than flattened.

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Genetic Associations

1

IFNAR1 (Causal)

Gene: IFNAR1 hgnc:5432

Show evidence (7 references)

PMID:31270247 SUPPORT Human Clinical

"The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations."

Establishes IFNAR1 as the causal gene for the recessive complete deficiency.

PMID:39680367 SUPPORT In Vitro

"Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%)."

Documents the dominant allele class and the population frequency of its commonest member.

PMID:35442418 SUPPORT Human Clinical

"All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*)."

Establishes p.Glu386* as a recurrent founder allele shared across five unrelated kindreds.

+ 4 more references

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Medical Actions

3

Avoidance of Live Attenuated Viral Vaccines

Action: avoidance of live attenuated viral vaccination Ontology label: Preventive Intervention NCIT:C15843

Platform: Behavioral / lifestyle

The single most important intervention once the diagnosis is known. Live attenuated viral vaccines are attenuated only relative to an interferon-competent host, and in IFNAR1 deficiency they cause disseminated, potentially fatal infection. This is the agents-and-circumstances-to-avoid consideration for this disease, and it is the reason the Oceania guideline is built around early identification before routine immunisation.

Mechanism Target:

Unrestricted Viral Replication in Permissive Cells — Withholding the live vaccine removes the replicating viral challenge that the absent interferon response cannot contain.

Show evidence (1 reference)

PMID:42116640 SUPPORT Human Clinical

"This document outlines expert consensus regarding early identification, diagnostic workup and management of IFNAR1 deficiency in Australia, Aotearoa New Zealand and Western Pacific nations."

The existence and stated purpose of a regional consensus guideline built on early identification. The specific avoidance recommendation is in the guideline body rather than the abstract, so this snippet supports the management framework rather than quoting the recommendation itself.

Supportive and Antiviral Management of the Viral Episode

Action: Supportive Care NCIT:C15747

Platform: Other

There is no disease-specific pharmacotherapy. Management during an episode is organ support and, where one exists for the virus concerned, directed antiviral therapy. One negative point is mechanistically important and worth stating explicitly: exogenous type I interferon is not a treatment here. The lesion is the receptor, so giving more ligand cannot restore signalling - this is the opposite of the situation in an interferon-production defect, where replacement is rational.

Mechanism Target:

Disseminated Viral Disease — Organ support and antiviral therapy act on the established viral disease rather than on the signalling defect that permitted it.

Show evidence (1 reference)

PMID:42116640 SUPPORT Human Clinical

"This document outlines expert consensus regarding early identification, diagnostic workup and management of IFNAR1 deficiency in Australia, Aotearoa New Zealand and Western Pacific nations."

The consensus management framework this treatment sits inside. The specific supportive-care detail is in the guideline body rather than the abstract, so this snippet establishes the framework rather than quoting the regimen.

Cascade and Pre-Vaccination Genetic Screening

Action: genetic screening Ontology label: Genetic Screening NCIT:C92803

Platform: Behavioral / lifestyle

The diagnosis is usually made after a catastrophic event, which is too late for the index patient but not for relatives. Screening at-risk relatives - and, in the populations carrying a founder allele, screening before live attenuated vaccination - is what converts this from a lethal disease into an avoidable one. This is the intervention the Oceania guideline is organised around.

Mechanism Target:

Disseminated Viral Disease — Identifying the genotype before exposure is what allows the triggering exposure to be withheld, so the screening acts by preventing the disease rather than treating it.

Show evidence (2 references)

PMID:42097348 SUPPORT Human Clinical

"Our findings advocate for precision vaccinology by screening relatives of AEFI-YF cases for type I IFN EIIs and auto-antibodies prior to live-attenuated vaccination."

The authors' explicit recommendation, arising from a family in which two of three affected siblings died.

PMID:35442418 SUPPORT Human Clinical

"Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses."

The population-targeted version of the same recommendation.

🌍

Environmental Factors

1

Live attenuated viral vaccination

The exposure that converts a clinically silent genotype into life-threatening disease. Both index patients were healthy until vaccination - one with measles vaccine at one year, one with yellow fever 17D at twelve. This is the gene-environment interaction that defines the disease's presentation, and it is why avoidance is the principal intervention.

Show evidence (1 reference)

PMID:31270247 SUPPORT Human Clinical

"We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr."

Documents the vaccine exposure preceding disease in both index patients.

Mechanism Target:

TRIGGERS Unrestricted Viral Replication in Permissive Cells — A replicating attenuated virus is the challenge the absent interferon response cannot contain, so the exposure initiates the mechanism rather than merely aggravating it.

Show evidence (1 reference)

PMID:31270247 SUPPORT Human Clinical

"Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals."

States the causal role of the vaccine exposure in previously healthy individuals.

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Diagnosis

3

Whole-Blood IP-10 Induction Assay

The functional confirmation, and the test that makes the diagnosis rather than merely suggesting it. Whole blood is stimulated with glycosylated IFN-alpha2, -beta or -omega and IP-10 (the product of the interferon-stimulated gene CXCL10) is measured; IFN-gamma is run in parallel as the type II control. In inherited IFNAR1 deficiency IP-10 is induced only by IFN-gamma, so a defect confined to the type I arm is demonstrated directly rather than inferred. The same assay separates the inherited defect from its acquired phenocopy, because a patient with neutralising autoantibodies still responds to the type I interferons their antibodies do not neutralise.

whole-blood IP-10 induction immunoassay NCIT:C25294

Show evidence (2 references)

PMID:39312669 SUPPORT Human Clinical

"In patients with inherited IFNAR1, IFNAR2, TYK2, or IRF9 deficiency, IP-10 is induced only by IFN-γ, whereas, in those with auto-Abs neutralizing specific type I IFNs, IP-10 is also induced by the type I IFNs not neutralized by the auto-Abs."

Names IFNAR1 deficiency explicitly and states the readout pattern that distinguishes it both from a healthy response and from the autoantibody phenocopy.

PMID:39312669 SUPPORT Human Clinical

"The measurement of type I and type II IFN-dependent IP-10 induction therefore constitutes a simple procedure for detecting rare inborn errors of the type I IFN response pathway and more common auto-Abs neutralizing type I IFNs."

The authors' statement of what the assay is for, covering both the inherited and acquired conditions.

Molecular Genetic Testing Including Copy-Number Analysis

Exome or genome sequencing, or an inborn-errors-of-immunity panel, establishes the genotype. Copy-number analysis has to be part of it rather than an add-on: two of the reported causal genotypes are structural - a large homozygous loss-of-function deletion and a multi-exon copy-number variant - and a sequencing-only workflow reports those patients as having no biallelic variant.

whole exome sequencing NCIT:C101295

Show evidence (2 references)

PMID:35091979 SUPPORT Human Clinical

"We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency."

A structural allele that establishes the diagnosis, and the reason copy-number analysis is not optional.

PMID:42097348 SUPPORT Human Clinical

"We conducted an integrative genetics and functional investigation of a Brazilian family with three siblings presenting AEFI-YF (two deceased), using whole exome sequencing (WES), and qPCR, molecular modeling, in vitro YFV-17D stimulation of leukocytes, cytokine quantification, immunophenotyping,..."

The diagnostic workflow in a family whose causal allele was a copy-number variant, showing sequencing and qPCR used together.

Differential Diagnosis Against Neutralizing Anti-Type-I-Interferon Autoantibodies

The acquired phenocopy, and the main differential. Autoantibodies neutralising type I interferons produce a functionally similar block without a genetic lesion, and they are far more common than the inherited disease - found in roughly one in ten patients with life-threatening COVID-19 in several cohorts. A functional assay alone cannot separate the two; the IP-10 pattern above and the genotype together can. Binding note: NCIT:C17455 (Enzyme Immunoassay) is the exact concept for this assay and for the one above, but it is not reachable from NCIT:C25218 and so fails the TreatmentActionTerm dynamic enum. Both are bound to the broader NCIT:C25294 (Laboratory Procedure) with the specificity carried in preferred_term.

autoantibody assay NCIT:C25294

Show evidence (2 references)

PMID:39680367 SUPPORT Other

"Patients with neutralizing auto-Abs against type I IFN can, thus, be considered to display autoimmune, partial phenocopies of AR IFNAR1 or IFNAR2 deficiency"

States the phenocopy relationship directly, and the word "partial" is why the assay above can discriminate them at all.

PMID:42524028 SUPPORT Human Clinical

"Autoantibodies neutralizing type I interferon (AAN-I-IFN) have been found in at least 10-15% of critical COVID-19 pneumonia cases in various studies across North and Latin America, Oceania, Europe, and Asia."

Quantifies how much commoner the phenocopy is than the inherited disease, which is what makes it the differential rather than a footnote.

📊

Prevalence

3

Western Polynesian ancestry

Birth Prevalence 16.7 per 100,000 live births 1–9 per 10,000 (births)

The guideline reports approximately one in six thousand live births affected in people of Western Polynesian ancestry, attributed to the founder allele p.Glu386*. Recorded here as 16.7 per 100,000 live births (1 in 6,000). This is a population-specific figure and must not be read as a worldwide rate, where the disease is very rare.

Show evidence (1 reference)

PMID:42116640 SUPPORT Human Clinical

"Autosomal recessive interferon alpha and beta receptor subunit 1 (IFNAR1) deficiency is a rare and heritable inborn error of immunity (IEI) predisposing individuals to severe and life-threatening viral infections. It is more common in people of Western Polynesian ancestry, with estimates of..."

The regional estimate is approximately one affected live birth in 6,000 among people of Western Polynesian ancestry, linked to homozygosity for IFNAR1 p.Glu386*. It is not a worldwide prevalence estimate.

Samoa

Point Prevalence 15.5 per 100,000 1–9 per 10,000

An independent estimate of the homozygote frequency in Samoa, 1 in 6,450, recorded as 15.5 per 100,000. It is reported as an estimated genotype frequency derived from allele frequency rather than as an ascertained case count, which is why it sits beside the guideline figure rather than replacing it.

Show evidence (1 reference)

PMID:39680367 SUPPORT Human Clinical

"The frequency of homozygotes in these isolated populations has been estimated at 1/6,450 in Samoa and 1/1,539 in Greenland"

The reported homozygote frequency estimate; the Greenland figure in the same sentence refers to IFNAR2, not IFNAR1.

Samoa and western Polynesia

Carrier Frequency Unknown

Reported as the minor allele frequency of the p.Glu386* founder variant, which is above 1 per cent in Samoa and is also present in the Cook, Society, Marquesas and Austral islands and Fiji, while being extremely rare or absent elsewhere including in other Pacific populations. This is an allele frequency, not a disease rate, and must not be read as one; it sits alongside the two genotype-level estimates above as the observation those estimates are derived from.

