Facilitator Script: [ See supplementary information for example introduction.]
Key Point: In workshop 2 we discussed three essential steps in genetic evaluation and testing decisions. Facilitator Script: Before we get started on the genetic testing process, let ’s briefly recap the three essential steps in genetic evaluation and testing decisions. In the last session, we learned how to use evaluations and labs, distinct features, and family patterns to rule out non-genetic causes and prioritize the differential in order of probability. We talked about how to use data (like phenotype, gene frequency, and genetic heterogeneity) to identify testing for the most likely causative variants and plan for first and second-tier testing. 3. Finally, we discussed how to use family patterns to identify at-risk relatives and sequence testing in the family. In the interest of time, we won’t be practicing these skills in every clinical example we discuss today, but you can assume these initial steps have been performed. But remember, the information you obtain during your evaluations is critical to guiding your testing process, so we are building on those decision-making skills.
Key Point: The genetic testing process involves planning and organization to optimize cost-effectiveness. Facilitator Script: Once you’ve decided to perform genetic testing, it is time to get your “ducks in a row” to ensure the most cost-effective and patient-centered process. The testing process requires careful planning and counseling to maximize benefits and reduce harms of genetic testing. In this workshop, we’ll discuss how to use test performance data and communication skills to guide your patients through the process.
Key Point: A step-wise pre-test protocol ensures you and your patients are prepared for the process and potential outcomes of testing. Facilitator script: In the following clinical examples, we’ll discuss how to: Use data to inform benefits, limitations and risks Provide anticipatory guidance to the family Navigate the logistics of test ordering This step-wise pre-test protocol ensures you and your patients are prepared for the process and potential outcomes of testing. Taking time for these steps empowers you to be a better guide for families. As we discuss these steps, consider how you might customize protocols for your institution and patient population.
Facilitator Script: In this workshop, we will practice these specific skills
-TRANSITION- Facilitator Script Let’ s walk through these steps with a model case. Here is James, a two-year-old male with a history of seizures James presented at age 7 months with his first febrile seizure He then presented to the ER one week later in status epilepticus. He has a history of both febrile and afebrile generalized tonic-clonic seizures which have been difficult to control with antiepileptic medications Additional information: Prenatal and Birth History: Normal Developmental History: Mildly delayed, functioning at the level of an 18 month old Past Medical History: Minor ear and respiratory infections Review of Systems: Unremarkable Social History: James lives with his parents, who would like to have more children. Family History: Intake form indicates seizures in James’ mother’s family
Key Point: The family history provides non-specific evidence pointing toward a genetic component to this disease. Facilitator script: James’ maternal aunt was noted to have multiple seizures in childhood. She passed away from an accident at the age of 10 years. There is no other family history of seizures. This is non-specific evidence pointing toward a genetic component to this disease. Interaction: What inheritance patterns are possible for this family? Answer: (Keep this discussion to a brief review) There are several possible patterns of inheritance, including: Autosomal dominant with reduced penetrance or variable expression Autosomal recessive Maternally inherited (X-linked or mitochondrial), with reduced expression in females Multifactorial
Key Point: Using the tools and skills we discussed in workshop 2, you decide that the history points toward Dravet syndrome as the most likely diagnosis. Facilitator script: Using the online tools and assessment skills we discussed in workshop 2, you generate a differential diagnosis based on the unique clinical features and family history point toward Dravet as the most likely diagnosis. We won’t take the time to review the specific steps and evidence involved in the differential diagnosis, but we can assume that labs and evaluations have ruled out treatable and non-genetic causes.
