Genomics for the Child Neurologist Facilitator Guide

Session Three: Genetic Testing Process

Background for Facilitator

This guide will help you implement the curriculum for your audience. It includes tips for preparation, setting up your workshop, and facilitating the session and working with your audience.

Pre-Workshop Preparation
You should plan to spend about 3 6 hours preparing for this workshop. This includes: 1. 2. 3. 4. Identifying the needs and expectations of your audience. Reviewing and practicing with the curriculum. Customizing the slides and script for your audience as needed. Printing hardcopy materials.

It is critical that you review and practice with the material prior to implementation with your audience. The impact of the learning is heavily influenced by the skill and preparation of the facilitator. This session includes cases with Dravet syndrome and an abnormal microarray result. A handout will be available for the participants with background information about Dravet syndrome and array CGH (comparative genomic hybridization). For more detailed information about Dravet syndrome, see the following resources: o o GeneReviews: SCN1A-Related Seizure Disorders NINDS Dravet Syndrome Info Page

The abnormal microarray case includes identification of consanguinity in the family (which is when blood relatives have a child together). For more information about consanguinity, see the following resources: Centre for Genetics Education When Parents are Relatives Consanguinity Genetic Counseling and Screening of Consanguineous Couples and Their Offspring: Recommendations of the National Society of Genetic Counselors

For more detailed information about chromosomal microarray in general, see the following resource: o NCHPEG The ABCs of CMA

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Facilities Preparation
Setting up 1. Make sure the room set-up is conducive to group learning. Recommended equipment includes: Appropriate space for your audience size Ideally, participants will be seated at tables and have the opportunity to move chairs around for small group work Computer hooked up to an overhead projector White board or paper easel with markers, or iPad hooked to projector Hard copy materials Pens 2. Set up the following handouts by the door so that participants can pick them up on the way in: Dravet syndrome (1 page) Genetic Testing Process Toolkit (7 pages) Suzie handout (2 pages) Array CGH handout (1 page) [evaluation survey] 3. Load the slides onto the computer that is connected to the projector.

1.1 Opening, introductions, housekeeping

[Welcome the attendees and introduce the facilitator] This workshop is the third of a four-part series on genomics in the Child Neurologists practice. The overall goal of this program is to improve the integration of genomics into the child neurologists practice by focusing on competencies in: o Collecting and analyzing family health history, o Synthesizing family and patient history for risk assessment, evaluation and management, o Determining the risks, benefits, and limitations of appropriate genetic testing, o Providing pre-test education and counseling, o Interpreting results of positive, negative, and variant, and o Communicating with families about genetic information. This second session focuses on the genetic testing process, which builds on the concepts of risk assessment and evaluation and testing decisions that we discussed in the last sessions. The subsequent workshops will build on this one by exploring: o Interpreting genetic test results, o Managing unanticipated findings from testing, and o Communicating with patients about test results. As you know, neurologists practice in many different settings and have many different areas of clinical specialty. Because of this, we cover the range of clinical activities that a clinician might take in a given area of genetic practice. o For example, some neurologists feel very comfortable ordering genetic/genomic tests, but not as comfortable interpreting results.

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3 o o Others can handle all aspects of ordering, interpreting, and acting on results. Others have expertise in a specific area, like NF, and can manage all of the genetic issues with that syndrome, but may not be as comfortable with genetic testing and management in other clinical domains. We have tried to address all of these different perspectives. The goal of each session is to help the learner self-reflect on where he or she is already doing well, and where he or she could benefit from additional practice, and then give that learner an opportunity to practice and to improve. And that balance may be different for each individual.

o o

This workshop is not like your typical lecture. This is an interactive experience where you actively participate and practice working through genomics cases. You will work through cases together both as a large group and in small groups. Because the learning process is active it hinges on your participation. I encourage you to feel comfortable participating and speaking out during the session. We can learn from each others experience and discussion.

Housekeeping You all picked up some materials on your way in. You have a stapled toolkit that you can reference during the workshop today and take with you to use in clinic, if helpful. You have a handout on Suzie, a case that we will be working through. You have a handout on Dravet syndrome and one on chromosome microarray, which we will be referencing during the cases. *And you have an evaluation survey. You can job down notes during the session, and Ill give you a few minutes to fill it out when we finish.]

Any questions? Lets get started!

1.2 Recap from Session 2 and introduction to the genetic testing process
Key Points from Session 2: 1. Use evaluations and labs, distinct features, and family patterns to rule out non-genetic causes and prioritize the differential 2. Use patient and scientific data to select the appropriate single-gene test, panel, or step-wise protocol 3. Develop a family testing strategy to maximize cost-effectiveness Learning objectives for this session: 1. Use data to identify limitations of genetic testing 2. Weigh the benefits and risks of testing in the patients individual scenario 3. Provide pre-test education and counseling 4. Develop a protocol for ordering appropriate testing

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1.3 Identify benefits, limitations, and risks