Show evidence (1 reference)

PMID:35442418 SUPPORT Human Clinical

"Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region."

The reported founder allele frequency and its geographic distribution.

{ }

Source YAML

click to show

name: IFNAR1 Deficiency
creation_date: "2026-09-13T00:00:00Z"
category: Mendelian
synonyms:
- immunodeficiency 106
- IMD106
- immunodeficiency 106, susceptibility to viral infections
- IFNAR1-related immunodeficiency
- autosomal recessive complete IFNAR1 deficiency
- type I interferon receptor alpha chain deficiency
description: >-
  IFNAR1 deficiency (immunodeficiency 106; IMD106) is an inborn error of immunity
  caused by variants in IFNAR1, which encodes the low-affinity chain of the
  heterodimeric type I interferon (IFN-alpha/beta) receptor. In the autosomal
  recessive complete form, biallelic loss-of-function alleles leave cells unable
  to transduce any type I interferon signal, so the interferon-stimulated gene
  programme that establishes the cell-intrinsic antiviral state is never induced.

  The clinical phenotype is narrow rather than broadly infection-prone. The
  defining presentation is catastrophic disease on systemic challenge with a
  replicating attenuated virus - severe measles vaccine disease, or viscerotropic
  disease after yellow fever 17D - in children who had been entirely healthy until
  that exposure. Severe disease with naturally circulating viruses (influenza,
  SARS-CoV-2, herpes simplex virus, respiratory syncytial virus, arboviruses) and
  virus-induced systemic hyperinflammation are also described. Management centres
  on avoiding live attenuated viral vaccines once the diagnosis is known.