Key Point: Dravet syndrome is a severe form of early onset epilepsy; the majority of cases being associated with SCN1A gene mutations. Facilitator script: Each of you has a handout providing details we will need in a few moments for an exercise. For now, let’s just highlight a few key points about this condition: The most common cause of Dravet syndrome is a variant in the SCN1A gene. However, 30-80% of cases may be due to other genetic alterations. SNC1A variants are associated with more than one phenotype – certain phenotypes are more likely to be associated with de novo mutations while others are more likely to be associated with inherited variants When inherited, SCN1A variants exhibit autosomal dominant inheritance, but with significant intra-familial variable expression and reduced penetrance Interaction : What might explain the variable expression we see among family members with SCN1A mutations? Answer: Modifier genes and environmental triggers Handout : To include the following facts: Features, natural history and prognosis: Appears during first year of life with frequent febrile seizures Febrile seizures typically, but not universally, decline after age 5 years After age 5 other types of seizures, including myoclonus, may occur Typically children develop language and motor skill delays, hyperactivity, and social difficulties. Degree of impairment correlates with frequency of seizures. Cognitive decline stabilizes with age, but most teenagers are dependent on caregivers. Genetics 30-80% associated with SCN1A mutations SCN1A normally functions in neuronal sodium channels. The molecular abnormality caused by gene mutations causes hyperexcitability of the cortical network Inheritance : SCN1A variants can be inherited or de novo Likelihood of inherited depends on phenotype: 95% with SMEI (Dravet) are de novo 95% with generalized epilepsy plus febrile seizures (GEFS+) are inherited When inherited, autosomal dominant, with significant intra-familial variable expression and reduced penetrance Testing : Sequencing detects 73-92%, deletion/duplication analysis detects 8-27% of mutations Treatment Seizures are difficult to control, but may be reduced by some anticonvulsant drugs and ketogenic diet
Facilitator script: The first task in the genetic process is to identify potential benefits, limitations and risks of testing. Let’s take a closer look at how this applies to our patient James.
Facilitator script: First, we want to assess the ability of the test to detect variants in the patient population. In other words, what is the sensitivity, or yield, of genetic testing in someone with James’ clinical and family history – specifically the presentation of SMEI? This step overlaps with skills used to narrow the differential in workshop 2, which involved assessing the evidence that suggests a particular diagnosis and looking at the likelihood of a particular genetic change based on the patient’s clinical features. Instructions: Provide 1 minute for audience to review handout, then ask for a volunteer to answer the discussion question. Fill in gaps in the discussion with subsequent debrief slides. Interaction Take a moment to review your handout on Dravet syndrome. What is the yield of genetic testing in someone with James’ personal and family history? (What is the sensitivity?)
Key Point: Genetic testing will identify a cause in the majority of individuals with Dravet. Facilitator script: Although the literature suggests a wide range of sensitivity in SCN1A testing, mutations in this gene are the most common cause of Dravet. This process of assessing sensitivity, or yield, is part of determining clinical validity of testing. Remember that there are different ways to interrogate a gene, such as sequencing or deletion analysis. As we discussed in workshop 2, you will need to use evidence (such as variant frequency in the patient population) to decide which method is likely to have the highest detection rate in your patient. In some cases a multi-step strategy is used. Interaction: 1. What does this information tell us about the benefits and limitations of testing? Answer: Genetic testing will identify a cause in most individuals with Dravet. Nevertheless, not all individuals with SMEI have a detectable mutation. This could be because current technology does not detect all possible SCN1A variants, or because SCN1A is not the only gene associated with SMEI.
Facilitator script: Our next step is to assess the predictive value and utility of the test In other words, how will we use a positive result? Instructions: Provide 1 minute for audience to review handout, then ask for a volunteer to answer the discussion question. Fill in gaps in the discussion with subsequent debrief slides. Interaction What outcomes might the family be most interested in? Which are you, as the provider, most interested in? How well will results inform your understanding of those outcomes? Take a moment to review your handout on Dravet syndrome. Would the detection of a variant predict future course of disease in James? Is the detection of a variant a reliable predictor of continued seizure activity and level of cognitive decline? Would genetic information inform risks for other family members? How well? Could you predict recurrence? Severity? Penetrance?
