Genetic Testing

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.

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.

What is Genetic Testing?

Genetic testing is a specialized test designed to look for the presence (or absence) of identifiable variants that cause disease. It is not the same thing as genetic screening which is used to identify individuals in a certain select population who are at a higher risk to have or develop a particular condition or carry a gene risk allele for a particular disorder. Genetic counselling is recommended for anyone considering genetic testing.

What are the types of Genetic Testing available?

There are many different types of genetic testing, however they can all be classified into two categories:

  1. Clinically indicated genetic testing: This refers to testing a medical provider has ordered based on your family history or personal history of clinical symptoms (your phenotype). Results from this type of testing will be part of your medical record protected by privacy laws. A thorough discussion occurs prior to testing to ensure understanding and acceptance of the risks and benefits of the test. This is called informed consent. Clinical genetic tests are performed through a certified laboratory with extensive experience in variant classification and result interpretation. Types of clinical testing that may be of interest to individuals with thrombocytopenia include:
  2. For more information on the different types of genetic tests available, click here.

    Common methods used in genetic testing include:

  1. Commercially available genetic testing: This is not a medical test. This type of testing is also called direct-to-consumers (DTC) testing. There are no requirements for specific symptoms or a family history of a condition to pursue DTC testing; testing is based on information/curiosity that often is not disease specific. DTC tests are not entirely accurate. Informed consent is limited since the test is often initiated (and paid for) by the consumer (you) without prior knowledge of the test’s risks, benefits, and limitations. This type of testing is not recommended unless it is arranged purely for recreational purposes.

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 through the process of genetic counseling.

How is genetic testing facilitated and carried out?

There are usually several steps to facilitate and carry out a genetic test. These include (but are not limited to):

  1. A visit to your hematologist or physician, or local medical genetics clinic. This step is necessary because most genetic tests need to be ordered by a medical provider. There are many forms the provider will fill out on your behalf, and a rationale will need to be provided for why the test is being requested.
  1. Request for funding
    Not all genetic tests may be covered under your insurance plan, and some may even be performed outside of your state/province.
  1. Provide a sample
    Genetic testing is usually completed using a fresh blood sample. It can also be performed on banked (or stored) DNA, and other types of tissue including saliva and skin. 
  1. Generating a result
    The lab will prepare your sample by extracting DNA for analysis. Only after the DNA is extracted can it be analyzed.
  1. Result interpretation
    The American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) system for variant classification is score based with five classes: benign, likely benign, variant of unknown significance (VUS), likely pathogenic, and pathogenic.

    If a variant is considered ‘benign or likely benign,’ it will be reported as a negative result, because this is a variant that does not change how the protein functions. In some cases where a variant has not been identified in the family, a negative result may be considered an uninformative negative result. Families with uninformative negative results are encouraged to contact a genetics expert regularly to update their medical history and learn if any new genetic tests might provide additional information, or if reanalysis of prior genetic testing might provide additional information. This is particularly true for exome and genome sequencing where reanalysis may provide new information as novel genes are identified or associated with immune or thrombocytopenic disorders. A negative result, therefore, may only mean that the medical field has not yet gained enough understanding to make the diagnosis for your family.

    If a ‘pathogenic or likely pathogenic’ mutation is identified, it will be reported as a diagnostic result. This is considered a ‘positive’ result because a variant was positively identified. Genetic counseling should be provided with the return of these results to help families understand the impact of any new diagnosis.

    A variant of uncertain significance (VUS) means that there is currently not enough information about the result to determine whether it is clinically significant. Variants of unknown significance are later reclassified and may turn out to be benign or pathologic. Therefore, it is important to follow up with your physician or genetic counselor periodically to check if more information is known about your particular VUS.
  1. Receiving your results
    The lab that ran your genetic test will put together an official report that will go directly to your ordering physician. Regardless of the results of your testing, you should be referred to a qualified genetic counselor. Sometimes, additional testing is required. If any medical screening is indicated this will be discussed with you. You can request a copy of your result. The amount of time it takes to receive your test result can vary. 

What do my results mean?

Negative result:

This is when genetic testing does not identify a pathologic variant. There are two types of "negative" results: a true negative result vs an uninformative negative result.

True negative genetic test result
This is when you learn you do not carry a disease-causing mutation that was previously identified in a close relative, as is in the case of doing predictive testing. A true negative result can also be given following receipt of a genetic test that looks for abnormalities in the genetic code that are either present or absent.