  Two features make this entry more than the IFNAR2 story with a different chain.
  First, a Western Polynesian founder allele, p.Glu386*, makes the recessive
  disease regionally common enough to have prompted a formal population-level
  diagnostic and management guideline. Second, IFNAR1 also carries dominant
  alleles that act by negative dominance and impair responses to IFN-alpha and
  IFN-omega while sparing IFN-beta - a partial, subtype-selective lesion with no
  counterpart in the recessive disease, and the reason this entry models two
  distinct molecular arms rather than one.
disease_term:
  preferred_term: IFNAR1 deficiency
  term:
    id: MONDO:0030970
    label: immunodeficiency 106, susceptibility to viral infections
parents:
- inborn error of immunity
- autosomal recessive disease
references:
- reference: PMID:42116640
  title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
inheritance:
- name: Autosomal recessive
  description: >-
    The complete deficiency results from biallelic IFNAR1 loss-of-function
    variants. Reported genotypes include homozygosity in a consanguineous kindred,
    compound heterozygosity, and homozygosity for the Western Polynesian founder
    nonsense allele p.Glu386*.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31270247
    reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations."
    explanation: Two independent biallelic genotypes in unrelated probands establish the recessive basis of the complete deficiency.
- name: Autosomal dominant (negative dominance)
  description: >-
    A separate, clinically distinct group of IFNAR1 alleles acts dominantly in the
    heterozygous state. The dominance is mediated by negative dominance rather than
    haploinsufficiency, and the resulting defect is partial and subtype-selective:
    responses to IFN-alpha and IFN-omega are impaired while responses to IFN-beta
    are preserved. This is recorded as a second inheritance mode rather than folded
    into the recessive entry, because both the mechanism and the severity differ.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Negative dominance, rather than haploinsufficiency, accounts for this dominance."
    explanation: Names the specific dominance mechanism, which is what separates this arm from simple carrier status for a recessive null.
pathophysiology:
- name: IFNAR1 Loss of Function
  description: >-
    Biallelic IFNAR1 variants abolish a functional low-affinity chain of the type I
    interferon receptor. Reported lesions include nonsense, frameshift and essential
    splice-site alleles that remove or truncate the protein, and the Western
    Polynesian founder nonsense allele c.1156G>T (p.Glu386*). Because IFNAR2 and the
    downstream JAK-STAT components are intact, the lesion is confined to assembly of
    a competent IFNAR1-IFNAR2 heterodimer.
  biological_scale: MOLECULAR
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Absent Type I Interferon Receptor Signaling
    causal_link_type: DIRECT
    description: >-
      With no functional IFNAR1 chain there is no competent receptor to transduce an
      IFN-alpha/beta signal, so loss of the protein translates directly into loss of
      signalling.
    evidence:
    - reference: PMID:32972995
      reference_title: "Inborn errors of type I IFN immunity in patients with life-threatening COVID-19."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "PHA-T cells from a patient with AR IFN-α/β receptor 1 (IFNAR1) deficiency had impaired IFNAR1 expression and responses to IFN-α2 or IFN-β"
      explanation: Couples the loss of IFNAR1 protein expression to loss of the interferon response in the same patient's cells.
  evidence:
  - reference: PMID:31270247
    reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations."
    explanation: Identifies loss-of-function IFNAR1 alleles as the molecular lesion in the index patients.
  - reference: PMID:42116640
    reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the regionally relevant pathogenic IFNAR1 variant c.1156G>T, p.Glu386*"
    explanation: Names the founder nonsense allele that accounts for most disease in the Western Polynesian population.
- name: Absent Type I Interferon Receptor Signaling
  description: >-
    With no functional receptor, type I interferons cannot initiate JAK-STAT
    signalling. Patient fibroblasts are unresponsive to recombinant IFN-alpha2 and
    IFN-beta alike, so the block is complete rather than partial and is not specific
    to any one interferon subtype. The defect is cell-intrinsic and reversible:
    transduction with wild-type IFNAR1 restores responsiveness, which is what
    establishes the variant as causal rather than merely associated.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Type I interferon-mediated signaling
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: Cellular response to type I interferon
    term:
      id: GO:0071357
      label: cellular response to type I interferon
    modifier: DECREASED
  downstream:
  - target: Failure of JAK-STAT ISGF3 Activation
    causal_link_type: DIRECT
    description: >-
      Signalling begins when ligand binding assembles a ternary complex that brings the
      receptor-associated kinases into proximity. With no competent receptor that
      assembly never happens, so the kinase step is never reached.
    evidence:
    - reference: PMID:38608537
      reference_title: "Structure-function of type I and III interferons."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Common to both are two distinct receptor chains (IFNAR1/IFNAR2 and IFNLR1/IL10R2), which form ternary complexes upon binding their respective ligands. This results in close proximity of the intracellularly associated kinases JAK1 and TYK2, which cross phosphorylate each other, the associated receptor chains, and signal transducer and activator of transcriptions, with the latter activating IFN-stimulated genes."
      explanation: >-
        States the mechanism the edge depends on - that receptor assembly is what
        juxtaposes JAK1 and TYK2. This is a structural review of the healthy pathway,
        not a study of IFNAR1-deficient patients, which is why it is graded OTHER.
  evidence:
  - reference: PMID:32972995
    reference_title: "Inborn errors of type I IFN immunity in patients with life-threatening COVID-19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the patient’s SV40-transformed fibroblast (SV40-Fib) cells did not respond to IFN-α2 or IFN-β"
    explanation: Establishes complete unresponsiveness to type I interferon in patient-derived fibroblasts.
  - reference: PMID:35442418
    reference_title: "A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β)."
    explanation: >-
      Independent confirmation in the Polynesian founder cohort, and it names all three
      interferon subtypes - which is what makes the block complete rather than
      subtype-selective, in contrast to the dominant allele class below.
- name: Failure of JAK-STAT ISGF3 Activation
  description: >-
    The step between the receptor and the genome. In a competent cell, ternary complex
    formation brings JAK1 and TYK2 together; they cross-phosphorylate each other, the
    receptor chains and STAT1/STAT2, and the phosphorylated STATs assemble with IRF9
    into ISGF3, which binds interferon-stimulated response elements. None of this
    occurs without a receptor to nucleate it. The node is recorded separately because
    it is where the diagnostic assay reads out: phospho-STAT1 flow cytometry measures
    this step, not the one above or below it.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Type I interferon-mediated signaling
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: DECREASED
  downstream:
  - target: Failure of Interferon-Stimulated Gene Induction
    causal_link_type: DIRECT
    description: >-
      ISGF3 is the transcription factor that induces interferon-stimulated genes, so an
      unassembled complex leaves them uninduced.
    evidence:
    - reference: PMID:38608537
      reference_title: "Structure-function of type I and III interferons."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "signal transducer and activator of transcriptions, with the latter activating IFN-stimulated genes"
      explanation: The final step of the canonical pathway, which is what fails when the complex does not form.
  evidence:
  - reference: PMID:38608537
    reference_title: "Structure-function of type I and III interferons."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This results in close proximity of the intracellularly associated kinases JAK1 and TYK2, which cross phosphorylate each other, the associated receptor chains, and signal transducer and activator of transcriptions"
    explanation: >-
      Describes the kinase and STAT steps this node represents. Graded OTHER because it
      is a structure-function review rather than primary patient or model data.
- name: Failure of Interferon-Stimulated Gene Induction
  description: >-
    Interferon-stimulated genes encode the effectors that make a cell hostile to
    viral replication. Because they are never induced, the cell-intrinsic antiviral
    state cannot be established at all rather than merely being blunted, leaving
    infected cells with no interferon-dependent restriction of incoming virus.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Antiviral defense response
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  downstream:
  - target: Unrestricted Viral Replication in Permissive Cells
    causal_link_type: DIRECT
    description: >-
      With no interferon-induced restriction factors, permissive cells support viral
      replication that an interferon-competent host would contain.
    evidence:
    - reference: PMID:31270247
      reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN."
      explanation: Shows that the cells' susceptibility is not rescued by adding interferon, which locates the failure at the receptor rather than at interferon production.
- name: Unrestricted Viral Replication in Permissive Cells
  description: >-
    Without an interferon-dependent brake, a replicating virus that would be
    contained in a healthy host expands unchecked. The causal direction is
    established by rescue rather than by correlation: transducing wild-type IFNAR1
    into patient-genotype cells restores control of infection.
  biological_scale: CELLULAR
  downstream:
  - target: Disseminated Viral Disease
    causal_link_type: DIRECT
    description: >-
      Uncontained replication in permissive cells is what converts a limited,
      immunising exposure into systemic viral disease.
    evidence:
    - reference: PMID:31270247
      reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals."
      explanation: States the link between the cellular defect and disseminated clinical disease after live vaccine exposure.
  - target: Virus-Induced Systemic Hyperinflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A large, uncontrolled viral burden drives the hyperinflammatory syndrome. The
      link is recorded as indirect because the intervening immune amplification is
      not itself characterised in IFNAR1-deficient patients.
    evidence:
    - reference: PMID:42116640
      reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Complications including virus induced systemic hyperinflammation (VISH) are associated with significant mortality."
      explanation: Names the hyperinflammatory complication and its clinical weight in this disease.
  evidence:
  - reference: PMID:32972995
    reference_title: "Inborn errors of type I IFN immunity in patients with life-threatening COVID-19."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SARS-CoV-2 infection levels were higher in mutant cells than in cells from healthy donors, and transduction of WT IRF7 or IFNAR1 rescued their defects"
    explanation: Complementation rescue demonstrates that the excess viral replication is caused by the IFNAR1 lesion itself.
  - reference: PMID:31270247
    reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The patients' fibroblast phenotypes are rescued with WT IFNAR1"
    explanation: The same rescue result in the index patients' own cells.
- name: Disseminated Viral Disease
  description: >-
    The organism-level consequence: a replicating virus spreads beyond the tissue it
    would normally be confined to. In the index cases this was severe measles vaccine
    disease and yellow fever viscerotropic disease; in later cohorts it extends to
    naturally circulating viruses.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:42116640
    reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IFNAR1 deficiency confers an increased risk of severe and life-threatening infections caused by naturally circulating viruses including influenza, SARS-CoV-2, herpes simplex virus, respiratory syncytial virus (RSV), arboviruses and viruses in live attenuated vaccines (LAVs) including measles-mumps-rubella (MMR) and yellow fever."
    explanation: The consensus statement of the disease's viral disease spectrum, covering both vaccine and wild-type viruses.
- name: Virus-Induced Systemic Hyperinflammation
  description: >-
    A hyperinflammatory syndrome overlapping haemophagocytic lymphohistiocytosis,
    described in the Oceania guideline under the name virus-induced systemic
    hyperinflammation. It is a major contributor to mortality and is a distinct
    clinical problem from the viral disease that triggers it, which is why it is
    modelled as its own node rather than as a severity grade of the one above.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:42116640
    reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complications including virus induced systemic hyperinflammation (VISH) are associated with significant mortality."
    explanation: Establishes the syndrome as a recognised and lethal complication of the disease.
  - reference: PMID:42097348
    reference_title: "Inherited IFNAR1 structural deficiency in severe adverse events following yellow fever vaccination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous IFNAR1 copy number variation (CNV Δ3-4-5) in the proband (heterozygous in five of 11 unaffected relatives) caused receptor dysfunction, suppressing baseline IFN responses but triggering inflammasome-driven innate cell activation upon YFV-17D exposure."
    explanation: >-
      Supplies a candidate mechanism for the hyperinflammation rather than only its
      existence - the same receptor defect that removes the baseline interferon response
      permits inflammasome-driven innate activation when the vaccine virus is
      encountered. This is a single family, so it is a lead rather than an established
      mechanism.
- name: IFNAR1 Negative Dominance
  description: >-
    A mechanistically separate arm. Certain in-frame IFNAR1 alleles are expressed and
    interfere with the wild-type product, so heterozygotes show a defect rather than
    being silent carriers. The dominance is by negative dominance and not by
    haploinsufficiency, and the resulting lesion is partial and subtype-selective
    rather than a complete signalling null.
  biological_scale: MOLECULAR
  genetic_context:
    functional_impact_category: DOMINANT_NEGATIVE
  downstream:
  - target: Subtype-Selective Loss of IFN-alpha and IFN-omega Responsiveness
    causal_link_type: DIRECT
    description: >-
      The interfering allele impairs signalling through the receptor for the
      leukocyte-derived interferons while leaving the IFN-beta response intact.
    evidence:
    - reference: PMID:39680367
      reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility."
      explanation: Establishes both the dominance in heterozygous cells and the selectivity of the signalling defect.
  evidence:
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Negative dominance, rather than haploinsufficiency, accounts for this dominance."
    explanation: Identifies the molecular basis of dominance for this allele class.
- name: Subtype-Selective Loss of IFN-alpha and IFN-omega Responsiveness
  description: >-
    A partial cellular defect, distinct from the complete block of the recessive
    disease. Responses to IFN-alpha and IFN-omega - the abundant, leukocyte-derived
    type I interferons - are impaired or abolished, while the IFN-beta response is
    preserved. Carriers of these alleles are prone to viral disease, which is what
    makes the residual IFN-beta arm insufficient on its own.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Type I interferon-mediated signaling
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: DECREASED
  downstream:
  - target: Unrestricted Viral Replication in Permissive Cells
    causal_link_type: DIRECT
    description: >-
      The partial signalling defect still leaves permissive cells unable to restrict
      some viruses, converging on the same downstream node as the complete block.
    evidence:
    - reference: PMID:39680367
      reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses."
      explanation: Shows that the partial, subtype-selective defect is sufficient to produce clinical viral disease.
  evidence:
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β."
    explanation: Defines the allele class and the exact shape of the signalling defect it produces.
mechanistic_hypotheses:
- hypothesis_group_id: narrow_phenotype_ifn_redundancy
  hypothesis_label: Type I interferon redundancy explains survival to adulthood with a complete signalling null
  status: EMERGING
  description: >-
    Complete IFNAR1 deficiency abolishes the type I interferon response in vitro, yet
    the reported patients were healthy until a specific viral challenge and some have
    reached their fifth and sixth decades. The proposed explanation is that human type
    I interferons are largely redundant for protective immunity under everyday
    conditions, with other cell-intrinsic antiviral mechanisms compensating, and become
    indispensable only on systemic challenge with a replicating attenuated virus or a
    particularly virulent one. The competing reading - that ascertainment favours the
    catastrophic presentations while milder susceptibility goes unrecorded - is not
    excluded, and the estimated homozygote frequency in Samoa is high enough that
    undiagnosed individuals are expected. Which reading is right determines whether
    population screening of the founder allele identifies people at risk or mostly
    people who will never present.
  evidence:
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surprisingly, the patients concerned had managed to live to the age of 1–38 years without experiencing other unusually severe viral illnesses, and some are still alive at the age of 45–55 years."
    explanation: The central observation the hypothesis rests on - a complete signalling defect without broad clinical susceptibility.
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of homozygotes in these isolated populations has been estimated at 1/6,450 in Samoa and 1/1,539 in Greenland, and these individuals appear to be prone to only a few severe viral diseases."
    explanation: The population-genetic side of the same argument, and the reason the ascertainment alternative cannot be dismissed.
  - reference: PMID:33729549
    reference_title: "Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated."
    explanation: >-
      A review stating the redundancy reading directly, and framing it as an emerging
      picture rather than a settled one - which is why this entry records the hypothesis
      as EMERGING. The same review's human-versus-mouse comparison is the reason
      mouse type I interferon data cannot settle the question.
phenotypes:
- category: Immunological
  name: Disseminated infection with live vaccine virus
  description: >-
    The defining presentation. Systemic challenge with a live attenuated viral
    vaccine produces disseminated vaccine-strain infection rather than the intended
    limited immunising exposure. Both measles-mumps-rubella and yellow fever 17D are
    implicated.
  phenotype_term:
    preferred_term: Disseminated infection with live vaccine virus
    term:
      id: HP:0031697
      label: Disseminated infection with live vaccine virus
  evidence:
  - reference: PMID:31270247
    reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr."
    explanation: The two index presentations, both after live attenuated viral vaccination in previously healthy children.
- category: Immunological
  name: Severe viral infection
  description: >-
    Beyond vaccine strains, affected individuals are at risk of severe disease from
    naturally circulating viruses. The reported spectrum includes influenza,
    SARS-CoV-2, herpes simplex virus, respiratory syncytial virus and arboviruses.
  phenotype_term:
    preferred_term: Severe viral infection
    term:
      id: HP:0031691
      label: Severe viral infection
  evidence:
  - reference: PMID:42116640
    reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IFNAR1 deficiency confers an increased risk of severe and life-threatening infections caused by naturally circulating viruses including influenza, SARS-CoV-2, herpes simplex virus, respiratory syncytial virus (RSV), arboviruses and viruses in live attenuated vaccines (LAVs) including measles-mumps-rubella (MMR) and yellow fever."
    explanation: The consensus statement of the natural-virus susceptibility spectrum.
- category: Respiratory
  name: Life-threatening COVID-19 pneumonia
  description: >-
    Autosomal recessive IFNAR1 deficiency was identified among previously healthy
    individuals hospitalised with critical COVID-19 pneumonia, in a systematic search
    for inborn errors of type I interferon immunity. This is the presentation that
    extended the disease beyond live vaccine reactions.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:32972995
    reference_title: "Inborn errors of type I IFN immunity in patients with life-threatening COVID-19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection."
    explanation: >-
      Places IFNAR1 deficiency, one of the 13 loci tested, among the inborn errors
      underlying critical COVID-19 in previously healthy people. The snippet names the
      class rather than the gene, so the gene-specific attribution rests on the same
      paper's finding of homozygous IFNAR1 among the four biallelic patients.
  - reference: PMID:35708626
    reference_title: "Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies"
    explanation: >-
      Names IFNAR1 deficiency explicitly among children hospitalised with COVID-19
      pneumonia, which the class-level snippet above does not.
  - reference: PMID:35708626
    reference_title: "Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2."
    explanation: The cellular counterpart of the clinical finding, in the same cohort's cells.
- category: Immunological
  name: Multisystem inflammatory syndrome in children
  description: >-
    A 3-year-old with a large homozygous IFNAR1 deletion presented with critical
    COVID-19 pneumonia and multisystem inflammatory syndrome concurrently, and died on
    day 56. The combination is unexpected: MIS-C is a post-infectious hyperinflammatory
    state whose causes were not established, and the type I interferon defects had been
    associated with the pneumonia rather than with it. The authors raise the
    possibility that dysregulated type I interferon immunity contributes to MIS-C more
    broadly, which is a hypothesis rather than a finding. This is one patient, and is
    curated as such.
  phenotype_term:
    preferred_term: Increased inflammatory response
    term:
      id: HP:0012649
      label: Increased inflammatory response
  evidence:
  - reference: PMID:35091979
    reference_title: "Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C."
    explanation: >-
      The single case establishing this presentation, together with the fatal outcome.
      HPO has no term for multisystem inflammatory syndrome in children, so the binding
      is to the closest available concept and the specificity is carried by the name and
      description.
  - reference: PMID:35091979
    reference_title: "Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C."
    explanation: >-
      The authors distinguish what they confirm from what they suggest, and that
      distinction is preserved here rather than flattened.
- category: Hematological
  name: Virus-induced systemic hyperinflammation
  description: >-
    A hyperinflammatory syndrome with features overlapping haemophagocytic
    lymphohistiocytosis, recognised in the Oceania guideline as a major cause of death
    in this disease.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:42116640
    reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complications including virus induced systemic hyperinflammation (VISH) are associated with significant mortality."
    explanation: >-
      Establishes the hyperinflammatory complication. The binding to Hemophagocytosis
      is the closest available HPO term for the syndrome the guideline names; HPO has
      no term for virus-induced systemic hyperinflammation as such.
diagnosis:
- name: Whole-Blood IP-10 Induction Assay
  description: >-
    The functional confirmation, and the test that makes the diagnosis rather than
    merely suggesting it. Whole blood is stimulated with glycosylated IFN-alpha2,
    -beta or -omega and IP-10 (the product of the interferon-stimulated gene CXCL10)
    is measured; IFN-gamma is run in parallel as the type II control. In inherited
    IFNAR1 deficiency IP-10 is induced only by IFN-gamma, so a defect confined to the
    type I arm is demonstrated directly rather than inferred. The same assay separates
    the inherited defect from its acquired phenocopy, because a patient with
    neutralising autoantibodies still responds to the type I interferons their
    antibodies do not neutralise.
  diagnosis_term:
    preferred_term: whole-blood IP-10 induction immunoassay
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:39312669
    reference_title: "A sensitive assay for measuring whole-blood responses to type I IFNs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with inherited IFNAR1, IFNAR2, TYK2, or IRF9 deficiency, IP-10 is induced only by IFN-γ, whereas, in those with auto-Abs neutralizing specific type I IFNs, IP-10 is also induced by the type I IFNs not neutralized by the auto-Abs."
    explanation: >-
      Names IFNAR1 deficiency explicitly and states the readout pattern that
      distinguishes it both from a healthy response and from the autoantibody phenocopy.
  - reference: PMID:39312669
    reference_title: "A sensitive assay for measuring whole-blood responses to type I IFNs."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The measurement of type I and type II IFN-dependent IP-10 induction therefore constitutes a simple procedure for detecting rare inborn errors of the type I IFN response pathway and more common auto-Abs neutralizing type I IFNs."
    explanation: The authors' statement of what the assay is for, covering both the inherited and acquired conditions.
- name: Molecular Genetic Testing Including Copy-Number Analysis
  description: >-
    Exome or genome sequencing, or an inborn-errors-of-immunity panel, establishes the
    genotype. Copy-number analysis has to be part of it rather than an add-on: two of
    the reported causal genotypes are structural - a large homozygous loss-of-function
    deletion and a multi-exon copy-number variant - and a sequencing-only workflow
    reports those patients as having no biallelic variant.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:35091979
    reference_title: "Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency."
    explanation: A structural allele that establishes the diagnosis, and the reason copy-number analysis is not optional.
  - reference: PMID:42097348
    reference_title: "Inherited IFNAR1 structural deficiency in severe adverse events following yellow fever vaccination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conducted an integrative genetics and functional investigation of a Brazilian family with three siblings presenting AEFI-YF (two deceased), using whole exome sequencing (WES), and qPCR, molecular modeling, in vitro YFV-17D stimulation of leukocytes, cytokine quantification, immunophenotyping, and RNAseq."
    explanation: >-
      The diagnostic workflow in a family whose causal allele was a copy-number variant,
      showing sequencing and qPCR used together.
- name: Differential Diagnosis Against Neutralizing Anti-Type-I-Interferon Autoantibodies
  description: >-
    The acquired phenocopy, and the main differential. Autoantibodies neutralising type
    I interferons produce a functionally similar block without a genetic lesion, and
    they are far more common than the inherited disease - found in roughly one in ten
    patients with life-threatening COVID-19 in several cohorts. A functional assay alone
    cannot separate the two; the IP-10 pattern above and the genotype together can.

