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Conditions

Type 1 interferonopathies

Type 1 interferonopathies are a group of rare autoinflammatory conditions caused by pathogenic variants in genes implicated in aberrant interferon (IFN) production and signalling. These encompass Aicardi-Goutières syndrome and STING-associated vasculopathy with infantile onset.

Overview

Interferonopathies are rare genetic conditions caused by dysregulated interferon signalling. They result from variants affecting type 1 interferon production or signalling pathways. Clinical presentations include early-onset systemic autoinflammation, skin manifestations (chilblains, rashes), central nervous system involvement and autoimmunity.

Aicardi-Goutières syndrome is caused by variants in genes involved in DNA and RNA metabolism and innate immune sensing. These include TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, IFIH1 and DDX58.

Both STING-associated vasculopathy with infantile onset (SAVI), which is caused by variants in the TMEM173 gene, and DNASE2 deficiency can also cause excessive interferon production.

Clinical features

Interferonopathies cause clinical features of systemic autoinflammation.

Aicardi-Goutières syndrome causes a classic triad of major features:

  • neurological symptoms that include progressive encephalopathy with white matter anomalies and intracranial calcifications on MRI brain imaging;
  • systemic autoinflammatory symptoms that include recurrent fever, arthritis and myositis; and
  • cutaneous features that include chilblain-like lesions, livedo reticularis, vasculitic rashes and panniculitis.

Aicardi-Goutières syndrome is caused by variants in several different genes, as described below.

  • TREX1 variants typically cause early-onset (often neonatal) disease with prominent encephalopathy, severe intellectual disability and high mortality. The key differential is of congenital infection.
  • RNASEH2A and RNASEH2C variants also cause prominent encephalopathy with high frequency of refractory seizures.
  • RNASEH2B variants have been associated with later onset and with relatively preserved intellectual function.
  • SAMHD1 variants typically present with milder neurological involvement but more prominent chilblains, with some overlap with familial chilblain lupus.
  • Variants in both IFIH1 and DDX58 cause variable clinical features with prominent SLE-like photosensitive rash.

SAVI is a severe autoinflammatory condition that typically presents in the first months of life. Clinical features are similar to Aicardi-Goutières syndrome but with prominent cutaneous manifestations, including indurated, purple inflammatory plaques on extremities and early-onset interstitial lung disease. Other features include recurrent low-grade fevers, failure to thrive, polyarthritis and lymphadenopathy. Most patients present with marked elevated CRP (>100mg/L).

Genomics

Aicardi-Goutières syndrome

This condition is caused by pathogenic variants in seven genes (see Table 1). These trigger innate immune sensing, which leads to excessive type 1 interferon.

Table 1: Genes implicated in Aicardi-Goutières syndrome

Gene Protein Inheritance Frequency Mechanism of action Type of variant
TREX1 DNA exonuclease Autosomal recessive 30% Aberrant DNA accumulation Loss of function (frameshift, nonsense, slice site)

Dominant negative (this is rare but has been reported)
RNASEH2A Component of RNase H2 enzyme Autosomal recessive 35% Defective RNA degradation Loss of function (mostly missense)
RNASEH2B Component of RNase H2 enzyme Autosomal recessive 20% Defective RNA degradation Loss of function (mostly missense)
RNASEH2C Component of RNase H2 enzyme Autosomal recessive 5% Defective RNA degradation Loss of function (mostly missense)
SAMHD1 deoxynucleotide (dNTP)ase enzyme Autosomal recessive 5% Accumulation of dNTPs Loss of function
(missense, frameshift, nonsense, slice site, insertions and deletions)
IFIH1 MDA5 pattern recognition receptor Autosomal dominant <5% Constitutive activation of interferon pathway Gain of function (missense)
DDX58 RIG-I pattern recognition receptor Autosomal dominant <5% Constitutive activation of interferon pathway Gain of function (missense)

Other recently described monogenic conditions that may present with Aicardi-Goutières syndrome-like features are caused by variants in the POLA1, PRIM1 and ADAR1 genes.

STING-associated vasculopathy with infantile onset (SAVI)

SAVI is caused by monoallelic, gain-of-function genetic variants in TMEM173. The gene encodes a DNA sensor that, in its altered form, causes constitutive activation. This leads to IRF3 and NF-κB activation, which triggers type 1 interferon production. Most cases of SAVI are de novo with autosomal dominant inheritance.

For more information about the genetic variants linked to hereditary autoinflammatory conditions, see the curated variant database Infevers, which is run by academics and clinicians in association with the International Society for Systemic Autoinflammatory Diseases.

Diagnosis

Genomic testing is required for definitive diagnosis of monogenic interferonopathies in a patient with suggestive clinical features.

Supportive clinical and laboratory findings include:

  • suggestive clinical features as outlined above;
  • markedly elevated CRP and ESR (in about 50% of cases);
  • characteristic anomalies on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes);
  • a positive ‘interferon signature’ – that is, persistent up-regulation of type 1 interferon-stimulated gene expression (these may be requested in specialist laboratories); and
  • elevated expression of interferon-stimulated genes (research-based testing).

For information about testing, see ‘Child with a suspected autoinflammatory condition‘.

Type 1 interferonopathies may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to autoinflammatory or specialist rheumatology services. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

Type 1 interferonopathies are typically caused by biallelic pathogenic genetic variants in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, PRIM1, POLA1 and ADAR1.

Incomplete penetrance can occur, which means that not everyone who has the variants develops the disease. Generally high penetrance is observed in autosomal recessive forms of these conditions, though some familial cases of asymptomatic biallelic carriers have been described.

  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Other genetic causes of Aicardi-Goutières syndrome (gain-of-function variants in IFIH1 and DDX58, and some dominant-negative variants in TREX1) are inherited in an autosomal dominant pattern. These interferonopathies demonstrate higher levels of incomplete penetrance and variable expressivity, despite biochemical evidence of enhanced type 1 interferon signalling, even into adulthood. While de novo variants are reported, dominant inheritance is more typically observed.

  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
  • Incomplete penetrance can occur.

SAVI is caused by heterozygous pathogenic variants in TMEM173, with high penetrance reported in gain-of-function variants. Most cases are de novo, likely due to low fertility in surviving patients.

Where a type 1 interferonopathy is suspected, a family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

Type 1 interferonopathies are rare, complex conditions and are best managed by a multidisciplinary autoinflammatory and/or specialist rheumatology service. Treatment is aimed at controlling inflammation and preventing life-threatening complications, such as prolonged seizures.

The main disease-modifying treatment for both Aicardi-Goutières syndrome and SAVI are JAK inhibitors, such as ruxolitinib and baricitinib. These are specific small proteins that can block the JAK signalling pathways that interrupt type 1 interferon signalling and production. Early initiation of treatment has been demonstrated to have more favourable outcomes.

Mild or intermittent inflammatory symptoms may be treated with non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids. Patients may also require anti-seizure medication for severe or refractory seizures.

Type 1 interferonopathies may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 16/01/2026
  • Next review due: 16/01/2028
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay