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Similar to Session Four: Results Interpretation & Application
Session Four: Results Interpretation & Application
- 1. Genomics for the ChildNeurologist: Results Interpretation & Application
- 2.
- 3. Re-Cap: Genetic TestingProcess Identify benefits, limitations, risks Provide informed consent Order testing appropriately
- 4. Workshop Four: Genetic ResultInterpretation & Application
- 5. Interpretation & Application LearningObjectives Interpret results in the context of the clinical situation Communicate with families about genetic test results Develop a management plan based on genetic data
- 6. Clinical Scenario: Alex 12month-old male Family history of optic glioma
- 7. Alex’s Family History 75y 45 y d. 70 Heart attack d. 50, accident optic glioma skin lesions Alex 12 mo 58 y 36 y 58 y 29 y
- 8. Overview of NF1 •Features: – Multiple dermatologic findings, neurologic tumors, learning disability – Emerge over time, and during puberty and pregnancy • Genetics: – Variants in NF1 found in 95% with a clinical diagnosis – Autosomal dominant inheritance – Variable expression • Management – Screening for vascular, neurologic and ophthalmologic complications – Surgical removal of uncomfortable, disfiguring or symptomatic neurofibromas, when possible – Developmental and educational assessment
- 9. Assessment: Alex’s PhysicalExam • Generalized freckling • 3 café au lait < 5mm • Height 25%tile • Weight 25%tile • Head Circ 75%tile
- 10. Deciding to Test: Giventhe level of family concern, you decide to test Alex for NF1. There are some limitations, but testing might clarify things…
- 11. Select the appropriatetest: NF1 testing should start with sequencing
- 12. Interpret results inthe context of the clinical situation
- 13. How do youinterpret a negative result in Alex? d. 50, accident Optic glioma Skin lesions No testing 36 y 3 small café au lait No NF1 variants identified Alex 18 mo Scenario 1: NF1 Suspected but Unconfirmed in Alex’s Father.
- 14. A negative resultreduces likelihood, but is not completely informative d. 50, accident Optic glioma Skin lesions No testing 36 y 3 small café au lait No NF1 variants identified NF1 less likely, but not ruled out. Alex 18 mo Scenario 1: NF1 Suspected but Unconfirmed in Alex’s Father.
- 15. How do youinterpret a negative result in Alex now? d. 50, accident Optic glioma Skin lesions Pathologic NF1 variant found 36 y 3 small café au lait No NF1 variants identified Alex 18 mo Scenario 2: A pathologic variant in NF1 was identified in Alex’s father.
- 16. A “true negative”rules out disease d. 50, accident Optic glioma Skin lesions Pathologic NF1 variant found 36 y 3 small café au lait No NF1 variants identified NF1 ruled out Alex 18 mo Scenario 2: A pathologic variant in NF1 was identified in Alex’s father.
- 17. Other possible results: Variantof Uncertain Significant (VUS) Seen in previous patients? Predicted effect on gene function?
- 18. Range of VUS Negative Suspected Benign Variantof Unknown Significance Significance Unknown Positive Suspected Pathogenic
- 19. Communicate with families aboutthe results
- 20. What is yourexperience with genetic results disclosure?
- 21. Genetic results mayimpact families differently Guilt & Shame Relief from uncertainty Stigma & Discrimination Privacy
- 22. What strategies doyou use to discuss uncertainty? d. 50, accident Optic glioma Skin lesions No testing 36 y Alex 18 mo 3 small café au lait No NF1 variants found NF1 less likely, but not ruled out.
- 23. Frame communication onfamily’s needs and concerns A malignant tumor is unlikely… …but we’ll keep checking to be sure.
- 24. Develop a managementplan based on genetic data
- 25. Are management decisions differentfor genetic conditions?
- 26. Genetic results mayhave broader implications Multi-system Whole Family Cognitive Profiles
- 27. What resources doyou use for management of genetic conditions?
- 28. Tools are availablefor management of a genetic diagnosis
- 29. Testing of familymembers Step-wise multi-gene panels: ATXN2 mutation found $ 13,330 Targeted ATXN2 analysis: $ 790
- 30. Management: Clinical diagnosis withoutmolecular confirmation Clinical diagnosis trumps genetic testing…
- 31. How would youmanage Alex given the negative result in this scenario? d. 50, accident Optic glioma Skin lesions No testing 36 y Alex 18 mo 3 small café au lait No NF1 variants found NF1 less likely, but not ruled out.
- 32. Individuals with uninformativeresults still need screening • Annual screening for features until past the average age of onset
- 33. At-risk family membersshould have screening
- 34. How would youmanage a VUS result? d. 50, accident Optic glioma Skin lesions No testing 36 y 3 small café au lait VUS in NF1 found Alex 18 mo
- 35. Treat a VUSlike an uninformative negative • Annual screening for features until past the average age of onset • Classification of VUS may change over time
- 36. Summary of testingoutcomes Scenario Outcomes 1: Pathogenic variant identified • Alex needs annual exam • Imaging/invasive procedures not typically indicated • Educational assessment indicated • Targeted testing available for family 2: True negative • Reassures family • Spares Alex follow-up screening 3: Uninformative negative • May reassure family, but uncertainty remains • Alex still needs annual screening • Testing not available for family 4. Variant of uncertain significance • Cannot rule NF1 in or out • Alex still needs annual screening • Testing not available for family
- 37. In retrospect, whatdo you think about the utility of testing for Alex?
- 38. Psychosocial concerns mayjustify testing, but aware of remaining uncertainty
- 39.
- 40. What is thebottom line for Lily?
- 41. The variant isa probable cause of ASD in Lily, but uncertainty remains Asperger Syndrome 15q11.2 del A/W Lily 6y Speech Delay Autistic Behaviors 15q11.2 del
- 42. What is thebottom line for Lily’s family?
- 43. Risk assessment islimited, but non-genetic screening may be indicated ✔
- 44. Summary: Interpretation andApplication • Interpretation of a genetic test result depends on the context of the individual and family • Keep counseling messages simple and be prepared with resources and teaching tools • Use tools to guide management • Be cautious with counseling and management changes when results are uninformative or VUS
- 45. Homework/Practice • Practice interpretingand communicating results – Interpreting results case study (Soledad) www.nchpeg.org/neuro
- 46. Thank you! [facilitator contactinformation]
Editor's Notes
- #2 Facilitator Script: [See supplementary information for example introduction.]
- #4 Recap previous workshopFacilitator script:Before we get started on test interpretation, let’s briefly recap the skills we learned in the last workshop. We discussed how a step-wise pre-test protocol can help you and and your patients prepare for the process and outcomes of testing. In particular we practiced: Using test performance data to inform benefits, limitations and risks, providing anticipatory guidance to the family and, navigating a higher maintenance ordering process, and ordering tests. For the purposes of this workshop, we will not be reviewing each of these steps in detail
- #5 Workshop title and introductionFacilitator Script: In this workshop, we’ll be discussing how to “put all the pieces together” to effectively interpret and apply genetic test results
- #6 Learning objectivesFacilitator script:In this workshop we will practice these skills: Interpret results within the specific clinical context Communicate with families about the significance and impact of results Develop a management plan that incorporates results, family history, and other data.
- #7 Transition to clinical scenario introductionFacilitator ScriptLet’s start by applying these skills to a model case. Here is Alex, a healthy 12 month-old maleHe was referred by his pediatrician for evaluation for neurofibromatosis type 1 due to a family history of optic glioma (see next slide)You see Alex in a multidisciplinary neurofibromatosis clinic, which includes neurology, clinical genetics, surgery, ophthalmology, cardiology, pediatrics, and other disciplines as needed. Additional information:Prenatal and Birth History: NormalDevelopmental History:NormalPast Medical History: Minor respiratory infectionsReview of Systems:UnremarkableSocial History: Alex lives with his mother, who is grieving the loss of her husband.
- #8 Key Point: Alex has a family history that is suggestive of, but not confirmation of, neurofibromatosis type 1.Facilitator script:Alex’s father recently died in a car accident.He had been referred to a geneticist for evaluation of NF1 due to a rapidly growing optic glioma.Upon further questioning, Alex’s mother reveals that Alex’s father had skin-colored bumps on his body.Alex’s mother has been reading about NF1, and is very concerned about the possibility of a brain tumor in Alex.Interactive discussion prompt:What is the inheritance pattern for NF1? (Autosomal dominant)If NF1 were confirmed in his father, what is the chance that Alex will have NF1? (50%)Additional information:The remainder of the family history is negative for intellectual disability, developmental delay, hearing or vision loss, birth defects, neuromuscular issues, seizures, abnormal movements, abnormal blood clotting or bleeding, sudden death, and multiple miscarriages. No one else in the family has cancer, tumors, or skin lesions.
- #9 Key Point: Neurofibromatosis is an autosomal dominant neurocutaneous disorder with variable expression and small increased risk for malignancies.Facilitator script:As you know, NF1 is a neurocutaneous disorder with characteristic skin findings and neurologic tumors, which are typically non-malignant.There is a small increased risk for malignant peripheral nerve sheath tumors and breast cancer.You have been provided with a handout that includes more details on the features of NF1 and clinical diagnostic criteria.Refer to this handout for the activities we’re about to do together on the next few slides.Handout includes:Elaboration on natural history, genetics and management.Clinical diagnostic criteriaAges of onset of key featuresIntra-familial variable expressionTesting strategy and detection ratesLifetime risk for malignancy
- #10 Key point: Alex has features overlapping with NF1, but does not fit clinical criteria.Facilitator ScriptOn Alex’s physical exam, you note 3 café au lait macules, each less than 5 mm in diameter.Alex’s mother reports that he has more freckles than either parent, but you do not note axillary or inguinal freckling.Other stigmata of NF1, including neurofibromas and lisch nodules, are absent.Height and weight were at 25th centiles, and occipital frontal circumference was on the 75th centile. Interactive discussion prompts:1. Using the handout provided, does Alex meet diagnostic criteria for NF1? Answer:Alex does not meet clinical criteria, which require two or more of the features listed in the checklist.2. Does this rule out NF1 in Alex? Answer: At 1 year of age, we cannot rule out NF1 in Alex based on his clinical presentation, but genetic testing might clarify things.More detail: He does not have sufficiently large or numerous café au lait, generalized freckling is not a feature, and NF1 was not confirmed in his father.The features of NF1 emerge over time in early childhood.Your NF1 summary handout lists the averageage of expression for key features.
- #11 Key Point: After assessing Alex’s presentation and family history, you weigh the benefits and limitations and counsel the family, as practiced in workshops 2 & 3.Facilitator script: Providers may have different opinions about whether genetic testing for NF1 provides sufficient immediate medical benefit in childhood to justify the costs of testing.We’ll come back to the question of utility later with some hindsight about potential outcomes of testing and how results can be used clinically.For now, let’s assume you’ve assessed the limitations and benefits of testing, and counseled the family appropriately, as we practiced in workshops 2 and 3.Given the level of anxiety the family has about a brain tumor in Alex, you decide to order genetic testing.(next slide discusses ordering)Additional information:The list price of NF1 sequencing and deletion/duplication analysis ranges from $1000-2500 (as of July 2013).Insurance coverage varies widely.Testing is less expensive when it can be targeted to a known familial mutation.
- #13 Transition to interpretation sectionFacilitator script:To demonstrate how the clinical context influences results interpretation, we will examine some different scenarios for Alex’s family.A positive result would be relatively easy to interpret, so in this exercise we’ll be looking at NEGATIVE results in 2 different scenarios for Alex.The other possible outcome of testing is a VARIANT OF UNCERTAIN SIGNIFICANCE, which we’ll be talking about as well.Remember that in the following scenarios, the utility of testing may not be clear, but we are using the example to demonstrate how to interpret results.
