IFIH1

The IFIH1 gene encodes MDA5, a key sensor in the innate immune system that detects viral double-stranded RNA and triggers antiviral defenses through interferon production. 

Changes in IFIH1 can either heighten inflammation, leading to autoimmune and inflammatory diseases, or weaken viral defenses, resulting in severe infections.

What is IFIH1?

The IFIH1 gene gives instructions for making a cytoplasmic protein called MDA5 (melanoma differentiation-associated protein 5). MDA5 is part of the body's first line of immune defense, called the innate immune system.

MDA5 works like an alarm system inside cells. It detects double-stranded RNA (dsRNA)—a type of genetic material viruses often make when infecting our cells. 

Once MDA5 senses this RNA, it triggers a chain reaction that tells the body to produce interferons—proteins that stop viruses from spreading and help alert the immune system to fight back.

When Is IFIH1 Genetic Testing Relevant?

IFIH1 genetic testing is not a routine test; instead, it may be considered in the following scenarios:

Research and Rare Conditions

Genetic testing of IFIH1 is not commonly done in everyday medical care. However, it can be helpful in special cases, especially in research or clinical assessment for certain rare conditions.

Autoimmune Diseases

Research shows that changes in the IFIH1 gene are linked to diseases where the immune system attacks the body, such as:

• Type 1 diabetes
• Systemic lupus erythematosus (SLE)
• Early-onset Inflammatory bowel disease (IBD)

Unusual Infections

In rare cases, IFIH1 testing may help explain why a person gets severe viral infections, especially in early life.

Rare Genetic Syndromes

Testing is sometimes done when a patient has signs of rare inflammatory diseases involving the brain, skin, bones, or blood vessels.

IFIH1 Genetic Testing: Test Procedure and Interpretation

Testing for IFIH1 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for IFIH1 genetic testing are considered to be without mutations that can alter the activity of the IFIH1 proteins.

What Do IFIH1 Gene Changes Mean?

Depending on the scenario, genetic mutations can have different effects:

Gain-of-Function Variants (Too Much MDA5 Activity)

Some people have genetic mutations that make MDA5 overactive. This leads to too many interferons, which causes chronic inflammation, even when there's no infection.

Conditions linked to this include:

Aicardi-Goutières Syndrome

Aicardi-Goutières Syndrome is a rare disease characterized by brain inflammation, calcium buildup, and skin or immune system problems.

Singleton-Merten Syndrome

Singleton-Merten Syndrome causes calcification in the heart and blood vessels, dental abnormalities, and bone problems.

These disorders are sometimes called interferonopathies, because they involve too much interferon signaling. Some people with these genetic mutations show overlapping symptoms of both syndromes, which suggests a disease spectrum.

Loss-of-Function Variants (Too Little MDA5 Activity)

Other people have mutations that make MDA5 unable to detect viruses. These people may get frequent, severe viral infections, especially in the lungs and airways (like from RSV, flu, or rhinovirus).

This rare condition is called MDA5 deficiency and usually appears in infants or young children.

Common Variants (Polymorphisms)

More common gene changes, called polymorphisms, can slightly change how active MDA5 is.

More active versions are linked to a higher risk of autoimmune diseases (like type 1 diabetes or lupus).

Less active versions may lower the risk of these conditions, but might slightly increase the risk of infections.

What If Someone Doesn’t Have These Gene Variants?

Not having these specific gene changes doesn’t mean the immune system works perfectly. Many other genes and environmental factors affect how our immune system responds to viruses or autoimmune triggers. IFIH1 is just one piece of a much larger puzzle.

Key Points for Clinicians

• MDA5 helps detect viruses early, triggering an interferon response.
• Overactive MDA5 causes autoimmune or inflammatory diseases.
• Underactive MDA5 increases risk for severe viral infections.
• IFIH1 gene testing may help diagnose:
  
  • Early-onset autoimmune or inflammatory syndromes
  • Unexplained viral infections in infants or children
• In some cases, treatment might include:
  
  • JAK inhibitors for conditions with too much interferon activity.
  • Preventive antivirals or vaccines for those with weak interferon responses.

Order Genetic Testing

Click here to compare genetic test panels and order genetic testing for health-related SNPs.