Key Point: SCNA1 testing has limited predictive value for affected individuals and their family members. Facilitator script: Variable expression – recall this is when people with the same condition and even same genetic variant have different clinical presentations - of SCN1A mutations limits what we can say about disease course. Prognosis for James depends on clinical findings, not genetic test results. Interaction: Does this change your thinking about benefits and limitations? Answer: Less value in family testing Cases like this may be a good opportunity to collaborate with a genetic counselor who can help craft family-centered messages about testing limitations. More detail: Although family testing clarifies if a specific genetic change was inherited, we can’t predict how the variant will be expressed in sibs or other carrier relatives. Understanding the inheritance risks may be sufficient reason for doing genetic testing, but it is still important to note the limitations of how that information can be used.
Key point: We need to think ahead not only about positive results, but also about how we will handle uninformative and uncertain results. Facilitator script: We need to think ahead not only about positive results, but also about how we will handle uninformative and uncertain results. We’ll discuss details of interpreting specific results in workshop 4, but to be fully prepared for testing, we need to touch on these concepts here. Let’s start with discussing a negative result. Interaction: What would a negative result mean for James? For his family members? Instructions: Prompt volunteers to share their thoughts. Fill in gaps in the discussion with subsequent debrief slides.
Key Point: Clinical diagnosis trumps genetic test results, but future genetic testing may be helpful. Facilitator script: A negative genetic test may be use to help narrow a differential, but keep in mind that a negative doesn’t firmly rule out the disease. There are three possibilities: 1. There may be a variant in the SCN1A gene that is not detectable with current technology, or the correct test was not selected to interrogate the gene 2. There may be other genes associated with Dravet syndrome, or 3. The patient may have a different diagnosis. The differential diagnostic skills we discussed in workshop 2 can help you decide whether to wait for future advances in testing for the same condition, or move on to another condition on the differential. This is also an opportunity to collaborate with a genetics specialist. A negative test result also means that we cannot confirm risks for family members. Due to variable expression, an apparently normal, healthy parent could carry a variant. Therefore, there is still an increased risk for sibs.
Key point: We need to think ahead not only about positive results, but also about how we will handle uninformative and uncertain results. Facilitator script: Let’s talk next about another type of result – the variant of uncertain significance. Interaction: Have you ever had a VUS on genetic test results before? How did you handle it? What would a VUS mean for James? For the family? What other tests yield results of uncertain significance? How do you handle those? Instructions: Prompt volunteers to share their thoughts. Fill in gaps in the discussion with subsequent debrief slides.
Key Point: A VUS is uninformative and shouldn’t be used clinically. Facilitator script: A variant of uncertain significant is a change from the expected gene sequence that has not been clearly associated with disease and has unknown effect on gene function. We can not determine whether it is a new pathogenic mutation, or a benign polymorphism seen in the general population. It is critical that a VUS not be over-interpreted. Until further information is available, a VUS should be treated like an uninformative negative. A VUS should not be used to make changes in management and predictive testing for at-risk family members is not recommended. We’ll talk more in workshop 4 about the spectrum of suspected significance for a VUS, and how you can work with the lab and family to help gather data and clarify the meaning of a VUS over time.
Key Point: The next step in our assessment is to weigh risks of testing against benefits in the context of your patient’s particular situation. Facilitator script: Our next step is to identify and weigh the risks of testing against benefits. There are some well discussed risks of genetic testing that do not apply in all situations. It is important to think not only about the general risks of genetic testing, but also a family’s unique clinical and psychosocial situation. Some families may be more vulnerable to certain risks than others. Interaction: What are some of the general risks of genetic testing? Which ones apply in James’ situation? Have you experienced cases where these issues arose? Instructions: Prompt volunteers to share their thoughts. Fill in gaps in the discussion with subsequent debrief slides.
