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The Predictive Value of Genetic Information: A Conversation with Dr. Steve Scherer, Director, the Centre for Applied Genomics, the Hospital for Sick Children and Professor of Medicine, University of Toronto

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December 2012

The Office of the Privacy Commissioner of Canada would like to thank Dr. Scherer for updating the answers to the questions he had originally provided to us, in collaboration with Genome Canada, in 2012. Dr. Scherer would like to thank Cheryl Shuman (genetic counselling; SickKids and University of Toronto), Stephen Meyn (medical genetics: SickKids and University of Toronto), Peter Ray (molecular diagnostics: SickKids and University of Toronto) and Michael Szego (genetics and bioethics: University of Toronto) for comments. The views expressed in this document are those of Dr. Scherer and do not necessarily reflect the views of the Office of the Privacy Commissioner of Canada.

1. Let's start with the basics. The field of genetics is still evolving. Most of us were taught that the genetic blueprint we inherited from our parents predetermines our physical attributes, our temperaments and our health. Is this accurate?

Our genome is the DNA instruction book contained in each of our body’s trillions of cells. DNA is packaged into chromosomes and we inherit one copy of each chromosome from our mother and the other copy from our father. Therefore we share 50 per cent of our genes with each of our parents, as well as approximately 50 per cent with our siblings. Our genome also archives the story of our ancestors and this is why common traits (and sometimes disease) are observed in families. Our genome sequence serves as a ‘blueprint’ to direct aspects of our development from conception to adulthood, so at least in the physical sense our life follows a biological plan. However, the influence of genes is not absolute. The environment (nutritional, geographical, social) we are exposed to, the choices we make (smoking, exercise) and even random events (birth order, family size) also have an impact. The combination of these factors is probably just as important as the DNA blueprint in influencing our minds, our personalities, and our health.

2. Can one's genes actually change over one's lifetime? If so, what factors modify our genes?

It is rare that a specific copy of a gene will change over one’s lifetime, because there are many safeguards in place to keep our genomes stable.  However, changes can and do happen. These changes can occur as a result of mistakes made when a cell makes a copy of its DNA during the process of cell division. Some organs (such as the skin) require continuous cell division and occasionally mistakes happen when DNA is copied. Other DNA changes occur when a cell makes a mistake in repairing DNA damage such as that caused by the sun’s UV radiation. These changes are known as mutations and typically happen randomly throughout the DNA of individual cells. When mutations are present in the DNA of germ cells (egg or sperm) they can be passed on to offspring.

The personal effects of these genetic alterations depend on which genes and tissues are affected as well as the environment one lives in. Fortunately, most mutations are harmless, while a few can be advantageous.  Sometimes mutations are deleterious, and can result in disease or death.  Nonetheless, a constant low-level production of mutations is critical for producing the genomic variation needed for evolution of our species.

3. We have long assumed that genes are highly unique to each individual. Is this accurate?

The genome sequences of any two unrelated individuals in the world are approximately 99 per cent identical (except for identical “monozygotic” twins who start out life with identical genomes). This relatedness reflects the common humanity we all share stemming from our ancestors who emerged from Africa only a few hundred thousand years ago. The 1 per cent difference in our genome sequences is also significant because of the vast size of the genome, which typically contains 6 billion chemical letters in its complete code. So while we are all 99 per cent similar, we are also unique individuals because 1 per cent of a very large genome equates to millions of genetic letter differences or combinations that are specific to our own genome. There can also be many differences in our gene copy numbers that contribute to our variation. As mentioned, some of these genomic variants are advantageous, most neutral, and some deleterious. So the true beauty of genetics is that we can be both common and unique at the same time. In my opinion, the more this becomes apparent to society, the more hope there will be for equality.

4. In your experience, why do most patients get tested? What is it that they typically want to know or hope to get out of it?

It is important to point out that genetic tests, except direct-to-consumer tests, are ordered by physicians and not by patients. Genetic testing is indicated for the following reasons:

    1. To try to make a diagnosis in cases where a definitive genetic diagnosis cannot be made from the clinical phenotype (observed characteristics).

    2. To confirm a diagnosis at an early stage of disease when the phenotype is not fully developed or detectable.

    3. To determine genetic subtypes of a disease so that prognosis can be clarified and management optimized.

    4. To offer cascade testing to other family members who may be at increased risk for the genetic disorder including offering presymptomatic testing of “at risk” individuals. 

