Genetic testing is key to diagnosing primary immunodeficiencies

Key takeaways:

• Genetic testing can definitively distinguish between immunodeficiencies.
• Many genetic testing laboratories offer clinical consulting.
• Sponsored programs support access to genetic testing.

There are more than 450 monogenetic immune deficiencies. While many of these rare conditions have similar hallmarks, it is crucial for clinicians to differentiate between them.

Primary immunodeficiencies (PIs) can be easily mistaken for each other because they make patients susceptible to a host of symptoms, especially infections, usually from an early age. However, each has a distinct cause and must be managed differently, with treatments ranging from off-label therapies to targeted drugs.

The best way to ensure that our patients receive appropriate care is to diagnose them via genetic testing, which can definitively distinguish between immunodeficiencies. It is a responsibility the medical community shares, as patients with these diseases typically seek answers from doctors across a host of pediatric and adult specialties, including allergy and immunology, hematology and oncology, rheumatology, gastroenterology and pulmonology.

That is why genetic testing of these patients should become a best practice for all of us, whether we order and interpret the assays ourselves or refer our cases to expert colleagues.

Better disease management

For decades, the mainstay in diagnosing immune deficiencies was functional testing, along with immunophenotyping. But over the last 15 or 20 years, genetic testing has become a crucial part of the diagnostic framework.

By confirming a diagnosis, the testing not only can warn us that we need to monitor for certain dangerous symptoms, but it also can significantly shift our management approaches for better patient outcomes.

An excellent example is activated PI3K delta syndrome, or APDS.

APDS is a rare PI caused by variations in the PIK3CD or PIK3R1 genes. It manifests with severe, recurrent respiratory infections; swollen lymph nodes, liver and/or spleen; nodules or masses in the gastrointestinal tract; autoimmune cytopenias and autoinflammatory diseases; and/or enteropathy.

But without clarity about genetic drivers, APDS can be mistaken for common variable immune deficiency (CVID), hyper IgM syndromes, autoimmune lymphoproliferative syndrome, or Evans syndrome.

For patients with APDS, misdiagnosis can enable symptom progression resulting in hospital stays, missed school and work, scarring of the lungs, damage to the liver and/or kidneys or even early mortality. Furthermore, an estimated 12% to 25% of these patients are at risk for developing lymphoma.

Gaining a diagnosis via genetic testing can help manage progression both through monitoring for lymphoma and end-organ damage and by identifying appropriate therapeutic strategies.

While many other immunodeficiencies do not have designated treatments, doctors can still find it helpful to understand which cellular pathway is defective in their patients so they can intervene with symptomatic treatments and stay on the lookout for relevant clinical trials.

Whom to test, and when?

As a relatively new technique that is not widely used outside major academic centers, how can clinicians recognize when to order genetic testing, and in whom?

The rule of thumb is simple: Clinicians should order testing for any patient with CVID or suspected inborn error of immunity as soon as possible. A particular red flag is a patient diagnosed with CVID who has additional noninfectious symptoms that are significant and unexplained, such as a history of lymphoma or autoimmunity.

Doctors can find further information through resources from the Jeffrey Modell Foundation and the Immune Deficiency Foundation as well as from disease state-specific websites, such as All About APDS.

Their next task is to evaluate test results. Genetic variants are reported as pathogenic or likely pathogenic, confirming an illness and warranting a treatment plan; benign or likely benign, meaning there is no evidence of a genetically driven illness; or variant of uncertain significance (VUS), an inconclusive finding.

Some doctors may struggle with the nuances of interpreting genetic testing results, especially the sleuthing that can be involved in researching the relevance of a VUS finding, but their uncertainty should not prevent them from ensuring that their patients benefit from the assays.

Clinicians who want to better understand genetic findings can take advantage of the clinical consultation services offered at many genetic testing laboratories. They can also seek out CME activities through organizations including the American Academy of Allergy, Asthma & Immunology and the Clinical Immunology Society or academic medical centers. Those who are not comfortable ordering or interpreting genetic tests may refer their patients to geneticists.

If a primary immunodeficiency is confirmed, the ordering physician should also conduct genetic testing on biological relatives of the patient who might be affected.

Whom to test depends on how a disease is inherited. In an autosomal recessive disease, which is passed to a patient by both parents, genetic testing may be limited to siblings, who face a 25% chance of having the condition. In an X-linked recessive disease, it makes sense to test male relatives on the mother’s side.

Meanwhile, in an autosomal dominant disease such as APDS, in which patients only need one copy of a mutated gene to be affected, clinicians should start by testing siblings and parents and then continue through the family until a patient either refuses the testing or has negative findings. This process of family mapping may even extend as far as grandparents, aunts, uncles and cousins, with the goal of identifying shared genetic variants to help confirm diagnosis.

Making genetic testing accessible

Although I have succeeded in ordering genetic testing on all my eligible patients, I often have had to jump through hoops to do it, primarily due to health insurance rules that limit coverage for the technology.

Fortunately, a variety of sponsored programs exists to help facilitate access. One such example is navigateAPDS, a program sponsored by Pharming Healthcare that offers genetic testing for eligible patients in the U.S. or Canada with clinical histories that suggest APDS.

In this example, providers can order comprehensive genetic testing by selecting one of two immunology gene panels. These broad panels allow doctors to cast a wide net when investigating whether a patient has APDS or a similar disease.

Also, navigateAPDS provides added help by offering no-cost genetic counseling before and after testing, which can support physicians in explaining results and next steps to their patients.

In addition, navigateAPDS offers free genetic testing to all blood relatives of patients found to have a pathogenic or likely pathogenic variant or a VUS in the PIK3CD or PIK3R1 genes. This familial variant testing seeks to identify any additional individuals living with the identified disease and may provide information to assist in the resolution or reclassification of VUSs into the benign or pathogenic categories. The goal is to remove barriers to diagnosis, as research shows that, among the relatives of people with positive findings, just a small proportion pursues genetic testing.

A new best practice

The importance of genetic testing in diagnosing PIs cannot be overstated, and that creates a clear directive for doctors across numerous specialties who may encounter patients with symptoms of these conditions.

Whether we order the assays ourselves or refer patients to our colleagues, it is time for each of us to recognize the power of genetic testing to transform vexing clinical mysteries into confirmed and actionable diagnoses, bringing meaningful change to our management of patients with these rare and life-altering diseases.

References:

• Bousfiha A, et al. J Clin Immunol. 2022;doi:10.1007/s10875-022-01352-z.
• Carpier JM, et al. Front Immunol. 2017;doi:10.3389/fimmu.2017.02005.
• Coulter TI, et al. J Allergy Clin Immunol. 2016;doi:10.1016/j.jaci.2016.06.021.
• Elkaim E, et al. J Allergy Clin Immunol. 2016;doi:10.1016/j.jaci.2016.03.022.
• Jamee M, et al. Clin Rev Allergy Immunol. 2019;doi:10.1007/s12016-019-08738-9.
• Maccari ME, et al. Front Immunol. 2018;doi:10.3389/fimmu.2018.00543.
• Quinn J, et al. Immunol Res. 2020;doi:10.1007/s12026-020-09131-x.
• Rotz SJ, et al. Pediatr Blood Cancer. 2018;doi:10.1002/pbc.27260.
• Sturm AC. Front Cardiovasc Med. 2016;doi:10.3389/fcvm.2016/00011.

For more information:

Nicholas Hartog, MD, is a board-certified physician specializing in pediatric and adult allergy and immunology at Helen DeVos Children’s Hospital. He can be reached at nicholas.hartog@spectrumhealth.org.