Key Point: Clinical and psychological utility of genetic testing must be weighed against the financial, emotional, family and social risks. Facilitator script: In general, genetic testing can have financial, legal, social, and psychological impacts. Although there are limited protections in place against certain kinds of discrimination (see GINA info on next slide), families may still experience social stigma and financial limitations (like inability to get life insurance). Not all genetic tests have the same risks, and predictive tests raise the most concerns. In James’ case, the risks are low, since his family is seeking a diagnosis. More detail: However, results could result in unexpected emotional responses and family communication challenges, especially considering the unpredictability involved with variable expression and VUS. Some relatives may feel their “right not to know” has been violated, potentially resulting in estrangement. Family emotional responses to genetic test results can range from denial to grief, anger, and depression. Pre-existing psychosocial issues should be taken into account.
Key Point: Some limited legal protections exist against genetic discrimination. Facilitator script: GINA is a federal law that was passed in 2009 that provides some limited legal protections exist against genetic discrimination. More detail Protects against health insurance and employment discrimination for most individuals Does not address disability or life insurance Does not protect individuals who already have symptoms A discussion guide about GINA is available on the NCHPEG website.
Facilitator script: Given what we’ve discussed, how you would discuss the risks, benefits, and limitations of SCN1A testing for James with his parents?
Key point: The clinician and family must decide together whether the benefits justify the limitations and risks. Facilitator script: The bottom line is that the value of genetic testing is determined on a case-by-case basis after thorough discussions with the family. The clinician and family must decide together whether the benefits justify the limitations and risks. For some, the potential benefits may clearly outweigh the limitations and risks, which are summarized here. For others, the possibility of additional uncertainty, a lack of impact on management, or a may make genetic testing undesirable or unnecessary. In a few moments, we’ll have a small group exercise to practice the skills you’ll use in these conversations with families.
Facilitator script: Before we move on to the communication exercise, let’s summarize the steps to identifying benefits, risks, and limitations. Step 1 involves assessing data on test sensitivity and the frequency of variants in the population with your patient’s clinical features Step 2 involves assessing clinical utility and positive and negative predictive value of a variant. Step 3 involves thinking ahead about negative results and variants of uncertain significance Step 4 involves communicating the benefits, limitations, and risks of testing
Facilitator script: Let’s talk about informed consent and patient counseling
Interaction: Let’s start by discussing: What does pre-test counseling mean to you? What are you currently doing with families before ordering testing? How much pre-test counseling do they get? How much time do you spend on this? What messages do you prioritize before testing? What is involved in your current pre-test counseling? Instructions: Ask for volunteers to share their thoughts. Use the following slide to fill in gaps in the discussion.
Key Point: The process of informed consent paves the way for a smoother results disclosure process. Facilitator script: Aside from the ethical and legal imperative to provide informed choice regarding benefits and risks, families adapt better to results when they know ahead of time how they can and cannot be used. Making time for pre-test counseling paves the way for a smoother results disclosure later on. Informed consent should be thought of as a conversation, rather than just a form the family should sign.
Instructions: Signal of transition to small group practice. Make sure everyone has the patient handout and the CMA testing summary to complete the activity. Walk around the room to hear what the groups are saying. This will help you determine where there is confusion and what they already know that may need less explaining. Small group work for about 10 min, or as your time allows. Reconvene, and use the subsequent slides to step through each discussion question and debrief. Ask for a volunteer from each small group to share their thoughts. Use the answer slides to summarize or fill in gaps in the discussion. Facilitator Script Now, you will have an opportunity to practice translating benefits, limitations and risks for a family. We’ll look at a new patient’s clinical scenario. Break into groups of 3 – 5 and work together on the case for about 10 minutes. Read through the patient history and the disease and testing summaries. Then work through the discussion questions with your group. Identify one person to be spokesperson for the group. After you discuss as a small group we will reconvene and discuss your findings with the larger group.
Facilitator Script This case is about Suzie, a 7 year old girl with a history of developmental delay, hypotonia, and dysmorphic features detected on physical exam (which are not shown in this image) Suzie’s family history is notable for mild learning delays in her mother. There is limited family history information available and Suzie’s father is unknown. You recommend a microarray
Key message: The first step in pre-test counseling is to communicate the reasons for testing. Facilitator script: Our first goal is to communicate the goals of testing. Interaction: What minimum information does the family need to understand? What did you decide were your key messages for the family? What kinds of language would you use with them to explain these concepts? Would you use any teaching tools or strategies besides conversation? Instructions: Ask a volunteer from each small group to share their counseling priorities.