1. The first part of the pre-testing process is to identify the benefits, limitations, and risks of genetic testing 2. Large group activity: James a. James has a clinical presentation suspicious for Dravet syndrome. b. His family history provides non-specific evidence pointing toward a genetic component to this disease. c. Assume that you have already used the tools and skills discussed in workshop 2 to formulate and prioritize your differential diagnosis, which points toward Dravet syndrome as the most likely diagnosis. d. Dravet syndrome is a severe form of early onset epilepsy; the majority of cases being associated with SCN1A gene mutations. e. Point out the handout on Dravet syndrome, which will help the participants complete the activity. Make sure to give participants time to review the handout during each Q & A. 3. Large group activity: Use James case to work through the steps in assessing benefits, limitations, and risks prior to ordering genetic testing. a. Step 1: Assess the ability of the testing to detect variants (What is the sensitivity of the test?) b. Step 2: Assess the ability of a variant to predict outcomes (What is the utility of the test for James and family members?) c. Step 3: Anticipate the implications of a negative and variant result d. Step 4: Identify risks of genetic testing, in general and for James. i. Introduce the Genetic Information Nondiscrimination Act (GINA) emphasizing that there are some legal protections against genetic discrimination for health insurance. ii. Explore communication approaches for discussing the balance of risks, benefits, and limitations for James. 4. Debrief after each step Q & A and make sure to emphasize these points: a. Step 1: Genetic testing will identify a cause in the majority of individuals with Dravet. However, not all individuals with SMEI have a detectable mutation. i. This could be because current technology does not detect all possible SCN1A variants, or because SCN1A is not the only gene associated with SMEI. b. Step 2: SCNA1 testing has limited predictive value for affected individuals and their family members. c. Step 3: It is important to consider the utility of a positive result, but also about how we would handle uninformative and uncertain results. i. If an individual has a negative test result but has a clinical presentation of SME1, the negative result does not change management. Possible explanations for a negative result include: 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. ii. A VUS is uninformative and shouldnt be used clinically. d. Step 4: Clinical and psychological utility of genetic testing must be weighed against the financial, emotional, family and social risks. The clinician and family must decide together whether the benefits justify the limitations and risks.

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1.4 Provide informed consent

1. Large group activity: Discuss the participants approach to pre-test counseling in their current practice. 2. Debrief and make sure to emphasize these points: a. The process of informed consent paves the way for a smoother results disclosure process. 3. Small group practice: Break into groups of 3 5 and work together on the case for about 10 minutes. Have groups read through Suzies history and then work through the discussion questions within the group. Have them refer to the toolkit, aCHG handout, and information provided in the Suzie handout to help formulate informed consent and communication messages. Have each 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. -Hints Walk around the room to hear what the groups are saying and assess their understanding so you can tailor your answers to target areas of misunderstanding. Assemble the large group and have the designated person in each group report each of their answers to the large group. 4. Large group debrief: Discuss the small group responses to the steps in informed consent. Make sure to emphasize these points: a. Step 1: Communicate goals. i. The first step in pre-test counseling is to communicate the reasons for testing. ii. Initial counseling can be simple, expanding detail with feedback from the family. b. Step 2: Assess family goals and understanding of testing i. It is important to assess understanding and family expectations so we can refine our counseling. ii. Most families want to understand the cause, and hope for treatments, prognosis, or preventive measures. c. Step 3: Set realistic expectations i. Using the information you gathered from listening to the family, you can adjust and add detail to your counseling. ii. Add detail to reinforce limitations and risks based on the familys prior understanding. 5. Large group activity: Present the results of Suzies SNP array and ask participants to reflect on their pre-test counseling. a. Make sure to pause and give the participants a chance to review the result before beginning discussion b. Results show unanticipated regions of homozygosity, suggesting a consanguineous relationship between her parents 6. Debrief and make sure to emphasize these points: a. Be sure to prepare the family for unexpected information, especially when clinical or family information is lacking. b. Genome wide tests like microarray and whole genome sequencing have an increased risk of identifying unexpected information. i. This can include incidental diagnoses or genetic risk unrelated to the indication for testing. ii. It can also include information about family relationships, including non-paternity and consanguinity.
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6 c. Missing family information is a red flag for counseling about the possibility of unexpected genetic testing results. 7. Support is available to improve your informed consent and pre-test counseling: Consider referral or consult when you are faced with a complicated consent process or complicated family situation.

1.5 Order testing appropriately

1. [This section should be customized in advance to cover the key genetic testing logistics at your own institution (or the participants institution).] 2. Large group activity: Discuss the participants experience with ordering genetic tests. 3. 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. 4. Discuss the four general considerations in genetic testing logistics: a. Finding a lab. i. Discuss institutional and external resources for finding a lab b. Cost and insurance i. Cost and coverage can be unpredictable, but there are ways to facilitate the process. ii. It is critical to determine whether prior authorization is required. iii. 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. c. Preparing the sample and forms i. Sample collection procedures and paperwork requirements may be specific and unusual. d. Reporting practices i. Use a labs website or requisition and supporting materials to determine turn-around time and practices for reporting results. ii. Turnaround time for genetic testing may be longer than your patients are used to.

1.6 Summary, reflections and setting the stage for session 4

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

Preview next session: we will build on what we learned today in the next session on genetic testing interpretation and management. Assign Homework to be completed by the next session. Consider a short review of participants experiences using the informed consent tools and review of the web exercise at the beginning of session 4.

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7 Homework 1. Additional practice exercise: visit www.nchpeg.org/neuro and click on Case Studies Menu, and select the Ataxia telangiectasia case study 2. Use the informed consent checklist and talking points with at least one patient before the next workshop.

1.7 Evaluation and follow-up

If you have distributed an evaluation survey, collect the surveys and analyze the data.

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