    Binding note: NCIT:C17455 (Enzyme Immunoassay) is the exact concept for this assay
    and for the one above, but it is not reachable from NCIT:C25218 and so fails the
    TreatmentActionTerm dynamic enum. Both are bound to the broader NCIT:C25294
    (Laboratory Procedure) with the specificity carried in preferred_term.
  diagnosis_term:
    preferred_term: autoantibody assay
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Patients with neutralizing auto-Abs against type I IFN can, thus, be considered to display autoimmune, partial phenocopies of AR IFNAR1 or IFNAR2 deficiency"
    explanation: >-
      States the phenocopy relationship directly, and the word "partial" is why the
      assay above can discriminate them at all.
  - reference: PMID:42524028
    reference_title: "Auto-antibodies neutralizing type I interferons in ~10% of Moroccan patients with life-threatening COVID-19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoantibodies neutralizing type I interferon (AAN-I-IFN) have been found in at least 10-15% of critical COVID-19 pneumonia cases in various studies across North and Latin America, Oceania, Europe, and Asia."
    explanation: >-
      Quantifies how much commoner the phenocopy is than the inherited disease, which is
      what makes it the differential rather than a footnote.
genetic:
- name: IFNAR1
  association: Causal
  gene_term:
    preferred_term: IFNAR1
    term:
      id: hgnc:5432
      label: IFNAR1
  notes: >-
    Two distinct allele classes cause disease at this locus. Biallelic
    loss-of-function alleles cause autosomal recessive complete deficiency, including
    the Western Polynesian founder nonsense allele c.1156G>T (p.Glu386*). Separately,
    a set of in-frame alleles acts by negative dominance in heterozygotes and impairs
    responses to IFN-alpha and IFN-omega while sparing IFN-beta; one of these,
    P335del, is common in Southern China. IFNAR2 and the downstream JAK-STAT
    components are intact in both classes, so the defect is confined to type I
    interferon reception.

    Two further points about the allele spectrum matter diagnostically. Structural
    variants are a recurring route to biallelic loss: a large homozygous
    loss-of-function deletion and a multi-exon copy-number variant are both reported
    causal genotypes, so copy-number analysis belongs in the workflow rather than
    beside it. And not every complete deficiency removes the protein from the cell
    surface - a distinctive form is described in which a non-functional IFNAR1 is
    expressed at levels similar to wild type, which means a flow-cytometry
    surface-expression assay can look normal in a patient who has no signalling at all.
  evidence:
  - reference: PMID:31270247
    reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations."
    explanation: Establishes IFNAR1 as the causal gene for the recessive complete deficiency.
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%)."
    explanation: Documents the dominant allele class and the population frequency of its commonest member.
  - reference: PMID:35442418
    reference_title: "A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*)."
    explanation: Establishes p.Glu386* as a recurrent founder allele shared across five unrelated kindreds.
  - reference: PMID:35442418
    reference_title: "A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function."
    explanation: Characterises the molecular consequence of the founder allele - a truncated protein that never reaches the membrane.
  - reference: PMID:42097348
    reference_title: "Inherited IFNAR1 structural deficiency in severe adverse events following yellow fever vaccination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous IFNAR1 copy number variation (CNV Δ3-4-5) in the proband (heterozygous in five of 11 unaffected relatives) caused receptor dysfunction"
    explanation: >-
      Documents a copy-number route to biallelic loss of function, which single-nucleotide
      variant screening would miss.
  - reference: PMID:35091979
    reference_title: "Inherited IFNAR1 Deficiency in a Child with Both Critical COVID-19 Pneumonia and Multisystem Inflammatory Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency."
    explanation: >-
      A second, independent structural allele, which is what makes copy-number variation
      an allele class here rather than a single reported oddity.
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a distinctive form of AR complete IFNAR1 deficiency in which a non-functional IFNAR1 is expressed on the cell surface at levels similar to those typically observed for the wildtype IFNAR1"
    explanation: >-
      Records the allele class in which surface expression is preserved despite complete
      loss of signalling - relevant because it is the case a surface-expression assay
      would call normal.
prevalence:
- population: Western Polynesian ancestry
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 16.7
  rate_denominator: LIVE_BIRTHS
  notes: >-
    The guideline reports approximately one in six thousand live births affected in
    people of Western Polynesian ancestry, attributed to the founder allele p.Glu386*.
    Recorded here as 16.7 per 100,000 live births (1 in 6,000). This is a
    population-specific figure and must not be read as a worldwide rate, where the
    disease is very rare.
  evidence:
  - reference: PMID:42116640
    reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive interferon alpha and beta receptor subunit 1 (IFNAR1) deficiency is
      a rare and heritable inborn error of immunity (IEI) predisposing individuals to severe
      and life-threatening viral infections. It is more common in people of Western Polynesian
      ancestry, with estimates of around one in six thousand live births affected, due to
      being homozygous for or having two copies of the regionally relevant pathogenic IFNAR1
      variant c.1156G>T, p.Glu386*.
    explanation: >-
      The regional estimate is approximately one affected live birth in 6,000 among people of
      Western Polynesian ancestry, linked to homozygosity for IFNAR1 p.Glu386*. It is not a
      worldwide prevalence estimate.
- population: Samoa
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 15.5
  notes: >-
    An independent estimate of the homozygote frequency in Samoa, 1 in 6,450, recorded
    as 15.5 per 100,000. It is reported as an estimated genotype frequency derived from
    allele frequency rather than as an ascertained case count, which is why it sits
    beside the guideline figure rather than replacing it.
  evidence:
  - reference: PMID:39680367
    reference_title: "A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of homozygotes in these isolated populations has been estimated at 1/6,450 in Samoa and 1/1,539 in Greenland"
    explanation: The reported homozygote frequency estimate; the Greenland figure in the same sentence refers to IFNAR2, not IFNAR1.
- population: Samoa and western Polynesia
  measure_type: CARRIER_FREQUENCY
  prevalence_class: UNKNOWN
  notes: >-
    Reported as the minor allele frequency of the p.Glu386* founder variant, which is
    above 1 per cent in Samoa and is also present in the Cook, Society, Marquesas and
    Austral islands and Fiji, while being extremely rare or absent elsewhere including
    in other Pacific populations. This is an allele frequency, not a disease rate, and
    must not be read as one; it sits alongside the two genotype-level estimates above
    as the observation those estimates are derived from.
  evidence:
  - reference: PMID:35442418
    reference_title: "A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region."
    explanation: The reported founder allele frequency and its geographic distribution.
treatments:
- name: Avoidance of Live Attenuated Viral Vaccines
  description: >-
    The single most important intervention once the diagnosis is known. Live
    attenuated viral vaccines are attenuated only relative to an interferon-competent
    host, and in IFNAR1 deficiency they cause disseminated, potentially fatal
    infection. This is the agents-and-circumstances-to-avoid consideration for this
    disease, and it is the reason the Oceania guideline is built around early
    identification before routine immunisation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: avoidance of live attenuated viral vaccination
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  target_mechanisms:
  - target: Unrestricted Viral Replication in Permissive Cells
    description: >-
      Withholding the live vaccine removes the replicating viral challenge that the
      absent interferon response cannot contain.
  evidence:
  - reference: PMID:42116640
    reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This document outlines expert consensus regarding early identification, diagnostic workup and management of IFNAR1 deficiency in Australia, Aotearoa New Zealand and Western Pacific nations."
    explanation: >-
      The existence and stated purpose of a regional consensus guideline built on early
      identification. The specific avoidance recommendation is in the guideline body
      rather than the abstract, so this snippet supports the management framework
      rather than quoting the recommendation itself.
- name: Supportive and Antiviral Management of the Viral Episode
  description: >-
    There is no disease-specific pharmacotherapy. Management during an episode is organ
    support and, where one exists for the virus concerned, directed antiviral therapy.
    One negative point is mechanistically important and worth stating explicitly:
    exogenous type I interferon is not a treatment here. The lesion is the receptor, so
    giving more ligand cannot restore signalling - this is the opposite of the situation
    in an interferon-production defect, where replacement is rational.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Disseminated Viral Disease
    description: >-
      Organ support and antiviral therapy act on the established viral disease rather
      than on the signalling defect that permitted it.
  evidence:
  - reference: PMID:42116640
    reference_title: "Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This document outlines expert consensus regarding early identification, diagnostic workup and management of IFNAR1 deficiency in Australia, Aotearoa New Zealand and Western Pacific nations."
    explanation: >-
      The consensus management framework this treatment sits inside. The specific
      supportive-care detail is in the guideline body rather than the abstract, so this
      snippet establishes the framework rather than quoting the regimen.
  notes: >-
    The deep-research report for this entry proposed NCIT:C15320 for Supportive Care.
    That CURIE resolves to "Study Design" and was rejected; NCIT:C15747 is the term
    actually used here and it was read from the ontology, not from the report.
- name: Cascade and Pre-Vaccination Genetic Screening
  description: >-
    The diagnosis is usually made after a catastrophic event, which is too late for the
    index patient but not for relatives. Screening at-risk relatives - and, in the
    populations carrying a founder allele, screening before live attenuated vaccination -
    is what converts this from a lethal disease into an avoidable one. This is the
    intervention the Oceania guideline is organised around.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic screening
    term:
      id: NCIT:C92803
      label: Genetic Screening
  target_mechanisms:
  - target: Disseminated Viral Disease
    description: >-
      Identifying the genotype before exposure is what allows the triggering exposure to
      be withheld, so the screening acts by preventing the disease rather than treating it.
  evidence:
  - reference: PMID:42097348
    reference_title: "Inherited IFNAR1 structural deficiency in severe adverse events following yellow fever vaccination."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings advocate for precision vaccinology by screening relatives of AEFI-YF cases for type I IFN EIIs and auto-antibodies prior to live-attenuated vaccination."
    explanation: The authors' explicit recommendation, arising from a family in which two of three affected siblings died.
  - reference: PMID:35442418
    reference_title: "A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses."
    explanation: The population-targeted version of the same recommendation.
environmental:
- name: Live attenuated viral vaccination
  description: >-
    The exposure that converts a clinically silent genotype into life-threatening
    disease. Both index patients were healthy until vaccination - one with measles
    vaccine at one year, one with yellow fever 17D at twelve. This is the
    gene-environment interaction that defines the disease's presentation, and it is
    why avoidance is the principal intervention.
  exposure_term:
    preferred_term: exposure to live attenuated viral vaccine
  influences_mechanisms:
  - target: Unrestricted Viral Replication in Permissive Cells
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      A replicating attenuated virus is the challenge the absent interferon response
      cannot contain, so the exposure initiates the mechanism rather than merely
      aggravating it.
    evidence:
    - reference: PMID:31270247
      reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals."
      explanation: States the causal role of the vaccine exposure in previously healthy individuals.
  review_notes: >-
    ECTO was searched for a term covering exposure to a live attenuated viral vaccine
    and none was found; the exposure_term is left with a free-text preferred_term and
    no binding rather than forced onto an inaccurate CURIE. This follows the same
    decision recorded in the sibling IFNAR2_Deficiency entry.
  evidence:
  - reference: PMID:31270247
    reference_title: "Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr."
    explanation: Documents the vaccine exposure preceding disease in both index patients.
notes: >-
  Relationship to sibling entries. IFNAR2_Deficiency and STAT2_Deficiency cover the
  other components of the same pathway and are curated separately; the phenotype and
  pathophysiology naming here deliberately parallels IFNAR2_Deficiency so the three
  can be read against each other. The clinical phenotypes overlap almost completely,
  and the discriminating test is genetic rather than functional.