Key message: Initial counseling can be simple, expanding detail with feedback from the family. Facilitator script: There are many ways to initiate pre-test counseling, but consider keeping it simple at this stage. Most families can only absorb small chunks of information at any one time. For example, you might limit your initial discussion to just these few points: Why you think there is a genetic contribution How you would use results How results cannot be used You can refine your message and add detail later in the discussion, including the possible different outcomes of testing, and risks and benefits, as you check understanding with the family and address their specific concerns. More detail: Specific initial messages for Suzie may include: Suzie’s features and family history suggest a genetic contribution Testing could give us an explanation for her delays, hypotonia, and unique features. Testing could inform family/reproductive risks Testing may or may not inform prognosis or management
Key message: Our next step is to assess understanding and family expectations so we can refine our counseling. Instructions: Prompt a volunteer from each small group to share highlights of their discussion about these questions. Use the suggested prompts below to stimulate discussion. Fill in gaps in the discussion with subsequent debrief slides. Interaction: What do you think their motivations and aims might be? What do families typically want from results? What are they hoping for? How would you probe for this information? What language would you use?
Key Point: Most families want to understand the cause, and hope for treatments, prognosis, or preventive measures. Facilitator script: Most families are looking for an explanation, and perhaps a relief from guilt. They are also typically hoping that a diagnosis will lead to better treatment, maybe even a cure, or at least a better sense of what to expect in the future. Many families expect that genetic testing will always give a straightforward yes or no answer. They may be surprised by uncertain or uninformative results, and these types of results can generate the strongest emotional responses. More detail: Think ahead about potential family goals, but don’t just make assumptions. Use your interviewing and listening skills to be sure you and the family are on the same page. This kind of assessment will help save you time with families who have a high prior understanding, while allowing you to target counseling to families with particular misunderstandings.
Key point: Using the information you gathered from listening to the family, you can adjust and add detail to your counseling. Facilitator script: Once we’ve assessed what the family understands and their goals, we can adjust our counseling to help set realistic expectations. What additional information does the family need to be prepared for the various possible outcomes? Interaction: What benefits and limitations did you identify that the family should understand? How would you phrase these for the family? What can realistically be done with results? What uncertainty might remain? What unexpected information might come up? What are the risks? What is involved in testing?
Key Point: Add detail to reinforce limitations and risks based on the family’s prior understanding. Facilitator Script: We can tailor our counseling for each family based on our assessment of their prior understanding of genetic testing. Emphasize the possibility of unexpected or uninformative results, which are often the most surprising and frustrating for families. Finally, be sure to discuss what to expect from the testing process, including the how the sample will be obtained, what will happen to it, how long results will take, and how they will be disclosed. It is important to inform families prior to testing that additional tests may be requested depending the results of the ordered test , i.e. requesting blood for parental carrier testing for clarification of a variant, or additional testing for a different genetic cause for the patient. More detail: Specific counseling messages for Suzie’s case may include: Testing may not identify a cause for Suzie’s condition Testing cannot rule out all genetic diseases Results may or may not provide guidance for management Interpretation of a VUS is uncertain, and might change over time Reproductive risk estimates may be limited by variable expression Interpretation may require parental testing Could reveal information about family relationships Testing process, turn-around time and disclosure plans
