Providing family guidance in rapidly shifting sand: informed consent for genetic testing
Our understanding of the genetic basis of disease and the powerful tools available to diagnose these conditions are expanding at an exponential rate. At the same time, the potential for ambiguous test results – no longer simply dichotomous normal/abnormal, but now including both unclear and unexpected (incidental) findings – has also increased. This shifting sand has created major challenges for health care practitioners providing comprehensive yet understandable counseling to families regarding new genetic tests that are now clinically available.
In a recent genetics update in DMCN, Lucassen eloquently summarized the complexity of what may be revealed with genetic testing, recognizing the need to balance patient confidentiality with appropriate information dissemination. In discussing incidental findings, Professor Lucassen highlighted the need for clinicians ‘… to develop the skills to deal with them adequately during consent to genetic investigations, as well as to communicate findings appropriately.’ Given this requirement, clinicians at the beginning of the diagnostic process need practical guidelines for obtaining informed consent, so that patients and families satisfactorily appreciate what can be revealed from these investigations, make informed decisions, and be prepared for the implications of the results.
A wide range of genetic tests are currently available for clinical diagnostic use, including chromosome microarray (CMA), single-gene tests, multi-gene panels, and now whole exome and whole genome sequencing. Medical geneticists and genetic counselors are in an excellent position to determine test indication(s), as well as to provide a complete explanation of the testing including informed consent to families. They help patients and families understand testing options and potential implications and can address the wide range of associated medical, psychosocial, and ethical issues that may arise before and after results are known. Now that guidelines have been published recommending chromosome microarray as a ‘first-tier’ test for the evaluation of developmental delay,[2, 3] chromosome microarray is the initial genetic test increasingly ordered by neurologists, developmental pediatricians and primary care providers. As more complex genetic tests are now becoming routine and frequently ordered outside of the traditional medical genetics clinic, non-genetic clinicians need to develop skills to counsel families, starting with test explanation through to family preparation for the possible outcomes of test results.
In the clinical arena, informed consent may sound easy in theory, but in practice may be more elusive to provide for a variety of reasons including patient/family knowledge and expectations as well as uncertainty of results. Physician surveys have identified challenges and barriers, such as discomfort with incidental findings and variants of unknown significance, lack of education and training, and time constraints. Large-scale efforts are currently under way regarding genomics education, with the recognition that clinicians need to weave genetics into primary and subspecialty care. As a small part of these initiatives, in this paper we offer a simple framework that clinicians can use in their current practice. Since chromosome microarray is the most common genetic test ordered in the initial diagnostic work-up of patients with developmental delay/disability, we will use it as an example of how to provide informed consent reliably. We offer specific suggestions using language/terms that can be understood by families in the counseling and consenting process. We also believe that these guidelines and suggestions can be tailored to other genetic tests.
In order for consent to be truly informed, context and education must be provided. When formal genetic counseling is not available, the ordering clinician has the responsibility to provide an explanation and counseling, including informed consent. However, most published guidelines on using chromosome microarray as a diagnostic test do not include specific recommendations for pre-test counseling and consent. In Table 1, we propose a structured way of discussing the necessary components of this process, including the nature, scope, benefits, limitations, risks, and costs of testing, using chromosome microarray as an example.
Table 1. Basic components of informed consent
|Nature and scope|
Purpose of test – determine genetic cause
Possible result outcomes: (1) normal; (2) abnormal; (3) variant of unknown significance; (4) incidental/secondary
May identify the genetic cause/diagnosis
Medical and psychosocial benefits to diagnosis
Does not rule out all genetic conditions
May not lead to definitive cure or treatment
May require further testing
Check with insurance
Advise on out-of-pocket expenses
Nature and Scope
The informed consent discussion should start with a simple explanation of the test and purpose. For chromosome microarray, a simple explanation is that this test is looking for small missing (deletion) or extra (duplication) piece/pieces of genetic material. The purpose of doing this test is to try to find the genetic cause of the patient's neurodevelopmental disorder or current condition under investigation.
The possible result outcomes (positive, negative, variant of unknown significance, incidental finding) should be specifically stated. A positive result means that the test identified a deletion or duplication associated with developmental delay/disability that is the underlying cause of the patient's condition. A negative result signifies that no chromosome abnormality was found; importantly, a negative result does not mean that the condition is not genetic nor that the child is normal. As negative does not mean normal, the clinician should ensure that patients/parents understand this distinction.