- #14 Group discussionFacilitator script:In the first scenario, Alex’s father unfortunately passed away before his scheduled appointment for NF1 evaluation.NF1 was suspected, but not confirmed by clinical criteria or genetic testing.As we’ve learned in past workshops, genetic testing should ideally begin with a symptomatic individual for the most informative result.This is not an option in this scenario.You perform testing in Alex, which does not identify any sequence variants, deletions or duplications.Discussion prompt: How do you interpret the results?Additional information:Unilateral optic glioma is highly suspicious for NF1, but is sometimes seen in isolation or as a feature of other conditions.Bilateral optic glioma is pathognomonic for NF1.
- #15 Key Point: In the absence of a known familial genetic variant, a negative gene test significantly reduces the possibility of NF1, but is not completely informative.Facilitator script:Remember that the detection rate of NF1 testing is less than 100%A negative result significantly decreases the likelihood of NF1 in Alex, but it cannot be completely ruled out without a known causative mutation in the affected relative.Possible interpretations include:Alex did not inherit the NF1 variant causing his father’s optic gliomaThe NF1 variant in the family is not detectable by current technologyThe optic glioma was associated with a variant in a different geneWe’ll come back to this result later to discuss how to apply it to clinical management.Additional discussion prompts:What if Alex met clinical criteria for NF1 based on features, but still had a negative genetic test? How would you interpret a negative result in that case?Answer: Clinical diagnosis trumps negative testing results, so the diagnosis of NF1 stands and Alex should be managed accordingly (we’ll come back to management)
- #16 Facilitator script:In our second scenario, Alex’s father had genetic testing prior to his death, which identified a pathologic variant in NF1You order testing for Alex targeted to the variant identified in Alex’s father.This is faster and less expensive than whole gene sequencing.Discussion prompt: How do you interpret a negative result in Alex now?
- #17 Key Point: A “true” negative result for a known familial variant rules out disease.Facilitator script:A negative test for a known familial variant is considered a “true negative”, and rules out disease.In this scenario, testing would be more useful for Alex.We’ll discuss specific impacts on management in a few moments.
- #18 Key Point: A VUS is a change from the reference sequence that has not previously been associated with disease.Facilitator script:As we have discussed, another potential outcome of genetic testing is a variant of uncertain significance, which we will look at more closely in a clinical example in a few minutes.A VUS is a change from a reference sequence that has uncertain clinical effects. The variant my be novel, or may be associated with conflicting evidence in the literature.Although VUSs are rare for well-described conditions like NF1, they can occur any time a test interrogates an entire gene or large region of DNA.VUSs are more common in genome-wide tests, and when there is a only small patient population available for comparison.
- #19 Key Point: There is a range of “uncertainty” in VUS based on the specific type of mutation and its predicted effect on gene function. Additional information:In Alex’s case, if we saw a VUS in Alex, in the absence of a diagnosis in his dad, this would be an uncertain result.There is a range of uncertainty in VUS, based on the type of mutation and its predicted effect on gene function.The laboratory is responsible for classifying the VUS on this spectrum.Over time the lab may reclassify variants based on new evidence.Check with the lab about how they communicate changes in classification.
- #20 Transition to communication sectionFacilitator script:Now that we’ve reviewed some of the outcomes of testing, we’ll discus strategies for communicating these nuances to the family.
- #21 Facilitator script:Let’s reflect on your experiences giving genetic test results. Discussion prompts:What challenges have you had?Is genetic result disclosure different from counseling about other types of test results?How do family responses differ?
- #23 Facilitator script:We just discussed some of the family implications of a genetic diagnosis, but as we demonstrated in Alex’s case, genetic testing may also involve uncertainty. Let’s talk about strategies for addressing some of the challenges of genetic testing, GOING BACK TO THE FIRST SCENARIO, WHERE ALEX’S FATHER DID NOT HAVE A KNOWN NF1 MUTATION.Discussion prompts:What challenges do you see in Alex’s case?How would you communicate an uninformative negative result to the family?Have you had a similar family in your clinic?What were your counseling strategies?Additional discussion prompts:How do you decide whether to disclose in person or by phone?What teaching tools and resources do you use?How do you make adequate time for education and counseling?