Key point: Suzie’s test result suggests a consanguineous relationship between her parents Facilitator script: This is a modification of a real result seen in clinic. - PAUSE FOR PARTICIPANTS TO REVIEW RESULT AND PROCESS- Suzie’s result shows long continuous regions of homozygosity, sometimes called identity by descent. This is suggestive of a close biological relationship between Suzie’s parents. Consanguinity increases the chance for rare autosomal recessive disorders. We’ll discuss interpretation, disclosure, and use of these types of results further in workshop 4. For now, let’s focus on the communication implications of these results. Interaction: Did you adequately prepare the family for this possibility? Did you have any clues this might occur? Additional detail: Consanguinity increases the chance for rare autosomal recessive (AR) disorders. It is possible that Suzie has an AR recessive disorder that is the cause of her condition. Additional genetic evaluation may be able to identify the specific AR syndrome, or it may be an unknown disorder. Suzie’s test results show that she does not have a chromosome abnormality. However, they suggest that she may have an autosomal recessive condition caused by mutations in a single gene. This testing technique cannot identify the specific gene, but a genetic evaluation with additional testing may be able to detect the single gene mutations underlying Suzie’s condition. Collaborate with a genetics professional, either from the lab or locally, to determine a plan for further genetic evaluation for Susie. Labs will typically report the amount of homozygosity, which correlates to the degree or relationship (e.g., first-degree, second-degree). The size and distribution of regions of homozygosity can provide some additional information about degree of relationship. However, the additive percent of homozygosity cannot always predict degree of relationship in families or cultures with multiple degrees of consanguinity. If this information is important to the counseling and care of your patient and his/her family, discuss the findings directly with the laboratory.
Key Point: Be sure to prepare the family for unexpected information, especially when clinical or family information is lacking. Facilitator Script: Remember that some genetic tests have a higher risk of identifying unexpected information. Genome wide tests like microarray and whole genome sequencing have the greatest risk. This can include incidental diagnoses or genetic risk unrelated to the indication for testing. It can also include information about family relationships, including non-paternity and consanguinity. Missing family information is a red flag for counseling about the possibility of unexpected genetic testing results. In this case, multiple explanations are possible: It could be that Marie was aware that Suzie’s father was related to her, but did not wish to share this information. This could have been a consensual relationship or a case of rape. Marie may not have been comfortable disclosing this information in the presence of her mother Jane. Alternatively, Marie may have unknowingly had sexual relations with a family member, such as a half-brother she never knew through her estranged father.
Facilitator script: We’ve provided an informed consent checklist and some clinical examples with talking points for further illustration and practice.
Key Point: Support is available to improve your informed consent and pre-test counseling. Facilitator script: Everyone has a different comfort level with counseling about the genetic testing process, and genetic tests vary widely in their complexity. Consider referral or consultation with a genetics specialist when you are facing a complicated consent process. More detail: Consider referral for complex scenarios such as: You don’t feel you can devote adequate time to a lengthy consent process The patient/family has a low literacy level or other barrier to informed decision-making The patient/family expresses an emotional response to testing or genetic information that warrants further exploration The patient or family has a pre-existing psychosocial issue that may be complicated by emotional responses to test results The patient/family is undecided about doing testing and would benefit from further discussion and exploration The test performance data is weak and it is unclear whether benefits outweigh limitations. Additional detail: Genetic counselors are trained in patient education strategies and psychosocial counseling interventions and can assist with: Facilitating decision-making by discussing benefits and risks in a patient/family centered way Explaining genetic information to patients/families in lay terms Exploring family motivations and setting realistic expectations Addressing psychosocial concerns Accessing support resources for specific genetic concerns and conditions
Instructions: The following slides cover the general concepts regarding ordering logistics, but the details will vary based on your institution. Facilitators can customize this section to cover the important points in your own institution.
Interaction: How often do you order a genetic test? How is the process of ordering genetic testing different from other types of blood tests? What additional steps did you need to go through? What was most difficult? What solutions did you find?
Key Point: Obtaining a genetic test often involves more steps than other types of testing because of the expense and technology involved that not every lab has. Facilitator script: We’ll talk briefly about four general aspects of genetic testing logistics: Locating a specialty lab Managing insurance and pre-authorization requirements Extra paperwork that may be required for genetic testing And what to expect for results reporting Instructions: Facilitators can customize this section to cover the important points in your own institution.