Uninformative negative genetic test result
This is when you learn your genetic test did not uncover a pathogenic mutation to explain the cause or constellation of symptoms present in yourself or a close relative. Not finding a mutation does not eliminate the chance a condition is hereditary. 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 nucleotide changes in the genetic code) rather than a mutation not being present. It could also be because the gene that is involved wasn’t included on the multi-gene panel test selected for use. Research in this area is progressing rapidly and new genes causing immune dysfunction and platelet disorders are being identified. Therefore, when a pathologic variant is not identified, the result is not "normal". Rather, it is interpreted as an uninformative result or “nondiagnostic” result. In such cases, management is then based on personal and/or family history.

It is always a good idea for individuals to stay in touch with their physician who ordered their genetic test because as technology advances, and if the detection rate has improved, re-testing may be an option including testing for new genes.

It is important to understand that an uninformative negative result is not the same as a variant of uncertain significance and cannot be used when analyzing chromosomes. With an uninformative negative result, an underlying mutation cannot be ruled out. It may have been missed for various reasons.

Pathogenic result:

When a pathogenic variant is identified, it 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 disorder will be. Even with the same gene mutation, some family members experience different symptoms, at all different ages, and with different levels of severity. This is due to variable expressivity. Some family members with the same pathogenic result may not develop symptoms. This is due to reduced penetrance. Not all genetic disorders display reduced penetrance.

Uncertain significance result:

What is a VUS (Variant of Uncertain Significance)?
Genetic testing can also reveal variants with uncertain meaning called variants of uncertain significance (VUS). These are non-medically actionable results and should not be used in clinical decision-making. Since many VUSs in time are 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 pathologic 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. Instead, management decisions should be based on personal and family history. Patients should understand that the VUS result is basically a research result until it is reclassified as either benign/likely benign or pathologic/likely pathologic.

Why might ITP patients consider Genetic Testing?
Since it is not possible to clearly distinguish primary vs inherited ITP, if certain risk factors are present, you may wish to talk to your physician about genetic testing.

Common Benefits of Genetic Testing

Genetic testing gives individuals the opportunity to:

  • Identify a pathologic gene variant that might put them at risk for future health concerns or confirm their clinical diagnosis.
  • Feel a sense of personal empowerment over being able to know ahead of time concerns that may impact them in the future to pro-actively plan and prepare.
  • Feel relief that their clinical diagnosis is confirmed, or that genetic testing has ended their diagnostic odyssey.
  • Guide treatment and bring more additional 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.
  • 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.
  • Use for family planning purposes. Major life decisions are often made based on a genetic test result.

Common Risks and Limitations of Genetic Testing

Genetic testing may:

  • Lead to anxiety and other mental health consequences.
  • Reveal a pathologic variant that puts an individual at risk for health concerns that they are unable to plan for or prepare for.
  • Not lead to additional treatment or surveillance options.
  • Result in a new diagnosis.
  • Bring on conflict. Sometimes family dynamics change upon learning about a hereditary condition in the family. 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.
  • Not pick up a mutation if it is too small to be detected by that test or the incorrect test was ordered.
  • Not always test for the gene of interest for your disorder, or lead to a conclusive diagnostic result, especially if a VUS is identified or there is not enough known about the condition at this time.
  • Lead to insurance discrimination. In the US, the Genetic Information Non-discrimination 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.

Side bar: 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. Some countries do not have any laws to protect against genetic discrimination. Therefore, the long-term implications of a genetic diagnosis should be considered, 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.

What clinical genetic testing options exist for patients with ITP?
ITP is a complex heterogenous autoimmune disorder. There are many hereditary thrombocytopenias that may present in the exact same way as ITP, such as with easy bruising, and variable bleeding. A few examples include (but are not limited to): 22q11.2 deletion syndrome, Gaucher disease, and inherited immune deficiency disorders including Common Variable Immune Deficiency (CVID) and other Primary Immunodeficiencies (PIDs).

There are multiple clinical thrombocytopenia and immune disorder multi-gene panel tests 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. 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 some of the common hereditary thrombocytopenia syndromes
Some secondary causes of ITP may be due to an underlying genetic cause. Known as inherited or familial thrombocytopenia syndromes, low platelets are caused by a genetic mutation (not by autoantibodies as is the case with primary ITP). Getting the right diagnosis is extremely important to avoid unnecessary treatments, receive the most effective care, and manage the risk of related symptoms. The genetics of autoimmunity in autoimmune conditions is an evolving and exciting area of research. There are many forms of inherited thrombocytopenia, all of them rare. This means that physicians, even hematologists, will frequently mistake them for something else.

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