  Deep-research provenance. The openscientist report for this disease is committed
  alongside this entry. Its reference validation resolved 21 of 21 citations with a
  confabulation rate of 0.0, but its term validation returned needs_review: true, and
  two of the flagged bindings were real errors rather than parsing artefacts -
  HP:0032251 offered as "Abnormal susceptibility to viral infection" (the ontology
  label is "Abnormal immune system morphology") and NCIT:C15320 offered as "Supportive
  Care" (the ontology label is "Study Design"). Neither CURIE was bound here. Every
  term in this entry was read from OLS at the time it was written.

  A third report error is worth recording because neither of those checks covers it.
  The report's identifier section gives this disease's OMIM entry as "#619304
  (Immunodeficiency 45)". Immunodeficiency 45 is the IFNAR2 disease, curated separately
  here as IFNAR2_Deficiency against MONDO:0014727, and MONDO cross-references
  MONDO:0030970 to a different OMIM entry. That is Named Entity Confusion in the
  identifier layer, and just preflight-dr is what surfaced it - the report's own
  reference validation (21 of 21 verified, confabulation rate 0.0) and its term
  validation both pass over OMIM numbers entirely, because neither treats OMIM as an
  identifier class it checks. No OMIM identifier is recorded in this entry.

  On haematopoietic cell transplantation. The deep-research report names HSCT as a
  "rational curative option" for severe cases and the reasoning is sound - it would
  restore an interferon-competent haematopoietic compartment. It is not curated as a
  treatment here because the report supplies no citation for it and none of the
  references used reports a transplanted IFNAR1-deficient patient. Recorded so the
  omission is legible as a decision rather than an oversight. Note also that the
  rationale is weaker here than it looks: IFNAR1 is ubiquitously expressed and the
  fibroblast work shows the defect is cell-intrinsic in non-haematopoietic cells, so
  replacing the marrow would not restore interferon responsiveness in the tissues the
  virus actually replicates in.

  Two things this entry deliberately does not claim. Prevalence figures are
  population-specific and are recorded as such; there is no worldwide rate in the
  sources used. And the negative-dominance arm is modelled as a second molecular route
  to the same downstream nodes rather than as a milder grade of the recessive disease,
  because the defect it produces is qualitatively different - subtype-selective rather
  than complete.

📚

References & Deep Research

References

1

PMID:42116640

Guideline for the Diagnosis and Management of Heritable IFNAR1 Deficiency in Oceania.

No top-level findings curated for this source.

Deep Research

1

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.

Evaluations and curation notes (2)

Record notes

Relationship to sibling entries. IFNAR2_Deficiency and STAT2_Deficiency cover the other components of the same pathway and are curated separately; the phenotype and pathophysiology naming here deliberately parallels IFNAR2_Deficiency so the three can be read against each other. The clinical phenotypes overlap almost completely, and the discriminating test is genetic rather than functional. Deep-research provenance. The openscientist report for this disease is committed alongside this entry. Its reference validation resolved 21 of 21 citations with a confabulation rate of 0.0, but its term validation returned needs_review: true, and two of the flagged bindings were real errors rather than parsing artefacts - HP:0032251 offered as "Abnormal susceptibility to viral infection" (the ontology label is "Abnormal immune system morphology") and NCIT:C15320 offered as "Supportive Care" (the ontology label is "Study Design"). Neither CURIE was bound here. Every term in this entry was read from OLS at the time it was written. A third report error is worth recording because neither of those checks covers it. The report's identifier section gives this disease's OMIM entry as "#619304 (Immunodeficiency 45)". Immunodeficiency 45 is the IFNAR2 disease, curated separately here as IFNAR2_Deficiency against MONDO:0014727, and MONDO cross-references MONDO:0030970 to a different OMIM entry. That is Named Entity Confusion in the identifier layer, and just preflight-dr is what surfaced it - the report's own reference validation (21 of 21 verified, confabulation rate 0.0) and its term validation both pass over OMIM numbers entirely, because neither treats OMIM as an identifier class it checks. No OMIM identifier is recorded in this entry. On haematopoietic cell transplantation. The deep-research report names HSCT as a "rational curative option" for severe cases and the reasoning is sound - it would restore an interferon-competent haematopoietic compartment. It is not curated as a treatment here because the report supplies no citation for it and none of the references used reports a transplanted IFNAR1-deficient patient. Recorded so the omission is legible as a decision rather than an oversight. Note also that the rationale is weaker here than it looks: IFNAR1 is ubiquitously expressed and the fibroblast work shows the defect is cell-intrinsic in non-haematopoietic cells, so replacing the marrow would not restore interferon responsiveness in the tissues the virus actually replicates in. Two things this entry deliberately does not claim. Prevalence figures are population-specific and are recorded as such; there is no worldwide rate in the sources used. And the negative-dominance arm is modelled as a second molecular route to the same downstream nodes rather than as a milder grade of the recessive disease, because the defect it produces is qualitatively different - subtype-selective rather than complete.

Create: IFNAR1_Deficiency (MONDO:0030970) · 2026-09-13T21:12:57Z · View source

De novo curation of autosomal recessive and dominant-negative IFNAR1 deficiency (immunodeficiency 106). Deep research: one openscientist report, committed alongside the entry (research/IFNAR1_Deficiency-deep-research-openscientist.md). Report reference validation resolved 21/21 citations with confabulation_rate 0.0; term validation returned needs_review: true with six mislabelled terms, two of which were real wrong bindings rather than parsing artefacts - HP:0032251 offered as 'Abnormal susceptibility to viral infection' (ontology label: Abnormal immune system morphology) and NCIT:C15320 offered as 'Supportive Care' (ontology label: Study Design). Neither was bound. NCIT:C15747 was used for supportive care instead, read from OLS. Separately, just preflight-dr flagged that the report gives this disease's OMIM entry as '#619304 (Immunodeficiency 45)'; immunodeficiency 45 is the IFNAR2 disease already curated here as IFNAR2_Deficiency, and MONDO cross-references MONDO:0030970 to a different OMIM entry. No OMIM identifier was recorded in the entry. Every ontology CURIE in the entry was resolved against OLS at the time of writing; one label error of my own (HP:0001751) was caught by just validate-terms in a sibling entry in the same session. Structure follows the curated sibling IFNAR2_Deficiency deliberately so the type I interferon pathway entries read against each other. Two molecular arms are modelled: the recessive complete signalling null, and the negative-dominance allele class that impairs IFN-alpha and IFN-omega responses while sparing IFN-beta. Validation: just validate passes schema, term and reference checks with 45/45 snippets verified against cached references; check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms and check-enum-values all pass.