    5. Carrier detection to provide genetic counselling in both high risk families and in population screening.

    6. Prenatal diagnosis.

    7. Newborn screening for rare diseases that can be treated if detected presymptomatically.
    8. To test for genetic influences on drug response (pharmacogenetics).

I can comment on some of the motivations of several different patient populations. Genetic testing ordered for diagnostic purposes usually involves a patient who already has a medical or developmental problem. Many patients (or parents of affected children) undergoing diagnostic testing want to know the cause of their medical problems and obtain any information that can help inform their prognosis and/or treatment. These serve as strong motivators for their decision to get tested. Often the parent of the affected child, or the adult seeking the test, also wants to know the chance of having another child affected with the same condition (aka recurrence risk). If a genetic diagnosis is made, we can be accurate about recurrence risks and provide counselling regarding the reproductive options for the family. Genetic testing for predictive purposes is usually ordered for individuals without symptoms of the disease but with a strong family history. Individuals proceed with predictive testing for many reasons, including surveillance for early detection of disease or medical management options to prevent the disease they may test positive for.  Even when there is no prevention or cure known for the condition, people may wish to know if their test result is positive or negative to help them make important life decisions such as family and career planning.

5. Can you explain the difference between a monogenic disorder and a mulifactorial genetic disorder?

A monogenic disorder is a condition that can be caused by harmful variants (mutations) in a single gene. Because genes typically exist in pairs, there are different forms of monogenic disease: dominant (one gene of a pair mutated), recessive (both genes in the pair mutated) and X-linked recessive (a gene on the X chromosome in males is mutated). The presence of a harmful variant in a monogenic disorder disease gene is a very strong indicator that the disorder will manifest itself, no matter what other genomic variants an individual has.  In contrast, multifactorial disorders require the simultaneous presence of harmful variants in multiple susceptibility genes, often acting in concert with environmental factors, to precipitate clinical manifestation. Therefore, it is generally more difficult to predict the onset of multifactorial disorders with any degree of certainty.

6. Scientists have made great advances in the development and access to genetic testing. What different types of genetic tests are available?

There are over 33 000 genetic tests according to the US National Institutes of Health Gene Testing Registry. Testing can be performed to confirm a suspected diagnosis, to predict future medical problems, to predict how an individual may respond to a specific therapy, or to detect the presence of a mutation in an asymptomatic individual (carrier testing). We currently use two major testing strategies.  The first, and most common, examines the DNA sequence of a specific gene(s) and tests for the presence of pathogenic variants (mutations). For example, a standard test for cystic fibrosis might screen for over 30 different disease-causing mutations in the CFTR gene.  As sequencing technologies have changed and our understanding of genetic diseases has improved, this gene specific approach has evolved so that we now can efficiently examine the DNA sequence of multiple genes simultaneously.  The second testing strategy examines the whole genome at once for genetic variants.  Historically, this could only be done at very low resolution through a test called karyotyping or chromosome analysis. This microscopy-based technique typically identifies 500 to 600 different features in the genome, so only large-scale structural changes can be detected.  In the past 10 years, karyotyping has largely been supplanted by microarray analysis, which can identify over 1,000,000 genomic features.  This increased resolution has greatly improved our ability to diagnose genetic disorders.  However, microarray analysis cannot detect the most common type of disease-causing genetic variant - changes in individual letters of the genetic code.  We are now in the midst of a revolution in genetic testing that will see these two testing strategies merge, as whole genome sequencing has the potential to replace both targeted gene sequencing and microarray analysis, and it will soon be more cost effective to sequence an individual’s entire genome rather than pursue traditional, hypothesis-driven diagnostic evaluations of genetic disorders.

Another recent advance is our ability to perform prenatal genetic screening using a maternal blood sample. This non-invasive screening test was developed following the discovery that fetal DNA can be detected in maternal blood. Gold standard prenatal genetic testing still involves amniocentesis (sampling some of the amniotic fluid) or chorionic villus sampling, both of which carries a very low risk of causing miscarriage. However, in the near future we may be able to perform prenatal genetic testing, including single gene or even whole genome sequencing, following a simple maternal blood test. 

