CONTENTS:
- What Individuals with ITP and Their Health Care Providers Should Know When Considering Genetic Testing
- How often should I have my platelets checked?
What Individuals with ITP and Their Health Care Providers Should Know When Considering Genetic Testing
Within the medical community there appears to be a growing interest and appreciation for the application of genetics in health care. The impact of genetic knowledge on the outcome, safety, and quality of patient care continues to expand with advances in genetic and genomic research and the integration of new technologies. There isn’t one area of medicine that genetics is not part of. As a result, there are stronger relationships between medical genetics and other specialties in the health care setting, including hematology. Within hematology, many current studies on immune thrombocytopenia (ITP) are using genetics to further understand the development and progression of ITP. ITP patients and their families are also looking towards genetic testing to learn more about their disorder, and to establish whether their ITP is primary or a symptom of another condition. With more genetic tests marketed each year from companies promising technological superiority over others, it is important now more than ever for patients and their health care providers to understand the “ins and outs” of genetic testing.
If we think of our genetic code (the DNA) and our genes as directions for how to make all the different proteins that make up our cells and our bodies, then genetic testing looks for “spelling differences” at the gene level or the protein level for the purpose of medical decision making.1,2 Using specialized techniques, specific genes are examined in an attempt to identify a disease causing “spelling” variations (variants).3 A variant is a change in the genetic code, but not all of the variants cause a change in the protein and not all changes in the protein actually change how that protein works within a cell. Gene variants are classified as disease-causing (pathogenic), likely disease-causing, likely benign, or benign.2 If there isn’t enough information about a particular variant yet to say whether it is benign or disease-causing, then it is labeled a “variant of uncertain significance: VUS.” A VUS is not the same as a pathogenic or likely-pathogenic variant and does not mean that a person has that disorder. Deciding where on this spectrum a variant falls is called “variant classification.” It is important for individuals with ITP and their families to be aware that there are different purposes for and types of genetic testing. Not all genetic testing is considered a medical test, even if they are marketed that way.
Clinically indicated genetic testing vs commercially available testing:
Clinical genetic tests are ordered through an individual’s own health care provider. Often, this is a clinical geneticist paired with a genetic counselor working in a medical genetics clinic; however, it is becoming more commonplace for physicians in other subspecialties, such as hematologists, to order clinical genetic testing.4 The decision to pursue a particular clinical genetic test is made on the basis of a detailed family history, collection of symptoms the patient has, and a thorough discussion with their patient to ensure understanding and acceptance of the risks and benefits of the test. This is called informed consent.5 Clinical genetic tests are performed through a CLIA certified laboratory, with extensive experience in variant classification and result interpretation.26 Results are sent back to the ordering health care provider and become part of the patient’s medical record protected by privacy laws.
Commercially available genetic testing, also called direct-to-consumers (DTC) testing does not always require a physician’s order. And if it does, it is usually a physician employed by the company who might not specialize in genetics who lends their signature so the test can be ordered.28 This is how some DTC companies are bypassing FDA regulation. There are no requirements for specific symptoms or a family history of a condition to pursue DTC testing. DTC genetic testing is not considered a medical test even though they are marketed that way.7-10 There are a variety of DTC tests available, however almost all do not offer testing to seek disease causing gene variants in genes associated with thrombocytopenia. In the near future, some DTC companies may start to provide more expansive genetic testing.28 A couple of DTC companies have formed partnerships with a certified laboratory. At this time, they do not target genes with increased risks for thrombocytopenia. If the goal of the test is to understand if an individual’s thrombocytopenia is due to an underlying genetic cause, DTC testing is not appropriate. Some DTC test companies do not even interpret results, but rather provide patients with raw genetic data.27
Most medical genetics clinics have policies around DTC testing and may not accept referrals to interpret the results generated from these companies, or order follow-up tests for patients when the DTC testing was initiated for non-medical reasons. Non-genetic professionals are often not equipped to interpret DTC raw results for their patients. Accurate result interpretation is why many DTC testing companies are hiring health care professionals with expertise in genetics, such as a genetic counselor, to comprehensively explain the results and limitations of the test, and what that mean for patients.7, 9,10
Because of differences in regulations and lab monitoring, disease causing variants identified through DTC testing companies need to be repeated in a CLIA certified lab to confirm the results.6,9,10 There have been a number of reports giving evidence that upon re-testing through a certified lab, DTC results could not be confirmed.2,10 In fact, in 2018 a well-known CLIA certified laboratory re-tested 49 results from DTC testing companies and reported that 40% of patients who had a positive result (an identified disease causing variant) identified on their DTC test actually had a false positive result, meaning the DTC testing results were wrong.6 Tests marketed to reveal your ancestry based on your DNA may not be accurate, and generate results by comparing slight differences in your DNA to other populations.15 Tests to determine an individual’s ethnicity are considered ‘recreational’ testing 7,9. It is not known how DTC testing companies maintain patient’s privacy and whether they use a patient’s genetic information for other commercial purposes.7,16
Whether considering clinical genetic testing or DTC testing, the American Medical Association (AMA), American College of Medical Geneticists (ACMG), and the Canadian Medical Association (CMA) encourage genetic tests to be facilitated under the guidance of a physician who is capable of addressing all relevant questions the patient may have, or a genetic counselor.11,16,30
Who are genetic counselors?
