Genetic testing can narrow CVID diagnosis

Chris Simpson spent most of his life thinking that common variable immunodeficiency (CVID) caused his critical illnesses. Last year, genetic testing showed a different diagnosis that allowed him to shift his treatment strategy and better understand his complicated health issues.

Simpson’s diagnosis of CVID came at age 2 after he almost died from the flu, gastrointestinal (GI) problems, and weight loss. He started on intravenous immunoglobulin (IVIG) replacement therapy, but the treatment didn’t help. As a child, he had multiple, lengthy hospital stays for severe infections that almost led to his death.

In adulthood, he developed liver disease and came close to dying again. In his 20s, after he lost weight and became malnourished, Simpson learned he had celiac disease, an autoimmune disorder that prevents nutrient absorption. A few years later, a chronic cough led to a diagnosis of bronchiectasis.

Simpson finally connected with an immunologist who ordered genetic testing and in May 2023, at the age of 37, he learned he didn’t have CVID—he has hyper IgM syndrome, a rare PI that has a life expectancy of less than 30 years.

“My whole life I’ve just gone about saying, ‘Oh I don’t have a working immune system.’ And then I’m told that I have hyper IgM, which is a little more severe than CVID. Statistically, I shouldn’t be alive,” said Simpson. “It was rough.”

Simpson is now on prophylactic antibiotics to prevent opportunistic infections related to hyper IgM. He also started a workout routine at a CrossFit gym where he is now a part-time trainer and focuses on proper nutrition to keep his body healthy. He is weighing the risks and benefits of treatments including bone marrow transplant, liver transplant, and gene therapy.

As genetic testing technology develops, more patients with CVID and their providers consider its use to pinpoint a more specific diagnosis. One of the most frequently diagnosed PIs, CVID is characterized by low levels of antibodies and caused by one or more genetic variants. Roughly one-quarter of people with CVID symptoms turn out to have a variant in a single gene, but for about three-quarters of the people with CVID, a single (or multiple) genetic variant/s cannot be identified.

Dr. Roshini Abraham, a diagnostic immunologist with Nationwide Children’s Hospital, in Columbus, Ohio, recommends patients with CVID pursue genetic testing, despite the relatively low yield in identifying PI-causing gene variants. Identifying the specific genetic variant through genetic testing, when a positive result is obtained, can provide a conclusive diagnosis and inform treatment.

“Common variable immunodeficiency is a broad umbrella term. It doesn't mean very much, without understanding what the term actually describes. There are a number of different monogenic (single gene) defects associated with CVID, and then there are genetically undiagnosed CVID, so the term, ‘CVID’ means that the individual has [an]...immune profile that fits that broad description. There can be a lot of depth to that term if properly understood,” said Abraham.

“Being able to put a clear genetic and diagnostic label is very helpful both for the patient and the physician in terms of management. When we understand the genetic basis of disease, we can use that information to predict disease severity and the approach to clinical management.”

Genetic testing can also assist in determining if other members of the family are affected. For example, parents want to know if they will pass on a PI-causing gene variant to their children or, if one of their children is affected, they want to know if siblings have the gene variant too.

“The ultimate goal is to improve survival and outcomes. Genetic testing is pretty integral to the diagnosis of rare diseases. Physicians (non-geneticists) are being trained to understand and interpret genetic testing, and it's become part of the evaluation of PIs,” said Abraham.

Sandy Adams, 69, diagnosed with CVID in her 40s, moved forward with genetic testing because she suspects family members may also have PI and wanted to provide them with information. The test results came back inconclusive, but Adams is still satisfied that she tested.

“It was frustrating at first because I really wanted to know. I wanted ideas. But then I looked at it and I said, ‘You know what? They now have my genetic information, so there’s a possibility that we might know more in the future. So that excited me,” said Adams.

“I think it's good for people to know that even if they don't get a result immediately those results still exist and as medicine makes progress, they can use that information.”

The three tiers of genetic testing currently available as clinical tests —targeted panel testing, exome testing, and genome testing—capture different levels of information. Targeted panel testing is the most limited in scope, exome offers a wider lens, and genome provides a vast amount of data.

Through genetic testing, clinicians can identify if there is a genetic cause for CVID symptoms. The gene variant may either be inherited or arise as a spontaneous variant in that individual.

Targeted panel testing is the most widely used genetic test. In targeted panel testing, the patient’s genes are analyzed for a group (or panel) of several hundred genes associated with the condition. A targeted panel is most useful when a person has well-defined clinical features suggestive of a PI and genes related to the list of possible symptoms that could be causing a patient’s condition are adequately represented on the panel, said Abraham.