7. What is the difference between a clinical genetic test and a direct-to-consumer genetic test?

A clinical genetic test is performed in a licensed healthcare setting in order to diagnose or assist with optimal management of an individual’s health. Prior to testing, the risks, possible benefits and potential outcomes are discussed with the patient or representative so he or she can make an informed decision about whether to undergo testing. After the test is performed the healthcare team will interpret the results and will discuss what the test results mean for the patient and the patient’s family.

Direct-to-consumer genetic testing is made available to consumers without the involvement of a healthcare provider. Individuals request these tests because they are interested in knowing their personal risk for certain common conditions, such as heart disease. The consumer does not have access to the same unbiased information prior to testing and usually does not have access to genetic counselling to put the results into context.

Furthermore, clinical genetic tests typically look for gene mutations in which there is strong evidence linking the mutation with a disease. In contrast, most direct-to-consumer genetic tests often examine genetic variants associated with common traits, in which the evidence linking the genetic variant with the trait can be weak. There are also some direct-to-consumer companies that offer tests for breast cancer genes.

8. What would you consider to be the advantages of a genetic consultation?

Patients are referred for genetic consultation when there is the suspicion of a genetic disorder in the patient and/or a family history suggestive of a risk of genetic disease. The main advantage of a genetic consultation is that the patient/family will be given all the information required to make an informed decision about whether to pursue genetic testing. The geneticist or genetic counsellor will take a full personal and family history in order to confirm the nature of the disorder or potential disorder, and the likelihood of it being caused by a genetic change. The patient will have an opportunity to ask questions about the disorder and the potential risks to themselves and family members. The availability of genetic testing will be discussed as will the likelihood of a positive test result, and the test’s potential impact on management of the patient’s health or condition. The patient will be offered the option of not having a genetic test, and what the implications would be if they decline testing. Insurance implications, and whether other family members should be offered testing will also be discussed. If the patient proceeds with testing, a follow up appointment will be arranged to discuss the results.

9. If the genetic test results are negative for certain gene-related disorder, does that mean that the individual will not develop the disease?

The answer depends on the specific disease and the test. For diseases such as cystic fibrosis and Huntington disease, if an individual tests negative for the mutation, they are highly unlikely to develop the disease. However, for other diseases such as colon cancer, there are both inherited forms (which run in families) and sporadic forms (which happen by chance). An individual could test negative for the mutation known to cause colon cancer in their family and still get the sporadic form of the disease.

10. What about the reverse? If you have a family history for a certain gene-related disease or you test positive, will you necessarily develop the disease?

A family history of a disease could be an indicator for genetic testing. If an individual tested positive for a harmful variant in a disease gene, then the likelihood of developing the disease depends on how predictive the presence of the variant is. For example, the presence of a harmful variant in a breast cancer susceptibility gene (BRCA1 or BRCA 2) can indicate a 60 per cent lifetime risk of developing breast cancer. In contrast, the presence of pathogenic variant in the Huntington’s disease gene can result in virtually a 100 per cent lifetime risk of developing the disease. 

11. If someone goes for a genetic test, what will they learn about themselves and their family? How should people think about the results they get?

Blood relatives are genetically related and the closer two blood relatives are on a family tree, the more genes they will share in common. As such, an individual’s genetic test result frequently has implications for other family members. Ideally, patients getting tested are willing to share their results in a way that is sensitive to wishes of each family member who may be at increased risk for the same disorder. One good approach to disclosing test results is as follows: prior to receiving any test results, the patient being tested could approach family members, tell them about the test, its implications and ask if they would want to know the results. After receiving their test results, the patient could then communicate the results to those family members who want to know. Or, in some cases, the patient might prefer to provide permission for family members to contact the physician or genetic counsellor to discuss their own risks and testing options.

12. Do patients feel they have an obligation to share their results with their family members?

Family dynamics can be complicated; however, part of the genetic counselling process involves discussing the implications of a genetic test result for other family members. For the most part patients are willing to share their results with family because they understand that their results may have health implications for those individuals. As such, they feel that the benefits of having this information outweigh the potential concerns or burdens of knowing one’s genetic risks. Geneticists/genetic counsellors can help educate patients on how to communicate their results or be directly involved in the disclosure process.

Individuals and families differ enormously with respect to what they consider “private” information on the one hand and their sense of obligation to other family members on the other hand.  There are cultural differences due to a diversity of beliefs, which have a huge impact on the willingness or perceived obligation of an individual to share information. 

13. Glimpsing into the (possible) future about oneself might be a scary experience for some. In your experience, do some patients prefer not to know? What are they most concerned about?