Genetic counselors are master level trained health care professionals with specialized education and experience in the area of clinical medical genetics and psychosocial counseling. They work as allied members of multi-disciplinary healthcare teams providing families and individuals with information on specific medical conditions, inheritance, and implications of genetic testing so informed personal and medical decisions can be made. In addition to analyzing family history data, interpreting risk, and translating complex medical genetics jargon to everyday language for patients, genetic counselors fiercely advocate for their patients. Genetic counselors are able to support their patients through the genetic testing process.12,13
What clinical genetic testing options exist for patients with ITP?
ITP is a complex heterogenous autoimmune disorder. At this time, there is no known genetic cause for primary autoimmune immune thrombocytopenia (ITP). There are many hereditary causes of low platelets that may present in the exact same way as ITP, such as with easy bruising, and variable bleeding, as well as other disorders that may be genetic and lead to low platelets such as: 22q11.2 deletion syndrome, Gaucher disease, inherited platelet disorders, and inherited immune deficiency disorders such as Common Variable Immune Deficiency (CVID) and other Primary Immunodeficiencies (PIDs).
In the past, inherited causes of thrombocytopenia were thought of if an individual had an enlarged liver/spleen called hepatosplenomegaly, or a strong family history of a specific inherited disorder. Now, individuals with chronic ITP who are resistant to steroids and other first line ITP treatments, have persistently low platelet counts but presented with a platelet count greater than 30 X 109/L, have variable bleeding, atypically large platelets, birth defects (called congenital anomalies) or experience other health concerns (such as frequent infections or cataracts not typical for age) are encouraged to inquire with their health care providers about genetic testing options.17,18,19,32
There are multiple clinical thrombocytopenia genetic test panels available; however, the number of genes on them, the types of genes on them, the panel’s accuracy and limitations vary depending on the laboratory used.17,26 This is because each laboratory uses a different testing platform, and each platform comes with its own ‘pros’ and ‘cons’. Cost also varies according to what test you select.
What are the benefits, risks, and limitations of genetic testing?
It is important to acknowledge that benefits and risks are subjective perceptions. What is a benefit to one individual, might be interpreted as a risk to someone else.
Benefits:
Genetic testing gives individuals the opportunity to identify a pathogenic gene variant that might put them at risk for future health concerns or confirm their clinical diagnosis. Some individuals express a sense of personal empowerment over being able to know ahead of time concerns that may plague them in the future to pro-actively plan ahead and prepare. Others could feel relief that their clinical diagnosis is confirmed, or that genetic testing has ended their diagnostic odyssey by establishing the true cause of their ongoing health concerns, perhaps eliminating additional unnecessary medical investigations. In some cases, establishing the true cause of symptoms can guide treatment, bring more opportunities for treatments and better surveillance. For instance, if an individual carries a pathogenic variant that has been associated more with severe bleeding risks, that individual may be managed differently and seen in clinic more regularly. It also allows individuals to connect with others who have the same condition for support. There are some families that feel closer to their relatives due to shared inherited risk factors and concerns. Genetic testing can also be used for family planning purposes. Major life decisions are often made on the basis of a genetic test result.21,23
Risks and limitations:
Genetic testing can lead to anxiety and other mental health consequences.22 Genetic testing might reveal a pathogenic variant that puts an individual at risk for health concerns that they are unable to plan for or prepare for. Uncovering a pathogenic variant that establishes the true cause of an individual’s health concern(s) may not lead to additional treatment or surveillance options and may even result in a previous diagnosis being taken away. For example, living with an ITP diagnosis for years and then learning an entirely different condition is the cause for low platelets. For some, this can be very surprising and could lead to a change in the way an individual sees themselves. There are some families that experience dysfunction as a result of a genetic condition being revealed.23 Gene variants can elicit feelings of shame and guilt and some individuals do not want to share their results with other relatives. There is no legal duty to share results with family members, but if others in the family are at risk, a genetic counselor will strongly encourage result sharing and can help provide strategies to open communication and understanding in the family.22,23
When a pathogenic variant is identified, that is called a ‘positive’ result. The main limitation of a positive result with thrombocytopenia is that it is not possible to predict when (or if) specific symptoms will begin in the person carrying it and how severe the disease presentation will be.26,29 Even with the same gene mutation, some family members experience different symptoms, at all different ages, and with different levels of severity.22,23
What does a “negative” result mean? Sometimes, genetic testing does not identify a pathogenic variant. This can lead to confusion and disappointment and can deepen the sense of uncertainty families had prior to pursuing genetic testing. Not finding a pathogenic variant does not eliminate the chance of developing the condition tested for, and it does not remove an existing clinical diagnosis in every situation because genetic testing is not perfect. Depending on the type of genetic test and platform the laboratory used, test accuracy and gene coverage will vary. It could be that the testing technology was unable to pick up the type of change(s) present (such as small changes in the genetic code) rather than a variant not being present. It could also be because the gene that is involved in a patient’s disease wasn’t included on the multi-gene panel test selected for use.26 For that matter, research in this area is progressing rapidly with new genes causing immune dysfunction identified at a rate of 3-4 new genes per year and 1-3 new platelet disorder genes per year.