Targeted panels are more likely than exome and genome to be covered by insurance. Funding is also available through some companies that manufacture drugs for certain diseases. If funding sources fail, the test usually costs about $250 out-of-pocket, when performed in commercial labs.

“The advantage is they are cost-effective and because the data is limited, more amenable to bioinformatics analysis and you can get reasonably good coverage of the genes on that panel. People like targeted panels for that reason,” said Abraham.

“However, we’ve now crossed the threshold of over 500 genes associated with PI, so the challenge with targeted panels is staying up to date with new genetic discoveries.”

The next level up in genetic testing is exome testing, which examines the part of genes that code for a protein or other molecule, called exons, and does not specifically target PI. Exome testing increases the amount of data obtained relative to targeted panel testing, and the interpretation of that data becomes more complicated.

Genome testing is the most in-depth genetic testing and further scales up the amount of data obtained from either a targeted panel or an exome. In genome testing, researchers look through the entire genetic material, or DNA, in an individual—both coding and non-coding areas of the genome. Because the data is so complex, testing a patient and their parents at the same time is preferable to sort through which variants track with inheriting PI.

“With the genome, it’s hard to know what is noise and what is signal, what is not relevant and what is relevant. That’s why it is preferable to include parents in the testing and do what’s called a trio analysis because it can focus the list of genetic possibilities. Otherwise, there's just too much data,” explained Abraham.

“In the bioinformatics filtering tools, if we have the proband (patient) data along with the parent data, we can filter out some of that noise and narrow down our signal.”

Most doctors start with the targeted genetic panel because it’s affordable and the data is manageable, particularly if the clinician is not an immunologist or well-versed in genetic testing.

“Some physicians may feel overwhelmed by the rapid growth in the field of immunology, and may sometimes use genetic testing as part of their differential diagnosis. In other words, they're using that test to give them some ideas of what conditions might fit the patient’s [symptoms] ,” said Abraham.

Proper interpretation of any data, including genetic data, is critical. The physician must have some knowledge of PI genes, which is helpful in figuring out when a piece of data is clinically meaningful, said Abraham.

“We always recommend appropriate genetic counseling and support. If you clearly explain important points about immunodeficiencies and the immune system, set expectations regarding genetic testing, and explain the different types of genetic tests and what potential results might or might not be obtained, it becomes much easier to help the patients on the back end when the results come in,” said Abraham.

“You've already educated them properly on what you might get, what you might not get, and what the next steps would be. Then you keep on educating them throughout the process of diagnostic evaluation and management.”

Sometimes genetic testing only turns up variants of unknown significance or VUSs. Test results may often show more than one VUS, and in multiple genes, which means that there is limited data or no data available to classify the role of that variant in that gene in regard to the patient’s disease.

In these cases, the physician can find individuals with expertise to further analyze the variant or specialized laboratories that can perform additional studies to clarify the impact of that variant in that gene. Also, engaging other physician and scientist colleagues around the globe can facilitate finding the right answers for a patient, said Abraham.

The goal of the genetics field is to eliminate VUSs in the not-too-distant future, said Abraham. VUSs are currently labeled as such because of an information and knowledge gap, and science is constantly working to eliminate those gaps, she said.

“In our diagnostic immunology lab, as in other similar specialized laboratories around the country and globe, we interrogate different compartments of the immune system using a variety of tools so that we can give the clinicians some idea of where the immunological aberrations might lie. They can then assess the ‘cupboard’ of ‘immunomodulatory’ drugs or other treatments, and determine which individual or combination of drugs or treatments might be best suited for that patient,” said Abraham.

“So, evaluation of the immune system, functionally and otherwise, is still very important because we may not always get a clear genetic answer with the tools we have at present.

“There is still a discovery process in PI because people are still describing new genes and/or new phenotypes associated with genes that affect the immune system and/or other organ systems. We have crossed over the threshold of 500 genes described as being associated with PI, but that does not appear to be the end.”

While doctors may differ in their opinions of whether and when a patient should proceed with genetic testing, immunologists are usually in support of genetic testing, said Abraham.

“We encourage genetic testing because we want to utilize all the tools available at our disposal for early diagnosis and improved management of disease. This is, after all, the era of precision medicine. So, I think the more knowledge, the better,” said Abraham.

“I think in 2024 the people who don't do any genetic testing at all, even in the cases where a genetic defect may be suspected, are a minority. This could be related to access and other resource constraints, though there could be other reasons as well. Hopefully, access and resource issues will be non-existent in the near future as we strive for more equitable healthcare.”

From his perspective as a patient, Simpson recommends genetic testing because it can provide clarity, something people seek most when they have a CVID diagnosis.

“I am thankful for it. If the option exists, it doesn’t hurt to try,” he said.