OpenScientist ▸

IFNAR1 Deficiency: A Comprehensive Disease Characteristics Report

openscientist-autonomous 21 citations 2026-09-13T21:05:52.286130

IFNAR1 Deficiency: A Comprehensive Disease Characteristics Report

Disease: IFNAR1 Deficiency (Autosomal Recessive) MONDO ID: MONDO:0030970 · OMIM: #619304 (Immunodeficiency 45) · Gene OMIM: IFNAR1 107450 Category: Mendelian inborn error of immunity (IEI)

Summary

IFNAR1 deficiency is an ultra-rare autosomal recessive inborn error of immunity caused by biallelic loss-of-function (LOF) variants in IFNAR1 (chromosome 21q22.11), the gene encoding interferon-alpha/beta receptor subunit 1. IFNAR1 pairs with IFNAR2 to form the shared cell-surface receptor for all type I interferons (IFN-α, IFN-β, and IFN-ω). When IFNAR1 is absent or non-functional, cells cannot respond to any type I IFN, abolishing the JAK1/TYK2–STAT1/STAT2–ISGF3 signaling cascade that drives interferon-stimulated gene (ISG) expression and intrinsic antiviral defense. The functional signature is definitive: patient fibroblasts show no response to IFN-α2, IFN-ω, or IFN-β PMID: 35442418.

The clinical hallmark is a striking dissociation between baseline health and catastrophic response to specific viral challenges. Affected individuals are typically otherwise healthy and develop normally until they encounter a live attenuated vaccine (measles-mumps-rubella, MMR; or yellow fever 17D) or a select wild-type virus (notably SARS-CoV-2), whereupon uncontrolled viral replication produces severe, sometimes fatal disseminated disease — encephalitis, pneumonitis, hepatitis, and multiorgan involvement. This pattern illustrates an "essential but narrow" role for type I IFN in human antiviral immunity: unlike mice, humans display considerable redundancy in type I IFN protection under natural conditions, so the phenotype is dominated by attenuated-vaccine viruses and a handful of wild-type pathogens rather than by broad, everyday viral susceptibility.

The disease has a notable population genetics dimension: a Polynesian founder allele, p.Glu386* (nonsense), reaches a minor allele frequency above 1% in Samoa and is distributed across western Polynesia, making regional consideration essential before live vaccination. Diagnosis combines genetic testing (WES/WGS/IEI panels, with copy-number analysis for large deletions) and functional confirmation of absent type I IFN responses, while carefully excluding the acquired phenocopy — neutralizing autoantibodies against type I IFNs, found in 10–15% of critical COVID-19 pneumonia cases. Management is fundamentally preventive: strict avoidance of live attenuated vaccines, supportive/antiviral care during viral episodes, cascade screening of relatives, and hematopoietic stem cell transplantation (HSCT) as a rational curative option in severe disease. There is no approved disease-specific pharmacotherapy, and exogenous type I IFN is useless because the receptor is absent.

1. Disease Information

IFNAR1 deficiency is a Mendelian inborn error of immunity characterized by selective vulnerability to certain viruses and live attenuated viral vaccines, with intact immunity to most other pathogens. It was first described in 2019 in otherwise healthy patients who suffered life-threatening disease after MMR and yellow fever vaccination PMID: 31270247.

Key identifiers:

Resource	Identifier
MONDO	MONDO:0030970
OMIM (phenotype)	#619304 (Immunodeficiency 45)
OMIM (gene)	IFNAR1 107450
Gene (HGNC)	IFNAR1 (HGNC:5432)
Cytogenetic locus	21q22.11
Inheritance	Autosomal recessive

Synonyms / alternative names: Immunodeficiency 45 (IMD45); autosomal recessive IFNAR1 deficiency; interferon alpha/beta receptor 1 deficiency; type I interferon receptor 1 deficiency.

Information source: The disease-level knowledge derives primarily from aggregated case series and functional immunology studies (Hernandez et al. 2019; Bastard et al. 2022; Abolhassani et al. 2022; Azamor et al. 2026), not from EHR/population-scale data, reflecting the ultra-rare nature of the condition.

"Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses." — PMID: 35442418

2. Etiology

Disease causal factor (genetic): The sole cause is biallelic loss-of-function variants in IFNAR1. This is a monogenic, molecularly fully penetrant defect. Cellular responses to all type I IFNs are abolished PMID: 35442418.

Genetic risk factors: The disease is the genotype — homozygous or compound heterozygous LOF IFNAR1 variants. No additional susceptibility loci are required. The most important population-specific genetic risk factor is the Polynesian founder allele p.Glu386*, enriched in individuals of Polynesian (especially Samoan) ancestry.

Environmental "risk factors" (disease-precipitating triggers): Because baseline health is preserved, disease manifestation is triggered by specific environmental exposures: - Live attenuated vaccines: MMR, yellow fever 17D (YF-17D). - Wild-type viruses: SARS-CoV-2 (critical COVID-19 pneumonia), and other viruses in individual reports.

Protective factors: The principal "protective" measure is behavioral/medical — avoidance of live attenuated vaccines. No genetic protective modifier alleles have been established for this disease.

Gene–environment interaction: This disease is a paradigmatic monogenic gene × environment interaction — an inherited receptor defect that is clinically silent until an environmental viral trigger (vaccine or wild-type virus) unmasks it, producing life-threatening disease.

3. Phenotypes

The phenotype is dominated by infectious/post-vaccination events rather than constitutional features. Between triggers, patients are typically asymptomatic and grow normally.

Phenotype	Type	HPO suggestion	Onset	Severity	Frequency
Adverse reaction to live attenuated vaccine (MMR, YF)	Clinical event	HP:0002090 (Pneumonia), HP:0002383 (Encephalitis)	Childhood (post-vaccination)	Severe/life-threatening	Presenting feature in index cases
Viral encephalitis	Clinical sign	HP:0002383	Variable	Severe	Reported
Severe/critical viral pneumonia (incl. COVID-19)	Clinical sign	HP:0002090	Any age	Severe	Reported
Disseminated viral infection / viral hepatitis	Clinical sign	HP:0006562 (Viral hepatitis)	Variable	Severe	Reported
Susceptibility to viral infection	Lab/clinical	HP:0032251 (Abnormal susceptibility to viral infection)	Variable	Variable	Core
Otherwise normal immunity/health between triggers	—	—	—	—	Characteristic

Onset: Typically childhood, coincident with the routine live-vaccine schedule; can also present in adulthood upon wild-type viral challenge (e.g., adult critical COVID-19).

Severity/progression: Episodic and trigger-dependent. Individual episodes can be fulminant and fatal, but there is no constitutive, progressive organ degeneration between events.

Quality-of-life impact: Between episodes, QoL is generally normal. The dominant burden is the risk of catastrophic disease upon exposure and the lifelong requirement to avoid live vaccines and manage viral exposures. No disease-specific EQ-5D/SF-36 data are available (reflecting rarity).

"Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease." — PMID: 31270247

4. Genetic / Molecular Information

Causal gene: IFNAR1 (interferon alpha and beta receptor subunit 1), HGNC:5432, located at chromosome 21q22.11. Gene OMIM 107450; disease phenotype OMIM #619304.

Pathogenic variants (spectrum):

Variant	Type	Population	Consequence	Reference
p.Glu386* (nonsense)	Truncating LOF	Polynesian founder (MAF >1% in Samoa)	Truncated protein absent from cell surface	PMID: 35442418
Large homozygous deletion	Structural / CNV	Individual case	Complete LOF	PMID: 35091979
CNV Δ3-4-5 (homozygous)	Structural / CNV	Brazilian family	Receptor dysfunction; fatal YF vaccine adverse event	PMID: 42097348

Variant classification: Reported disease-causing variants are pathogenic (nonsense, large deletions, CNVs) per ACMG/AMP, all producing loss of function.

Functional consequence: Loss of function — abolished expression or surface localization of IFNAR1, eliminating the type I IFN receptor complex. The founder allele encodes a truncated protein absent from the cell surface.

Allele frequency: The founder p.Glu386* allele is >1% MAF in Samoa but is extremely rare or absent in non-Polynesian populations. Other variants are private/ultra-rare.

Somatic vs germline: Germline. (Somatic IFNAR1 down-regulation by viruses — e.g., SARS-CoV-2-induced IFNAR1 ubiquitination PMID: 34260266 — is a distinct immune-evasion phenomenon, not the inherited disease.)

Modifier genes / epigenetics / large chromosomal abnormalities: No established disease modifiers, epigenetic drivers, or aneuploidy associations specific to this monogenic disorder.

"All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function." — PMID: 35442418

5. Environmental Information

Environmental/infectious triggers (the operative "environmental" dimension): - Live attenuated vaccines: measles-mumps-rubella (MMR), yellow fever 17D. - Wild-type viruses: SARS-CoV-2 (critical COVID-19 pneumonia); other viruses in individual reports.

Toxins/pollution/occupational exposures: Not implicated. Lifestyle factors (smoking, diet, alcohol): Not relevant to disease causation.

Infectious agents: The relevant "pathogens" are the vaccine strains themselves (attenuated measles, mumps, rubella, YF-17D) and specific wild-type viruses that normally depend on type I IFN for host containment.

6. Mechanism / Pathophysiology

Ordered causal chain

Biallelic LOF variant in IFNAR1 (nonsense p.Glu386*, deletion, or CNV) → leads to absent or non-functional IFNAR1 protein at the cell surface.
Absent IFNAR1 → prevents assembly of the type I IFN receptor (IFNAR1 + IFNAR2) → results in no ternary receptor complex upon IFN-α/β/ω binding.
No ternary complex → fails to juxtapose the receptor-associated kinases JAK1 and TYK2 → they cannot cross-phosphorylate.
No JAK/TYK activation → abolishes phosphorylation of STAT1/STAT2 → the ISGF3 (STAT1–STAT2–IRF9) complex does not form.
No ISGF3 → eliminates induction of interferon-stimulated genes (ISGs) → cells lose the type I IFN-driven antiviral state.
Loss of the antiviral state → permits uncontrolled replication of attenuated-vaccine viruses and select wild-type viruses in infected/target cells (e.g., fibroblasts highly vulnerable to SARS-CoV-2).
Uncontrolled viral replication → causes disseminated viral disease (encephalitis, pneumonitis, hepatitis, multiorgan involvement), which may be fatal.
Branch (inferred): In some contexts, aberrant innate/inflammasome activation upon viral trigger contributes to immunopathology (e.g., inflammasome-driven innate-cell activation upon YFV-17D exposure in a CNV case PMID: 42097348).

