Why genetic testing for primary immunodeficiencies may be useful

Individuals with primary immunodeficiencies (PIs) and their healthcare providers may not pursue genetic testing for a variety of reasons. Yet, it can be a powerful tool for confirming (or ruling out) a diagnosis. For those who get definitive information from it, which certainly isn’t everyone, genetic testing can inform everything from clinical management to decisions about family planning. 

PIs are caused by changes, or variants, in a person’s DNA. Four nucleotides make up DNA: adenine (A), thymidine (T), guanine (G), and cytosine (C). The order of these nucleotides, or the DNA "sequence," encodes instructions for making proteins, cells, and organs, similar to how specific sequences of letters form words, sentences, and paragraphs. Genetic testing for PI looks for variants in a person’s DNA sequence that are most likely to explain their condition.

Reasons people don’t get tested

Their condition’s genetic cause is unknown

Some of the most common PIs are antibody deficiencies like common variable immune deficiency (CVID) without known genetic causes. Often, healthcare providers are skeptical of genetic testing for people with these diagnoses because they think testing is unlikely to provide any information.

However, the most recent classification of PIs lists variants in 23 genes that cause CVID-like disorders. It is impossible to determine whether someone with a CVID diagnosis has one of these conditions or not without genetic testing. 

Why does it matter if someone has CVID or a CVID-like disorder? Some of these disorders, like activated PI3K delta syndrome (APDS), have specific treatments or different risks for complications than CVID. It’s important to test for them if only to rule them out.

The outcome won’t affect clinical management or treatment

Another barrier to genetic testing is the belief that the outcome will not affect clinical management or treatment for a particular person. In fact, in a study conducted by the Jeffrey Modell Foundation, clinical management and/or treatment changed for more than 35% of individuals with a clinical PI diagnosis who underwent panel testing. That same study found other benefits to genetic testing as well, including enabling more informed family planning decisions and identifying relatives at risk of PI or who could be genetic carriers. 

Finally, having a genetic diagnosis may not affect the current course of treatment or clinical management, but it could determine whether someone is a candidate for emerging therapies or whether they are eligible for clinical trials. 

Cost

The cost of genetic testing is a significant factor in whether people choose to get tested or not. Without insurance, genetic tests cost anywhere from $100 to several thousand dollars, depending on their complexity. Insurance companies will cover genetic testing if they deem it medically necessary, although the testing typically requires prior authorization. 

In addition, there are programs that offer free genetic testing to certain individuals, such as navigateADPS and PATH4WARD. The Jeffrey Modell Foundation also offers free genetic testing for anyone suspected to have PI through its Jeffrey’s Insights program, which is available to clinicians at any of the 400+ institutions in the Jeffrey Modell Centers Network (JMCN).

What (typical) genetic testing can miss

Like any medical test, genetic testing has technical limits, as well as limits related to how laboratories analyze the results. For example, some variants involve large chunks of DNA rather than single-letter changes or small insertions or deletions in a gene. These structural variants (SVs) are difficult to pick up and are not routinely included in data analysis. Less common types of genetic testing like chromosomal microarrays or long-read sequencing are better suited to detecting SVs. Researchers are also working on specialized analysis to look for SVs specifically.

Another example is somatic mosaicism. Somatic mosaicism describes when cells from the same individual have different DNA sequences. Dr. Megan Cooper identified TLR8 GOF, a relatively new PI, largely from patients who were mosaic for TLR8 gene variants. All of them had the variant in less than 30% of their cells. While somatic mosaicism can be detected with the technology used in standard genetic testing, it is very easy to miss or ignore during data analysis. Typically, specific analysis tools designed to catch mosaicism have to be used.

Until researchers understand the genetic basis of every type of PI and overcome all of the technical challenges of capturing every type of variant, genetic testing won’t give everyone answers. But even if you don’t receive a genetic diagnosis from it, testing may be worthwhile for you.