- #25 Transition to managementFacilitator script: Let’s talk next about how genetic information can influence your management decisions, as well as scenarios where management decisions are limited.We will address: Management of the individual and family with a diagnosis confirmed through genetic testing, and Management of the individual and family when diagnosis is uncertain or when molecular confirmation is not available.
- #26 Group discussionFacilitator script:Before we discuss specific management issues for Alex’s case, let’s talk in general about how you use genetic information in your management decisions.Discussion prompts:Are management decisions different for genetic conditions? How does genetic information influence your management decisions?Is management for genetic conditions different from management for non-genetic conditions?
- #28 Group discussionFacilitator script:Where do you currently get information on management of genetic conditions?
- #29 Key Point: A number of tools have been developed to guide management of genetic conditions.Facilitator script:A number of tools have been developed to guide management of genetic conditions.Some are general databases of genetic diseases., such as OMIM or Gene Reviews.Some focus on specific types of genetic variation, such as Unique which provides information about chromosome microdeletion syndromes.Others focus on specific management applications, such as Gemss, which provides information to schools about educational needs for specific genetic conditions.You have been provided with a handout listing the web addresses for these resources.Some of the management recommendations for NF1 are listed on the disease summary handout.
- #30 Key Point:Management of genetic conditions involves discussion of risks and options for at-risk family members and reproductive testing.Facilitator script:As we’ve discussed, management of genetic conditions involves discussion of risks and options for at-risk family members and reproductive testing.Once you have a diagnosis for the patient, at-risk relatives should be offered testing. Or, as we will discuss in a moment, if a mutation is NOT identified in the family, relatives can be offered screening for the disease.Testing should be offered to all first degree relatives of any individual with a confirmed diagnosis.Here is an example from session 2 in a family with spinocerebellar ataxia type 2When the causative mutation or alteration is known in a family, you can test at-risk relatives for that specific mutation. This is the most time and cost effective approach.
- #31 Key Point: Clinical diagnosis trumps genetic testing.Facilitator script:Occasionally an individual meets clinical diagnostic criteria,but testing fails to identify a genetic variant.Alternatively, you may have decided that confirmatory testing would not change management.As we discussed previously, clinical diagnosis trumps genetic test results, and the patient should be managed according to guidelines for the diagnosis.However, if the patient has an atypical disease course, referral to a genetics specialist is indicated to rule out other diagnoses with overlapping phenotypes.For example, NF1 has an overlapping phenotype with variants of Noonan syndrome and Tuberous Sclerosis.
- #32 Group discussionFacilitator script:How do we manage a patient like Alex for whom genetic testing was not completely informative?
- #33 Key Point: At risk individuals with uninformative test results still need to be screened.Facilitator script:Although NF1 is less likely in Alex, there is still a small chance he has the condition.The family history alone is indication for regular screening for emerging signs of disease.Screening should continue until past the average age of onset, according to guidelines.Additional information:Screening for NF1 involves annual dermatologic and ophthalmologic exams. MRI and other imaging or invasive procedures for internal neurofibromas are not indicated.About 50% of children with NF1 will meet diagnostic criteria based on clinical findings by age 1 year.A definitive diagnosis of NF1 can be made in most children by the age of 4 years using NIH criteria.
- #34 Key Point: Non-genetic screening methods are available for a number of genetic conditions when molecular testing is unavailable or uninformative.Facilitator script:…And the same principles of management for a clinical diagnosis without molecular confirmation applies to family members, too.When a causative genetic variant is identified, screening for the family is simplified with targeted mutation testing.Although negative results are less useful for the family, non-genetic screening may be available.For example, dermatologic and ophthalmologic screening for features of NF1 are available.Screening for other genetic conditions may include MRI or other radiology, echocardiogram or EKG, and metabolic lab tests.