Key Point: There are resources available to help you locate a laboratory for specialty genetic tests. Facilitator script: The availability of genetic testing varies widely, depending on how common the particular condition is, and the level of technical complexity the test requires. You may find you have several labs to choose from for chromosomal microarray testing, but only one or two for specialty testing for rare neurologic conditions. In some cases, genetic testing may only be available on a research basis. Start with your institution’s referral laboratory to determine whether a relationship already exists with a genetics lab. For specialty testing, use online databases of laboratories such as GeneTests or the Genetic Testing Registry. Finally, if you are having trouble locating a genetic testing lab for a particular condition, a geneticist or genetic counselor may be able to help.
Key Point: Cost and coverage can be unpredictable, but there are ways to facilitate the process. Facilitator script: The cost and insurance coverage for genetic testing varies widely (300-15000) depending on technology, clinical utility, and population frequency. It can be very difficult to predict whether an insurance company will cover the costs of genetic testing. Medicaid and Medicare have very specific guidelines for which genetic tests will be covered, and some private companies follow their lead. It is critical to determine whether prior authorization is required. Be prepared to write a letter of medical necessity to support the claim. Some labs and genetic counseling resources provide templates for these letters. Some genetic testing laboratories will facilitate the insurance claim process. Ask the lab what options are available– some will submit the claim, while others bill the ordering institution, and still others bill the patient directly. Genetic counselors may be able to help with this process.
Key point: Sample collection procedures and paperwork requirements may be specific and unusual. Facilitator script: You may find that there is more paperwork for genetic testing. If you are ordering testing through an electronic system, be sure to check with the lab to determine whether additional paperwork should be sent with the sample. It is important to provide the lab with sufficient clinical and family history detail on the requisition, which may influence interpretation of results. The paperwork may include specifications about billing and insurance filing discussed on the previous slide. In addition, some labs, institutions, and states require documentation of informed consent for genetic testing. Finally, be sure to review the sample requirements, which are sometimes unique for genetic testing, involving buccal swabs, mouthwash, specific blood tubes, or even biopsy of other tissues.
Key point: Use a lab’s website or requisition and supporting materials to determine turn-around time and practices for reporting results. Facilitator script: Turnaround time for genetic testing may be longer than your patients are used to. TAT may range from 2 weeks to several months. Find out ahead of time whether you will be receiving results directly from the genetics lab, or if you will get a summary from the referral lab. Referral lab reports sometimes leave out critical information for interpretation. You may receive a call from the laboratory to clarify clinical information or to provide extra context for the test interpretation. Be ready to call the lab yourself to check on status, obtain reports, and get help with interpretation of results (we’ll discuss this more in workshop 4)
Key Point: Genetic testing can be complicated, but help is available Facilitator script: This is a testing algorithm for intellectual disability – the point is to demonstrate complexity not to see details Keep in mind that genetic testing labs typically employ genetic counselor who can help you determine the best approach for a specific patient. See the collaboration tool for specific resources to help you find a genetics professional.
Facilitator Script: In summary, we have explored these key points in this workshop on the genetic testing process: Use test performance data and information on variable expression and genetic penetrance to assess limitations, benefits, and risks Anticipate potential results and how you will use them Set family expectations Expect a higher maintenance ordering process
Session Three: Genetic Testing Process
Genomics for the
Genetic Testing Process
Re-Cap: Evaluation & Testing Decisions
Narrow the differential
Select appropriate tests
Develop a family testing strategy
Identify benefits, limitations, risks
Provide informed consent
Order testing appropriately
Take time to prepare
for outcomes of testing
Evaluation & Testing Decisions
1. Use data to identify limitations of genetic testing
2. Weigh the benefits and risks of testing in the patient’s
3. Provide pre-test education and counseling
4. Develop a protocol for ordering appropriate testing
2 yo male
History of febrile and
Clinical Scenario: James
James Family History
Evaluations and unique features point
toward Dravet syndrome
Differential Diagnosis includes:
•Severe myoclonic epilepsy of
infancy (SMEI, or Dravet
•Pyridoxine, B6 and Folic acid
•Autosomal dominant nocturnal
frontal lobe epilepsy
•Simple febrile seizures
Overview Dravet Syndrome
•Severe myoclonic epilepsy of infancy
•Cognitive decline over time
•30-80% cases associated with a variant in SCN1A
•Typically de novo (depends on phenotype)
•When inherited, autosomal dominant with significant
intra-familial variable expression
•Difficult to control
•Anticonvulsant drugs and ketogenic diet may reduce
Step 1: Assess ability of the test to detect
variants in your patient’s population
What is the yield of genetic testing in a
child with severe myoclonic epilepsy?
