Diagnostic Tools for Autoinflammatory Diseases
Genetic testing and other resources for periodic fever syndromes diagnosis.
Genetic Testing as a Diagnostic Tool
In Textbook of Autoinflammation published in 2019, Drs Ceccherini, Rusmini, and Arostegui state, “The importance of genetic tests to reach a definitive diagnosis has become evident during the past few years.” They also note that advancements in genetics, “has resulted in the increased awareness of the clinical diversity of these diseases, best therapeutic approaches and follow-up schemes for the patients…”
Since many of the autoinflammatory diseases share similar symptoms that may include recurrent high fevers, mouth ulcers, swollen lymph nodes, rashes, joint pain and/or swelling and other symptoms, running a genetic panel that tests for multiple syndromes at once is both efficient and cost effective. It also reduces the chances of missing the cause of the symptoms or missing comorbid conditions when an individual patient has genetics for multiple autoinflammatory diseases.
The most common fever syndrome PFAPA does not have a genetic test, but ruling out fever syndromes that can have similar symptoms, such as HIDS, CAPS, FMF, Behcet-like familial autoinflammatory syndrome (HA20) and TRAPS is important when diagnosing PFAPA. It’s been noted in research that, “A relevant number of patients with monogenic periodic fevers also meet the diagnostic criteria for PFAPA syndrome (Gattorno et al., 2008). In a preliminary experience, 83% of patients with MKD, 57% of patients with TRAPS, and 8% of patients with FMF satisfied the criteria for PFAPA syndrome.” Without genetic testing as part of the diagnosis these patients could easily be misdiagnosed and this may delay getting proper effective treatment.
Any doctor (including a pediatrician or primary care doctor) can order a genetic panel, and in the U.S. in most cases insurance will cover the costs of these tests as they are medical tests. But when needed, all labs have reasonable self-pay and payment plan options. Call the lab to find out your payment options. If you are outside the U.S., call the lab to find out the process for order a panel in your region.
Immune Dysregulation Genetic Panels Available
Several labs used in the U.S. and around the world have panels available that include periodic fever syndromes and other immune dysregulation syndromes, such as immune deficiencies, inflammatory bowel disease, and autoimmune conditions which can all have similar symptoms. All use next generation DNA sequencing, are very accurate tests, and can be ordered by doctors around the world. You can call the lab to find out the process for your region.
As of 2021 Invitae has the least expensive and most comprehensive 407 gene immune dysregulaion panel for autoinflammatory diseases in the US market at this time, and bills to insurance. They are the only lab in the US at this time that are offering a program for self-pay, with a telemedicine Dr ordering for the genetic test, if needed.
Self-pay for the genetic test alone (if your doctor orders the test) is only $250 for self pay* for 407 genes, and is the same cost for any of their genetic testing panels, so going for the largest, most comprehensive PI panel for a patient that has to self-pay for a test may be the most ideal option, but you can discuss this with your doctor.
The Invitae PI panel includes the most all known autoinflammatory genes, (51 in total), including some of the newer discovered syndromes. such as TNFAIP3, the gene for Behçet-like familial autoinflammatory syndrome and NLRP1-associated autoinflammation with arthritis and dyskeratosis. The LYN gene and the RELA gene are in this panel, which are not in the second most comprehensive panel from Fulgent at this time.
Invitae also has medical experts available to order genetic testing for patients at an additional cost of $129 to cover the telemedicine appointment with a geneticist to order the test, and then go over the results after they are completed. They do offer a payment plan to self-pay customers. Click here to learn more about Invitae’s Genome Medical Experts.
Also, Invitae is able to work with international doctors that want to order genetic testing for their patients, and this has been a less-expensive option, which has improved access to genetic testing for patients in a number of countries.
*$250 is the self-pay (no insurance used) price ONLY. When choosing to go through your insurance make sure you understand your insurance coverage, copay, deductibles and Invitae’s payment policies as insurance companies are billed up to $1500 according to Invitae’s website. Not all with high deductible plans have qualified for Invitae’s financial assistance. Read more here.
Fulgent has expanded their smaller, Periodic Fever/Autoinflammatory Disorders Panel to 47 genes, which is an improvement, and is one of the most comprehensive small panels now available, but this smaller panel lacks many of the genes in the larger PI panel. But the Fulgent 47 gene panel does has more genes in their autoinflammatory panel that are autoinflammatory than Invitae’s smaller autoinflammatory 12, 72 or 109 gene autoinflammatory panels, that are missing so many essential genes.