- #35 Group discussionFacilitator script:How do we manage a patient like Alex when we find a VUS?
- #36 Key Point: Treat a VUS like an uninformative negativeFacilitator script:When a patient has a VUS, it should be treated like an uninformative negative, and management should be based on symptoms and family history.A VUS is an opportunity for collaboration with the laboratory.Although family genetic testing isn’t useful clinically, the lab may be interested in family studies to help clarify the significance of a variant or contribute to research.Many labs collect data on VUSs over time, so let the lab know if Alex eventually meets clinical criteria for the diagnosis.At a minimum, you should check back with the lab every few years to determine if the VUS has been reclassified.And again, family members should be screened like an uninformative negative result as we just discussed.
- #38 Group discussionFacilitator script:As promised, let’s talk briefly about the utility of testing, given what we now know about potential outcomes in various scenarios.In retrospect, would you have made the same decision about ordering testing in each scenario?Did testing sufficiently change management in each scenario to justify costs and risks?What other factors do you weigh in your decision?
- #39 Key Point: Psychosocial concerns may be sufficient to justify testing, but be wary of residual uncertainty.Facilitator script:Becausesevere complications of NF1 are atypical in childhood, and clinical exam is relatively sensitive, some providers feel the benefits of NF1 testing do not justify the costs.However, in Alex’s case, significant psychosocial benefit to the family may be sufficient to justify testing.In this case, residual uncertainty is the biggest risk of testing, which may be ameliorated by sufficient pre-test counseling.Additional information:The American Society of Human Genetics and the American College of Medical Genetics have published a joint policy statement on genetic testing of asymptomatic minors. Generally, it states that when medical benefits of testing will not accrue until adulthood, testing should be deferred.Other considerations include potential psychosocial benefit,harms, parental rights, autonomy of the child, expense of the test and the family’s ability to pay.Refer to handout: American Journal of Human Genetics 57: 1233-1241 (1995)
- #40 Transition to small group exerciseFacilitator ScriptNow, let’s practice interpreting a VUS result within the context of a specific patient.Break into groups of 3 – 5 and work together on the case for about 10 minutes.Read through the patient history, the disease summary, and testing specifications.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 INSTRUCTIONS-Small group work for about 10 min, or as your time allows.Make sure everyone has the handouts to complete the activity:Clinical scenario & discussion questionsOverview of CMA testingInterpretation of results tool 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.
- #41 Group debriefFacilitator script:In your small groups you discussed how you would apply clinical information to your interpretation of testing as it emerged over three phases: initial results, family testing, and family phenotypes. Let’s discuss your conclusions, focusing first on the implications for Lily. We’ll come back to the family implications in a moment.Discussion prompts:How did your interpretation of the VUS result evolve over time?How would your management of Lily change based on those interpretations?
- #42 Key Point: Family information points toward the variant being pathologic, but uncertainty remainsFacilitator script:Initially, we had conflicting evidence about the significance of the variant. Without more information, a VUS should be treated like an uninformative negative.When we thought Lily’s father was asymptomatic, family testing pointed toward the variant being benign.However, the revelation that Lily’s father has features on the autistic spectrum points toward a pathogenic variant of variable expression.Although some uncertainty about the diagnosis remains, in practice a VUS can be combined with family information for a “soft” or “working” diagnosis.Nevertheless, until a firm association can be made between autism and the variant, the clinician should remain vigilant for other features that may point toward a different diagnosis.
- #43 Group debriefFacilitator script:Now let’s focus on implications for the family. Recall that Lily’s parents want to have more children.Discussion prompts:How did your counseling messages and management priorities for the family change as your interpretation evolved?
- #45 Summary of key teaching pointsFacilitator script:To conclude, today we saw how the specific clinical scenario can change the interpretation and application of test resultsUncertain results are a possibility for many types of lab tests, but a genetic result may have broader implications for the patient and family.Caution must be taken when results are uninformative or uncertain, but tools can assist with counseling and management decisions.