30-80% of individuals with Dravet
have a detectable mutation in SCN1A
Step 2: Assess the ability of a variant
to predict outcomes
What could the detection of a variant tell the
clinician about future outcomes for the patient and
risk for family members?
Variable expression limits prognostic
value and family risk counseling
Step 3: Anticipate other results
How would you use a negative result?
What would you do with a variant of uncertain
Negative genetic test doesn’t rule out
disease in a symptomatic individual
Portion of variants
missed by test
Step 3: Anticipate other results
How would you use a negative result?
What would you do with a variant of uncertain
A VUS is uninformative and
shouldn’t be used clinically
Not seen in any
Contradictory reports in
Unknown effect on
Step 4: Identify and weigh risks
What are the general risks associated with
genetic testing, and which ones apply to James?
General risks of genetic testing
• Family impact and privacy
• Psychosocial coping and adaptation
(GINA) affords some
How would you discuss the
risks, benefits, and limitations
Balance benefits, limitations, and risks in
the context of the patient and family
• End diagnostic odyssey
• Clarify reproductive risk
• Refine differential
• Variable expression limits predictions
• Uninformative negative
• Uninformative VUS
• Clinical uncertainty
• Psychosocial impact
Summary: Steps To Assessing
Limitations and Risks
Step 1: Assess likelihood of detecting a variant
Step 2: Assess ability of a variant to predict
Step 3: Anticipate other results
Step 4: Identify benefits and risks
7 yo female
Clinical Scenario: Suzie
What are your initial counseling
Step 1: Communicate goals of
Keep initial messages simple
Step 2: Check understanding and
assess family expectations
What might Suzie’s family be expecting
from results? How would you find out?
Families want explanations and
Did I cause it?
What will the
Step 3: Set realistic expectations
What additional information does the family need
to be prepared for the various possible
Reinforce limitations and risks;
and discuss the process
Did you adequately prepare the
family for this outcome?
Patient Name: Suzie Hubbard
Test Performed: SNP Array Analysis
Indication: Developmental Delay
Normal Dosage; Long contiguous regions of
homozygosity, see interpretation.
Copy number analysis was within normal limits, but there are
extended contiguous regions of allele homozygosity (>10Mb)
observed in multiple chromosomes that suggests limited
outbreeding (possible consanguinity).
Recommendations: Consanguinity increases the chance for
rare autosomal recessive disorders. Clinical correlation and
genetic counseling are recommended.
Prepare the family for unexpected
results, especially when family
information is lacking
Summary: Steps to Pre-test
• Step 1: Outline goals
• Step 2: Assess family motivations and aims
• Step 3: Set expectations
Consider referral or consult for
When to consult/refer:
•Lack of time
•Data is weak with unclear
Genetic Testing Process
• Use data to assess limitations, benefits and risks
• Anticipate potential results and how you will use them
• Set family expectations
• Expect a higher maintenance ordering process
• Refer or consult with genetics
• Interpret results in the clinical context
• Communicate with families about the
• Develop a management plan based on
the genetic data
To be discussed in workshop 4
•Practice assessing limitations, benefits and risks and
composing pre-test counseling messages for
– Ataxia telangiectasia
•Use the informed consent checklist and talking points with at
least one patient before the next workshop. Be prepared to
share your experiences with the group.