Detail by category

Molecular pathway: The type I IFN → JAK-STAT (ISGF3) → ISG axis (KEGG hsa04630 Jak-STAT signaling; Reactome "Interferon alpha/beta signaling"). Type I IFNs bind a receptor formed by IFNAR1 and IFNAR2, forming a ternary complex that brings JAK1 and TYK2 into proximity; they cross-phosphorylate each other, the receptor chains, and STATs, which then activate ISGs PMID: 38608537.

"Common to both are two distinct receptor chains (IFNAR1/IFNAR2 and IFNLR1/IL10R2), which form ternary complexes upon binding their respective ligands. This results in close proximity of the intracellularly associated kinases JAK1 and TYK2, which cross phosphorylate each other, the associated receptor chains, and signal transducer and activator of transcriptions, with the latter activating IFN-stimulated genes." — PMID: 38608537

Cellular processes: Loss of the cell-intrinsic antiviral state (impaired restriction of viral replication); GO:0060337 (type I interferon signaling pathway), GO:0051607 (defense response to virus).

Protein dysfunction: Loss of function of IFNAR1 — either the protein is truncated and fails to reach the plasma membrane (p.Glu386*) or is deleted entirely.

Immune system involvement: This is an immunodeficiency (impaired intrinsic antiviral immunity), not primarily an autoimmune or autoinflammatory disease — though excessive innate/inflammasome activation can accompany a viral trigger. Notably, the opposite pole of IFN biology (excessive IFN-I signaling) causes type I interferonopathies, underscoring the pathway's dose-sensitivity.

Species contrast (why the human phenotype is narrow): In mice, type I IFN is essential against a broad range of viruses; in humans there is far more redundancy under natural conditions PMID: 33729549.

"A picture is emerging of greater redundancy of human type I IFNs for protective immunity to viruses in natural conditions than was initially anticipated." — PMID: 33729549

Molecular profiling / functional readout: IFNAR1-deficient fibroblasts show no ISG induction to IFN-α2/-β/-ω and are highly vulnerable to SARS-CoV-2 (P = 1.2×10⁻¹¹ vs benign controls) PMID: 35708626.

"Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2." — PMID: 35708626

Cell types / GO / CL suggestions: Broadly acting because IFNAR1 is ubiquitously expressed — fibroblasts (CL:0000057), epithelial cells (CL:0000066), leukocytes/monocytes (CL:0000576), and other nucleated cells. GO terms: GO:0060337 (type I interferon signaling pathway), GO:0034340 (response to type I interferon), GO:0051607 (defense response to virus).

7. Anatomical Structures Affected

Because IFNAR1 is expressed on virtually all nucleated cells, the disease has no fixed anatomical target; rather, the organ affected is dictated by the tropism of the triggering virus.

Organ level: Variable and virus-dependent — lung (viral/COVID-19 pneumonia; UBERON:0002048), brain/CNS (encephalitis; UBERON:0000955), liver (viral hepatitis; UBERON:0002107), with potential multiorgan dissemination.
Body systems: Immune system (primary defect), with secondary respiratory, nervous, and hepatobiliary involvement during infectious episodes.
Tissue/cell level: Any infected cell type; fibroblasts and epithelial cells are demonstrably permissive in vitro. CL terms: CL:0000057 (fibroblast), CL:0000066 (epithelial cell), CL:0000576 (monocyte).
Subcellular level: IFNAR1 is a plasma membrane receptor (GO:0005886); signaling proceeds via cytoplasmic kinases/STATs to the nucleus (GO:0005634) for ISG transcription.
Localization / lateralization: Determined by viral tropism; typically bilateral/systemic in disseminated disease.

8. Temporal Development

Onset: Congenital genetic defect, but clinically silent until a triggering exposure. Classic presentation is in childhood at the time of routine live-vaccine administration; adult presentation occurs with wild-type viral challenge (e.g., adult critical COVID-19).

Onset pattern: Acute — fulminant illness following vaccination or infection.

Progression / course: Episodic, trigger-dependent. There is no constitutive progressive degeneration; between episodes patients are typically well. Individual episodes can progress rapidly to severe/fatal disease.

Disease duration: The underlying genetic condition is lifelong; the risk persists indefinitely and requires lifelong avoidance of live vaccines.

Remission: Recovery from a viral episode is possible with supportive care and viral clearance; there is no "remission" of the underlying genetic defect.

Critical periods: The peri-vaccination window (routine childhood immunization schedule) is the key period of vulnerability and the main opportunity for prevention (withholding live vaccines).

9. Inheritance and Population

Inheritance pattern: Autosomal recessive. Recurrence risk for siblings of an affected proband is 25%.

Penetrance/expressivity: At the molecular level, biallelic LOF fully abolishes type I IFN responses; clinical penetrance is trigger-dependent (an individual may remain well if never exposed to a triggering live vaccine or virus). Expressivity is variable, driven by which virus is encountered.

Epidemiology: Ultra-rare globally. Prevalence has not been formally established; knowledge is based on case reports and small series.

Founder effect / affected populations: A strong Polynesian founder effect — the p.Glu386* allele has MAF >1% in Samoa and is also present in the Cook, Society, Marquesas, and Austral islands, and Fiji; it is extremely rare or absent elsewhere. Seven children from five unrelated western Polynesian kindreds were homozygous for this variant PMID: 35442418.

Consanguinity: Contributes to homozygosity in some families (as typical for AR IEIs), and to the appearance of private homozygous deletions/CNVs.

Sex ratio: No sex predilection (autosomal).

"All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*)... this IFNAR1 variant has a minor allele frequency >1% in Samoa." — PMID: 35442418

10. Diagnostics

Diagnostic approach combines genetics + function:

Genetic testing: Whole-exome (WES) or whole-genome (WGS) sequencing, or targeted inborn errors of immunity (IEI) gene panels, to identify biallelic IFNAR1 LOF variants. Copy-number/CNV analysis is essential because large deletions and structural CNVs (e.g., the homozygous deletion and CNV Δ3-4-5) are recurrent mechanisms PMID: 35091979; PMID: 42097348.
Functional confirmation: Demonstrate absent cellular responses to type I IFNs (IFN-α2, IFN-β, IFN-ω) using fibroblast or whole-blood ISG-induction assays. A sensitive whole-blood assay (e.g., IP-10/CXCL10 readout) can detect both inborn errors and the autoantibody phenocopy PMID: 39312669.

Differential diagnosis — critical: The key acquired phenocopy is neutralizing autoantibodies against type I IFNs, present in ~10–15% of critical COVID-19 pneumonia cases; these must be excluded PMID: 42524028. Other differentials include IFNAR2, STAT1, STAT2, TYK2, IRF9 deficiencies and other IEIs of type I IFN immunity.

Screening: Not part of routine newborn screening; cascade genetic screening of relatives of affected individuals is recommended, particularly in high-prevalence Polynesian populations, prior to live vaccination.

"Human inborn errors of the type I IFN response pathway and auto-Abs neutralizing IFN-α, -β, and/or -ω can underlie severe viral illnesses. We report a simple assay for the detection of both types of condition." — PMID: 39312669

"Autoantibodies neutralizing type I interferon (AAN-I-IFN) have been found in at least 10-15% of critical COVID-19 pneumonia cases." — PMID: 42524028

11. Outcome / Prognosis

Mortality: Individual triggering episodes can be fatal. Documented fatalities include a child with concurrent critical COVID-19 pneumonia and MIS-C who died on day 56 PMID: 35091979, and two deceased siblings following yellow fever vaccination in a Brazilian family with a homozygous IFNAR1 CNV PMID: 42097348.

Between-episode outlook: Generally good — patients are otherwise healthy with normal growth and development, and can survive to adulthood if triggers are avoided.

Complications: Encephalitis, viral pneumonia/ARDS, hepatitis, disseminated viral infection, and — in the COVID-19 setting — co-occurring MIS-C.

Prognostic factors: The nature of the trigger (fulminant vaccine-strain disease vs manageable wild-type infection), timeliness of recognition/supportive care, and avoidance of further live-vaccine exposure. With appropriate prevention (no live vaccines) and prompt management of infections, long-term prognosis can be favorable.

12. Treatment

There is no approved disease-specific pharmacotherapy. Critically, exogenous type I IFN is ineffective because the receptor is absent — this is a mechanistic dead-end for IFN-replacement strategies.

Modality	Role in IFNAR1 deficiency	NCIT suggestion
Supportive/intensive care	Mainstay during viral episodes (organ support, ICU)	NCIT:C15320 (Supportive Care)
Antiviral therapy	Directed against the triggering virus where available	NCIT:C258 (Antiviral Agent)
Hematopoietic stem cell transplantation (HSCT)	Rational curative option in severe cases (restores IFNAR1-competent immune cells)	NCIT:C15431 (Hematopoietic Stem Cell Transplantation)
Exogenous type I IFN	Not applicable — receptor absent	—

Pharmacogenomics / advanced therapeutics: No established gene therapy, RNA therapy, or targeted small-molecule therapy exists for this disease as of this report. HSCT is the only potentially curative intervention and is considered on a case-by-case basis in severe presentations.

Treatment strategy: Prevention-first (avoid live vaccines) + aggressive supportive/antiviral management of breakthrough viral illness + consideration of HSCT for severe/recurrent disease.

13. Prevention

Prevention is the cornerstone of management.

Primary prevention: Strict avoidance of live attenuated vaccines (MMR, yellow fever, and other live vaccines) in affected individuals. Use inactivated/subunit alternatives where available and appropriate.
Secondary prevention: Cascade genetic screening of at-risk relatives; and — importantly — pre-vaccination screening for type I IFN inborn errors and autoantibodies in relatives of individuals with adverse events following yellow fever vaccination PMID: 42097348.
Population-targeted consideration: Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses, and consideration given before live vaccination in that population PMID: 35442418.
Genetic counseling: AR inheritance with 25% sibling recurrence risk; counsel families accordingly, including reproductive options.
Tertiary prevention: Prompt recognition and supportive/antiviral care to limit complications during viral episodes.