Therefore, when a pathogenic variant is not identified, the result is not ‘normal’. Rather, it is interpreted as a “nondiagnostic” result. The only way an individual can have a ‘normal’ result is if they are doing predictive testing for a pathogenic gene variant already identified in an affected relative, and they learn they are not carrying it.29
It is always a good idea for individuals to stay in touch with their health care provider who ordered their genetic test because as technology advances, if the detection rate has improved, individuals may be eligible for re- testing and for updated testing if new genes are available to test. In some cases, laboratories may have a legal duty to re-contact health care providers who ordered clinical genetic tests from them when new information becomes available that may change the way their patients result had been classified (such as from unknown significance to benign or disease-causing), so that re-testing can be arranged.31 However, this is highly dependent upon the method used for testing and specific procedures within the laboratory, so staying in touch and following up about every 2 years once genetic testing has been done is a good way to make sure your testing results are up to date.
What is a VUS (Variant of Uncertain/ Unknown Significance)?
Genetic testing can also reveal variants with uncertain meaning called ‘variants of unknown significance’ or VUS’s. These are non-medically actionable results and should not be used in clinical decision-making. Since many VUSs in time have be reclassified as benign, it is considered inappropriate to base major decisions on the finding of a VUS, and physicians could be found liable if their decision to act on a VUS causes harm to a patient. However, it is appropriate, especially since the laboratory doing the genetic testing often offers this at no cost to patients, to test any relevant family members to better understand a VUS (see if it is present in other family members with similar symptoms). In this way, it is possible to get some more information about the VUS that can help in moving it toward either benign or pathogenic classification. A VUS may also make patients eligible for evaluation in a research study to better understand the variant and its function. This could help to further our understanding of health and disease. However, this is unlikely to change management of the patient with the VUS in the short term.
Lastly, there are risks for insurance discrimination. In the US, the Genetic Information Nondiscrimination Act (GINA) was created to prevent misuse of genetic test results, encourage individuals to pursue medically indicated genetic testing, and prohibit an individual’s genetic results from impacting their ability to obtain health insurance and employment. Insurance companies are unable by law to use genetic information for decisions regarding an individual’s eligibility for health insurance or coverage. Employers are unable to use an individual’s genetic test results as part of the decision-making process when hiring, promoting, or managing employees but only if the employer has more than 15 employees on staff. Otherwise, GINA does not protect from employment type discrimination. GINA does not protect US citizens from genetic discrimination when applying for life insurance, disability insurance, or even long- term care insurance.22,24 Some countries do not have any laws to protect against genetic discrimination. Therefore, the long-term implications of a genetic diagnosis should be considered when considering genetic testing, especially in pediatric populations before those children can participate in the decision- making process. In some situations, having a diagnosed medical condition prior to genetic testing might mean discrimination risks are already present.
Summary:
Overall, clinical genetic testing is available for a subset of patients with ITP. This has the potential to lead to a more accurate diagnosis, and possibly better treatment options and surveillance. ITP patients need to be mindful that genetic testing varies in accuracy, cost, limitations, and coverage depending on what lab, and type of lab, the test is carried out in. DTC testing is not considered a medical test, and ITP patients should be aware of that. Thank you to PDSA Medical Advisor Michele Lambert, MD, MTR for contributing to this article.
Have you had genetic testing related to your low platelet count?
PDSA has recently launched a new survey within the ITP Natural History Study Registry, designed to help us understand how genetics may be contributing to ITP. We encourage everyone who has had genetic testing to participate in this survey. There is also an option to upload your genetic test results confidentially. If you have any questions about this new survey, please contract Jennifer DiRaimo, Research Program Manager, at jdiraimo@pdsa.org for more information.