A third possible result is a variant of unknown significance, which means that it is unclear whether the change is the cause of the condition or simply a normal variation with no currently known clinical effect. The fourth possibility is that the test detects a change that is associated with a condition or disease other than the developmental disability. These results are sometimes referred to as secondary or incidental findings. Examples include copy number variants associated with cancer, adult-onset disease, and carrier status of recessive disorders. Chromosome microarray may also reveal information about family relationships, such as non-paternity, parental consanguinity, or incest.[7-9] These possibilities should be explicitly discussed with the family during the consent process. Clinicians should contact the laboratory ahead of time to find out their policy on incidental findings (i.e. the types of findings that will or will not be reported), since laboratories may vary in this regard.
Patients and their families may have a wide range of knowledge of genetics, so it is important to probe for a level of understanding at the beginning of the discussion and address any educational gaps. A very brief background explanation usually suffices. One way to succinctly relay this information is to explain that DNA is the alphabet or language of our genetic information; genes are the instructions that our bodies use to develop and function; DNA and genes are packaged into structures called chromosomes, which are inherited from parent to child; and if there is a mistake in the genetic code such as misspelling of the DNA or a chromosome abnormality, this can cause problems with growth, development, or functioning.
It is essential that patients and their families have appropriate expectations of genetic testing. The identification of under-lying cause may provide a number of benefits including improved medical management, a better idea of prognosisand likely clinical course (stable vs progressive/degenerative), and surveillance for future health complications/other system involvement that may not otherwise have anticipated. Examples of psychosocial benefits expressed by families include ‘having a name’, peace of mind, relief of guilt, and social support via meeting other families of children with the same condition and/or support organizations. Knowing the genetic diagnosis allows for accurate genetic counseling regarding recurrence risk for parents and other family members as well as reproductive options such as prenatal testing and preimplantation genetic diagnosis, if applicable.
In addition to the above potential benefits, there are also important limitations to genetic testing that patients and their families must understand. For most genetic disorders, there is currently no cure or specific treatment. There is no single test that can diagnose or rule out all possible genetic disorders, and additional testing may be necessary. For chromosome microarray, this may include parental testing when there is a variant of unknown significance. If the test is negative, further genetic testing for other conditions may be recommended.
Although there are no physical risks to genetic testing (other than a typical blood draw), there are significant psychosocial risks. There is a risk of ambiguous results and some individuals may have difficulty coping with uncertainty. There is a risk of learning unexpected or unrelated information (i.e. incidental findings). Depending on the finding, a patient or family member might require ongoing screening, additional testing, new treatments or change in management. Incidental findings have the potential to add anxiety in situations where there is no available treatment or screening, or where there is uncertainty regarding later risk. These findings can also affect other family members by revealing unexpected information about their own disease susceptibility. Genetic testing also has implications for other family members, who may be unknowingly affected or carriers.
Lastly, we must be mindful of costs of genetic testing, which may or may not be covered by health insurance depending on the individual's policy. The family should be advised of potential out-of-pocket expense.
Genetic testing is not a routine laboratory test with clear normal/abnormal ranges and straightforward clinical implications. Some families may be uncertain as to whether to pursue genetic testing, and should be encouraged to consider all of the above aspects before making a decision and allowed sufficient time to do so – even if it means coming back another day for testing.
The following are some questions they might want to ask themselves to help clarify their feelings about pursuing genetic testing: What is their personal motivation or interest in seeking an etiologic diagnosis? How might it feel to know the underlying cause? Would it change any of their plans, such as reproductive decision-making? How might it affect their family? How would they feel if the tests were negative? How far would they want to go with pursuing further testing? How do they cope with uncertainty? How would they feel about incidental/secondary findings?
The in-person discussion can be supplemented by pamphlets or fact sheets, including ones that provide basic genetics education information and others tailored specifically for each genetic test. One could even create informational videos, which may be especially beneficial for families with lower literacy levels. A well-written consent form can serve two purposes: documentation for the patient's chart as well as a copy for the family to take home that summarizes the information discussed. Some families may need more than this for a variety of reasons, so for them it would be appropriate to refer for formal genetic counseling before ordering the test.
With the rapid advancement of genomic technologies along with decreasing cost and increasing analytic capabilities, whole exome sequencing has arrived into the clinical diagnostic arena, and whole genome sequencing is on the horizon. The challenges posed by chromosome microarray are magnified for these new genomic tests. Recognizing this, truly informed consent can be a daunting prospect even for the most experienced genetics professionals, let alone non-genetics clinicians such as neurologists, developmental pediatricians, and primary care providers. However, if thoughtfully considered and implemented, clinicians can provide adequate counseling to enable patients/families to understand the testing being offered and make informed choices.