If a doctor is looking for a smaller panel, this 47 gene Fulgent panel has more included, such as TNFAIP3, but is also missing the LYN and RELA gene in this small panel, and in their large PID panel as well.
- Click here for the Fulgent Primary Immunodeficiency (PI) panel.
- Click here for the Fulgent Periodic Fever/Autoinflammatory Disorders 47 gene Panel
Prevention Genetics has improved their genetic testing options recently, and they offer a 486 gene Inborn Errors of Immunity/Primary Immunodeficiency (PID) Panel that has most of the autoinflammatory genes, but is missing the LYN gene. Their small 13 gene Periodic Fever Syndromes Panel does include TNFAIP3, but it is lacking in many other genes, in comparison to the 47 gene Fulgent panel.
- Click here for the Pevention Genetics PID Panel
- Clicker here for the Prevention Genetics 13 gene Periodic Fever Syndromes panel
Blueprint Genetics‘ primary immunodeficiency (PI) panel includes 298 genes with 46 genes associated with autoinflammatory diseases. Of the autoinflammatory diseases, it is missing a few such as the TNFRSF11A (TRAPS11) and LYN genes. There smaller panel has 29 autoinflammatory genes in the panel, but many important ones are missing, but the small and large panels do have TNFAIP3 in them. Blueprint offers payment programs for self-pay clients, and you would need to contact them for more details.
- Click here for the Blueprint Genetics 298 gene PI panel.
- Click here for the Blueprint Genetics 38 gene Autoinflammatory Panel.
For a smaller panel, the ARUP 10 gene autoinflammatory panel is an improvement from their past offering, as now they have more autoinflammatory genes included, such as TNFAIP3. But it is very limited, and less comprehensive than the Fulgent Periodic Fever/Autoinflammatory Disorders Panel to 47 genes.
If a doctor really only wants a small panel then the Fulgent 47 gene panel is still more comprehensive of all the smaller autoinflammatory panels that are not PI panels. The Blueprint genetics 38 gene panel is more comprehensive than ARUP or the small Prevention 13 gene Periodic Fever Panel, and Blueprint is more comprehensive than the invitae 12, 72 or 109 Autoinflammatory panels, but the Fulgent 47 gene panel is the best of all the small panels labeled as Periodic Fever/Autoinflammatory panels. Again, if you are needing to cover the most autoinflammatory genes on one lab test, nothing compares at this time to the comprehensive coverage in the Primary Immunodeficiency (PI) Invitae panel.
GeneDx (not listed at this time on our table above) is familiar to doctors, as they were the first to have genetic testing available, for autoinflammatory diseases in a small panel back as far as 2002 (or earlier), but they have continued to keep their Periodic Fever Syndromes 7 gene panel very small, and limited to 6 autoinflammatory genes, plus ELANE (cyclic neutropenia.) This test panel is the smallest now on the market, yet one of the most expensive. They are a reputable lab, as are the other labs on the table above.
Your doctor will review the symptoms, labs and assess for various features to decide on what panel may be best, but it is often a challenge to get genetic testing covered with insurance, so we tend to suggest that if you have one chance for genetics, going for a larger panel may be beneficial in certain cases, but this is up to your doctor. If you are having to self-pay for genetics, then you may want to address this, as you are paying for it, and will want to get the most testing needed, in one test.
One of the reasons we have made the genetic labs table, and are addressing what is missing in the panels available at this time is due to some important diseases that are newer, but can present like more known periodic fever syndromes, and it would be helpful to get a genetic test that was inclusive of more of these conditions.
TNFAIP3, aka HA20 is one disease that can have ulcers thoughout the oral and even genital region, with presentations in childhood that can mimic other periodic fevers, but have a familial Behçets-like presentation, but with fevers and some other features that are not typical for classic Behçets, and is emerging as a condition with a range of presentations. The hope is that with more comprehensive testing, these patients, and others with some of the newly classified and emerging autoinflammatory and immunedysregulatory diseases may be noted with the bigger testing panels now offered.
RELA also involves systemic inflammation, oral and genital ulcers, ulcerations and inflammatory bowel disease, and other features, but can also present as a mimic of Behçets disease, and is in a few panels above, but mostly in the larger PI panels.
There are many other important genes in the PI panels that are autoinflammatory diseases, that may have some immunedysregulatory or immunodeficiency component that can present in some ways like other more known autoinflammatory diseases.