References
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2. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4544753/.
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4. National Institute of Health, 2020. How is genetic testing done? Genetics Home Reference. https://ghr.nlm.nih.gov/primer/ testing/procedure.
5. National Institute of Health, 2020. What is informed consent? Genetics Home Reference. https://ghr.nlm.nih.gov/primer/ testing/informedconsent.
6. Tandy-Connor, S et al. (2018). False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical information testing for appropriate patient care. Genetics in Medicine. 20: 1515-1521. https://www.nature.com/articles/ gim201838.
7. Matloff, E. (2018). Healthcare Providers Can’t Afford To Ignore Direct-To-Consumer Genetic Testing. Forbes. https://www. forbes.com/sites/ellenmatloff/2018/04/25/health-care-providers- cant-afford-to-ignore-direct-to-consumer-genetic-testing/.
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9. Forbes Insights Team with Intel Al. 2019. Meet Your New Genetic Counselor. Forbes. https://www.forbes.com/sites/ insights-intelai/2019/02/11/meet-your-new-genetic-counselor/.
10. Almendral, A. (2018). Home Genetic Tests May Be Riddled With Errors, And Companies Aren’t Keeping Track. Health; HuffPost. https://www.huffpost.com/entry/home-genetic-test-false-positiv es_n_5ac27188e4b04646b6451c42.
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14. Hoffman-Andrews, L. (2017). The known unknown: the challenges of genetic variants of uncertain significance in clinical practice. Journal of Law and the Biosciences 4(3): 648-657. https://academic.oup.com/jlb/article/4/3/648/4820755.
15. CBC Marketplace: Twins get ‘mystifying’ DNA ancestry test results (Jan, 2019). https://youtu.be/Isa5c1p6aC0.
16. Canadian Medial Association: Policy on Direct to Consumer Genetic Testing. 2017. https://www.cma.ca/sites/default/ files/2018-11/cma-policy-direct-to-consumer-genetic-testing- pd17-05-e.pdf.
17. Almazni, I et al. (2019). Inherited Thrombocytopenia: Update on Genes and Genetic Variants Which may be Associated With Bleeding. Frontiers in Cardiovascular Medicine. Vol 6, Article 80. https://www.frontiersin.org/articles/10.3389/fcvm.2019.00080/ full.
18. Taghi Arzanian, M. (2016). Inherited Thrombocytopenia with a Different Type of Gene Mutation: A Brief Literature Review and Two Case Studies. Iranian Journal of Pediatrics 26(5):e4105 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294449/pdf/ ijp-26-05-4105.pdf.
19. Provan et al. 2019. Updated International Consensus Report on the investigation and management of primary ITP. Blood Advances. 3(22): 3780-3817. https://ashpublications. org/bloodadvances/article/3/22/3780/428877/Updated- international-consensus-report-on-the.
20. Reference removed from article.
21. National Institute of Health, 2020. What are the benefits of genetic testing? Genetics Home Reference. https://ghr.nlm.nih. gov/primer/testing/benefits.
22. National Institute of Health, 2020. What are the risks and limitations of genetic testing? Genetics Home Reference. https:// ghr.nlm.nih.gov/primer/testing/riskslimitations.
23. Genetic Alliance- UK. Benefits and Risks for Genetic Testing. 2018. https://www.geneticalliance.org.uk/information/service- and-testing/benefits-and-risks-of-genetic-testing/.
24. National Institute of Health, 2020. What is genetic discrimination? Genetics Home Reference. https://ghr.nlm.nih. gov/primer/testing/discrimination.
25. Pujol P, De La Motte Rouge T, Penault-Llorca F. From Targeting Somatic Mutations to Finding Inherited Cancer Predispositions: The Other Side of the Coin. Diagnostics (Basel). 2019;9(3):83. Published 2019 Jul 26. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC6787697/.
26. Megy K, Downes K, Simeoni I, et al. Curated disease-causing genes for bleeding, thrombotic, and platelet disorders: Communication from the SSC of the ISTH. J Thromb Haemost. 2019;17(8):1253–1260.https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC6852472/#!po=65.3846.
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31. David, K et al. 2018. Patient re-contact after revision of genomic test results: points to consider—a statement of the American College of Medical Genetics and Genomics (ACMG) https:// www.acmg.net/PDFLibrary/Patient%20recontact.pdf.
32. Neff, A. 2019. Immune Thrombocytopenia Purpura Versus Inherited Thrombocytopenia in Adults. The hematologist 16 (6). https://www.hematology.org/Thehematologist/Ask/9959.aspx.
How often should I have my platelets checked?
The recommended frequency can vary widely, depending on the individual's specific circumstances. Watch this video with Donald Arnold, MD to learn more.