"Our findings advocate for precision vaccinology by screening relatives of AEFI-YF cases for type I IFN EIIs and auto-antibodies prior to live-attenuated vaccination." — PMID: 42097348

"Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses." — PMID: 35442418

14. Other Species / Natural Disease

Orthologous gene: Mouse Ifnar1 (NCBI Gene ID 15975); human IFNAR1 (NCBI Gene ID 3454). The type I IFN receptor architecture and JAK-STAT signaling are evolutionarily conserved across vertebrates, including teleost fish PMID: 35906001.
Natural disease in other species: No well-characterized naturally occurring IFNAR1-deficiency disease in companion animals or wildlife is established; the condition is defined in humans. Viral immune-evasion strategies that degrade or block IFNAR1 are, however, widespread across animal pathogens (e.g., African swine fever virus p22 promoting TAX1BP1-mediated IFNAR1 degradation PMID: 40668839; lumpy skin disease virus LSDV122 disrupting IFNAR1/IFNAR2 assembly PMID: 41525414), underscoring the conserved centrality of this receptor to antiviral defense.
Evolutionary conservation of mechanism: High — the requirement for type I IFN/JAK-STAT signaling in antiviral immunity is conserved, though with a species difference in breadth: mouse type I IFN is essential against a broad range of viruses, whereas human type I IFN shows greater redundancy PMID: 33729549.

15. Model Organisms

The principal model is the Ifnar1-knockout (IFNAR1 KO) mouse (mammalian, germline knockout), one of the most widely used tools in viral pathogenesis and vaccine research.

Feature	IFNAR1 KO mouse	Human IFNAR1 deficiency
Type I IFN response	Abolished	Abolished
Viral susceptibility breadth	Broad — uniformly lethal to many viruses	Narrow — mainly live vaccines + select wild-type viruses
Utility	Pathogenesis + vaccine-efficacy studies	—

Phenotype recapitulation: The KO faithfully reproduces the loss of type I IFN signaling and its consequence (viral susceptibility). It is used as a uniformly lethal infection model across diverse viruses — Nipah PMID: 42623407; PMID: 42035922, Akabane PMID: 40209629, Zika PMID: 41754520, dengue PMID: 42149728, Bourbon PMID: 40910687, and other bunyaviruses — and for vaccine-efficacy testing.

Model limitation: The KO overstates the human phenotype. Because human type I IFN is more redundant than mouse type I IFN, KO mice are broadly and lethally susceptible to viruses that cause little or no everyday illness in IFNAR1-deficient humans PMID: 33729549. Related multi-deficiency models (e.g., triple IFNAR/IFNGR/IFNLR "AGL" mice PMID: 42463654) extend susceptibility further and reveal type III IFN as a backup layer.

"Mouse type I IFNs are essential for protection against a broad range of viruses in experimental conditions." — PMID: 33729549

Resources: MGI (Ifnar1), IMPC/IMSR for knockout lines; patient-derived fibroblasts and iPSCs for in vitro functional assays.

Mechanistic Model / Interpretation

  IFNAR1 biallelic LOF (p.Glu386*, deletion, CNV)
 │
 ▼
  No functional IFNAR1 at cell surface
 │
 ▼
  IFN-α/β/ω cannot form IFNAR1+IFNAR2 ternary complex
 │
 ▼
  JAK1 / TYK2 not juxtaposed → no cross-phosphorylation
 │
 ▼
  STAT1 / STAT2 not phosphorylated → no ISGF3 (STAT1-STAT2-IRF9)
 │
 ▼
  No ISG induction → loss of cell-intrinsic antiviral state
 │
┌────────┴─────────┐
▼                  ▼
  TRIGGER: live vaccine   TRIGGER: select wild-type
  (MMR, YF-17D)           virus (e.g., SARS-CoV-2)
│                  │
▼                  ▼
  Uncontrolled viral replication in permissive cells
│
▼
  Disseminated disease: encephalitis / pneumonitis /
  hepatitis / multiorgan; may be fatal
│
└─(inferred branch)─► aberrant innate/inflammasome
              activation on viral trigger

The unifying interpretation is that IFNAR1 deficiency removes a single, non-redundant node (the obligate IFNAR1 chain) of the type I IFN receptor, collapsing the entire IFN-α/β/ω arm of antiviral immunity. In humans, this arm turns out to be essential but narrow — dispensable for containment of most everyday viruses (thanks to redundancy with type II/III IFN and other pathways), but indispensable for controlling attenuated-vaccine viruses and a limited set of wild-type viruses. This explains the paradox of an "otherwise healthy" patient who nonetheless suffers catastrophic vaccine or COVID-19 disease. The parallel with IFNAR2 deficiency (fatal encephalitis after MMR, yet no prior heightened respiratory-virus susceptibility PMID: 26424569) confirms the pattern applies to the whole IFNAR receptor.

"Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens... supports an essential but narrow role for IFN-α/β in human antiviral immunity." — PMID: 26424569

Evidence Base

PMID	Study	Contribution	Source type
35442418	Bastard et al. 2022	Defines AR IFNAR1 deficiency; Polynesian founder p.Glu386* (MAF >1% Samoa); abolished IFN responses	Human clinical + functional
31270247	Hernandez et al. 2019	First description; MMR/YF live-vaccine adverse reactions in otherwise healthy patients	Human clinical
42097348	Azamor et al. 2026	Homozygous CNV Δ3-4-5; fatal YF vaccine AEs; advocates pre-vaccination screening	Human clinical + functional
35091979	Abolhassani et al. 2022	Homozygous LOF deletion; critical COVID-19 + MIS-C; fatal	Human clinical
35708626	Zhang et al. 2022	Recessive type I IFN IEIs in ~10.7% of pediatric COVID pneumonia; IFNAR1-deficient fibroblasts vulnerable to SARS-CoV-2	Human clinical + in vitro
38608537	de Weerd et al. 2024	Structure–function of type I/III IFN receptor signaling (ternary complex, JAK/TYK/STAT)	Review / structural
33729549	Meyts & Casanova 2021	Human vs mouse type I IFN redundancy; explains narrow human phenotype	Review
26424569	Duncan et al. 2015	IFNAR2 deficiency; "essential but narrow" role; otherwise-healthy phenotype	Human clinical
39312669	Gervais et al. 2024	Whole-blood assay detecting both inborn errors and autoantibody phenocopies	Methods
42524028	Kholaiq et al. 2026	Anti–type I IFN autoantibodies in 10–15% of critical COVID-19 (acquired phenocopy)	Human clinical

Consistency across independent kindreds and continents (Polynesia, Brazil, Iran, and pediatric COVID cohorts) reinforces the core disease definition. The mouse-model literature (Nipah, Akabane, Zika, dengue, Bourbon) both supports the mechanistic centrality of type I IFN and, by its broad lethality, usefully contrasts with the narrower human phenotype.

Limitations and Knowledge Gaps

Ultra-rarity: Total reported cases number in the low dozens; there are no formal prevalence/incidence estimates, no QoL instruments, and no natural-history cohorts. Epidemiology outside Polynesia is essentially unknown.
Variant spectrum incompletely mapped: Beyond the founder nonsense allele and a few deletions/CNVs, the full mutational landscape (missense, splice, regulatory) and genotype–phenotype correlations are undefined.
Trigger–outcome uncertainty: It is not fully resolved which wild-type viruses cause severe disease in IFNAR1-deficient humans versus which are contained by redundancy. The role of inflammasome/innate hyperactivation as a driver of immunopathology is inferred, not proven.
Therapeutics: No disease-specific therapy or gene therapy exists; HSCT experience is anecdotal, with outcomes not systematically reported.
Modifiers: No genetic/epigenetic modifiers of severity have been identified.
Model translation gap: IFNAR1-KO mice overstate susceptibility, complicating direct translation of preclinical antiviral/vaccine findings.

Proposed Follow-up Experiments / Actions

Establish an international patient registry for IFNAR1 (and broader type I IFN pathway) deficiency to capture prevalence, natural history, triggers, outcomes, and HSCT results.
Population screening in Polynesia: Systematic carrier screening for p.Glu386* and integration into pre-vaccination protocols; quantify carrier frequency and true regional prevalence.
Genotype–phenotype cataloging: Curate all IFNAR1 variants (with CNV detection) in ClinVar/IEI databases and correlate variant class with clinical severity and triggering virus.
Standardized functional diagnostics: Broaden validation and deployment of whole-blood ISG-induction assays (IP-10/CXCL10) that simultaneously flag inborn errors and neutralizing autoantibodies, enabling rapid differential diagnosis in severe viral illness.
Prospective evaluation of HSCT as curative therapy in severe cases; and preclinical exploration of IFNAR1 gene-addition/editing in patient iPSC-derived immune cells.
Precision vaccinology guidelines: Formalize recommendations to withhold/replace live vaccines and to screen relatives of individuals with severe adverse events following live-attenuated (especially yellow fever) vaccination.
Refine model systems: Complement IFNAR1-KO mice with humanized or conditional models, and patient-derived organoids/iPSCs, to better recapitulate the narrow human antiviral phenotype for therapeutic testing.

Report compiled from 9 confirmed findings across 5 investigation iterations, drawing on 38 reviewed papers. Evidence types are annotated as human clinical, model organism, in vitro, or review throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	21
Resolved	21
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	21
On topic	20
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	20
Resolved	19
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	16
Terms named correctly	8
Terms named as a different term	6
Terms whose name is worth a second look	2

Terms the report names something else

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:

MONDO:0030970 (2 mentions) - the report calls it "MONDO"; MONDO calls it immunodeficiency 106, susceptibility to viral infections
HP:0002090 (2 mentions) - the report calls it "Clinical sign"; HP calls it Pneumonia
HP:0002383 (2 mentions) - the report calls it "Clinical sign"; HP calls it Infectious encephalitis
HP:0032251 (1 mention) - the report calls it "Abnormal susceptibility to viral infection"; HP calls it Abnormal immune system morphology
GO:0005886 (1 mention) - the report calls it "Subcellular level: IFNAR1 is a plasma membrane receptor"; GO calls it plasma membrane**
NCIT:C15320 (1 mention) - the report calls it "Supportive Care"; NCIT calls it Study Design

Terms whose name is worth a second look

The 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:

GO:0060337 (2 mentions) - the report calls it "type I interferon signaling pathway"; GO calls it type I interferon-mediated signaling pathway, and lists "type I interferon signaling pathway" among its other names
NCIT:C258 (1 mention) - the report calls it "Antiviral Agent"; NCIT calls it Antibiotic, and lists "Antimicrobial Agent" among its other names

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IFNAR1 Deficiency: A Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

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