It is important to remember that patients undergoing genetic testing would usually have some experience with family members who have had the disease they are being tested for. Thus not knowing can cause as much anxiety as knowing. Some individuals will want to know if they have the disease gene and others will not. Many parents see pursuing genetic testing as an obligation to protecting their child, while others see opting out of testing as a way to keep their child’s future as open as possible. When the results of genetic testing are medically actionable, many patients  opt for testing. For example, if a person tested positive for a mutation leading to an increased risk for breast cancer, increased surveillance and preventive surgery are options. In contrast, if a person tested positive for a Alzheimer’s susceptibility gene, no preventative measures or treatments are currently available to change the course of the disease. Many individuals with a family history of a disease that cannot be treated or prevented opt not to be tested. Concerns about potential stigmatization or genetic discrimination can also be a barrier for individuals thinking about pursuing genetic testing.

14. The field of genetics offers an incredible glimpse into who we are but it also reveals a great deal of personal information. In your experience, how concerned are your patients about privacy? Do they worry that their test results will be shared with others without their knowledge or consent?

Initially many patients may be worried about their privacy; however, genetic test results are considered personal health information subject to legal protection and are kept private. Third parties do not have access to genetic test results without written patient consent. However, there are rare circumstances when a healthcare provider may feel a tension between their duty to protect a patient’s confidentiality and a duty to prevent harm in at-risk individuals. For example, there have been cases when a patient refuses to share genetic test results with at-risk family members. The legal landscape in Canada seems to favour maintaining confidentiality; however, disclosure may still be ethically justified. According to the American Society of Human Genetics, disclosure of confidential information is ethically justifiable under the following circumstances: attempts to encourage the patient to disclose the information to at-risk family members have failed; the harm  is highly likely to occur and is serious, imminent, and foreseeable; the at-risk relative(s) is identifiable; and the disease is preventable, treatable, or medically-accepted standards indicate that early monitoring will reduce the genetic risk. While cases involving disclosure of genetic results without consent are rare they do illustrate a potential limitation to the right to privacy in genetics.

15. Does it happen in your practice that patients may not want to be tested or share their test results for fear of having to release them to a third party, such as an insurance company?

Many patients decline genetic testing because of the possible insurance implications. However, as part of many insurance applications, a family history is taken and that information is used to assess the applicant’s genetic risks. A family history can point to the possibility of a genetic disease irrespective of whether genetic testing has been performed. While insurance companies cannot ask a client to undergo genetic testing, they can and do ask for any available medical test results, including genetic testing. Insurance companies can offer reduced premiums for individuals who test negative for a disease that runs in their family. Conversely, if an individual refuses to get tested or tests positive, they may become uninsurable depending on the disorder (for example, Huntington disease), or the premiums may be so high that the individual cannot afford the insurance.

The Genetic Information Nondiscrimination Act (GINA) in the USA prohibits discrimination on the basis of genetic information with respect to employment and health insurance (but not life or disability insurance) – nothing similar exists in Canada. In fact, Canada is the only G7 country that does not have legislation dealing with genetic discrimination.

16. Where do you see the field of genetics in five years?

As we gain more insight into the roles genes play in human health and clinical genomic analyses start to become routine, knowledge of our genomic variants will increasingly be used to diagnose existing diseases, refine prognosis, and personalize medical treatment, as well as detect hidden medical conditions and predict future illness. Consequently, the relevance of genetics in healthcare will continue to grow, as practitioners from all medical specialties use genetic knowledge to help deliver personalized medical care that improves health outcomes. To this day the most important question physicians ask is, “Do you have a family history of this or that?” Studies of the genome now provide us with the richest and most accurate form of family history: our individual DNA sequence. It is likely that genome sequencing, in a manner similar to magnetic resonance imaging, will become an indispensable diagnostic tool for “genome imaging”, thereby impacting medical decisions throughout one’s life.

Diagnostic genomics, the ability to identify and test for harmful genomic variants that affect health, is driving the current revolution in personalized genetic medicine. However, over the next five years we may also see major advances in interventional genomics, the ability to treat disease through gene manipulation. While there are numerous technical and ethical challenges to overcome, recent breakthroughs in our ability to “edit” genes by using bacterial enzymes that can change specific DNA sequences, offer the potential to correct pathogenic mutations in patients, thereby providing personalized treatment for the underlying cause of their genetic disorder.

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