Some doctors are also not as aware of these other conditions, so a broader testing panel may help to lead doctors to consider these diseases, and targeted treatments. Doing a small panel can lead to delays in a diagnosis and treatment if these other diseases are missed, and it can be harder to get more genetic testing approved later after a small panel has been done, with no findings.
Using a primary immunodeficiency (PI) panel does bring in more data, but until there is a more comprehensive, stand-alone autoinflammatory focused panel that features all the autoinflammatory diseases in it, that is updated regularly, the PI panel may be the best way to get all the known autoinflammatory genes tested that are possible to be tested in a commercial lab panel for some patients.
But Whole Exome (WES) or Whole Genome (WGS) sequencing or other big genetic testing methods may also be more effective and beneficial for some patients. but have other distinct features, such as PRAAS/CANDLE. At this time, only PSMB8 and POMP are in some of these panels on the chart above, so if PRAAS is considered, expanded genetics for other mutations for that condition will need to be ordered separately, or a WES or WGS may be helpful.
For the unclassified autoinflammatory/periodic fever patients that may have some other findings, immunoglobulin levels that are atypical, compement or frequent infections, or presentations that are very difficult to sort out between an autoinfammatory and immune deficiency, or even an autoimmune disease, the PI panels can address all of this better than the smaller autoinflammatory-specific panels that only have one or a few PI genes, most often ELANE (cyclic neutropenia) that can present very much like a periodic fever syndrome, but it is an immune deficiency.
In our private patient communities of over 6,100 members, the PI panel has actually helped some undiagnosed patients to have been diagnosed with an immune deficiency, or conditions, such as ALPS that were not even on the “radar” for the doctors, but the genetic test led to more diagnostics, care, and treatment that has helped those conditions, so there are benefits.
And lastly, a genetic test is still very beneficial, even if no clear genetics are found for a patient. This can be used to lead to other testing, or WES or WGS, or to continue with treating the symptoms, and waiting for more genetic findings to arise, as there is so much more to be discovered.
There are a number of patients that still may remain as unclassified or undifferentiated autoflammatory disease (uSAID) patients, but genetics can help to reassure that all that was currently possible was looked into, and if needed, WES or WGS may be offered, but not all may need that.
Regardless of genetic results, diagnosis by symptoms, and finding beneficial treatments that help the patient are essential, as we wait for science to progress in this field, especially for genetics. It is important to not use a genetic panel that comes back with no clear findings as the defining test to conclude someone then “must be PFAPA” if they are presenting differently than the criteria for that disease. Clinical diagnosis is most essential.
A referral for complex, systemic inflammation cases may be needed, and more testing may be needed for some patients. Labs that do WES and WGS, and even the panel tests listed above now will report later to the doctor, or patient (depends on the lab), if there are updates and new findings discovered in genes that may have not been reported in the past, or if there are updates in their classification from the original report, so genetic testing today has a lot more benefits to the patient, even beyond the initial data, that may be inconclusive. And having genetics done for a patient, even if nothing is clearly defined from it can be used in the application process for a referral for programs like the Undiagnosed Diseases Network, the NIH, or other research centers if the patient is complex, or not responding to treatments as hoped.
Edited and Co-authored by Autoinflammatory Alliance President Karen Durrant, RN BSN and leading experts on autoinflammatory diseases, this free online database describes the notable symptoms of currently known autoinflammatory syndromes. This database has become a highly respected and important diagnostic tool for doctors around the world. Since these diseases can be very similar and have overlapping symptoms, the chart can help narrow down which SAIDs to consider for a patient and can help guide further testing.
- Click here for the autoinflammatory online database.
- Click here for tips on using the autoinflammatory database.
Genetic Testing Registry
To find a doctor experienced with fever syndromes, contact the Autoinflammatory Alliance here.
We are trying to feature the most comprehensive panels for the widest number of classified autoinflammatory diseases available at this time, and have a limited area for the table. We are always on the lookout for more testing options, so please contact us for more suggestions.
Learn More About Genetic Testing
Blueprint genetics produced a series of informational webinars in their Blueprint Academy series that you can watch to learn more about genetics.
The 10/25/18 webinar Utility of genetic testing and application to immune-related disorders , a collaboration between the Autoinflammatory Alliance and Blueprint Genetics, features examples of autoinflammatory diseases.
This kit put out by the Global Genes Project has everything you need to navigate the medical system when trying to find a diagnosis for any rare condition. It includes information on staying organized, how to talk to doctors, how to get your medical records, and much more.