Genomics for the Child Neurologist Facilitator Guide Session Four Results Intepretation and Application

7/27/2019 Genomics for the Child Neurologist Facilitator Guide Session Four Results Intepretation and Application

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Genomics for the Child Neurologist

Facilitator GuideSession Four: Results Interpretation & Application

Published October 2013© NCHPEG

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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 PreparationYou should plan to spend about 3 – 6 hours preparing for this workshop. This includes:

1. Identifying the needs and expectations of your audience.

2. Reviewing and practicing with the curriculum.

3.

Customizing the slides and script for your audience as needed.

4. 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 Neurofibromatosis type 1 (NF1) and an abnormal microarray result. A handout will be

available for the participants with background information about NF1 and array CGH (comparative genomic

hybridization).

For more detailed information about NF1, see the following resources:

o GeneReviews: Neurofibromatosis 1

o Ferner et al. 2007. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med

Genet; 44: 81-88.

o Viskochil D. (2010). Neurofibromatosis type 1. In S. B. Cassidy, & J. E. Allanson (Eds.), Management of genetic

syndromes (3rd

edition, pp. 549-586). Hoboken, N.J.: John Wiley & Sons, Inc.

o Children’s Tumor Foundation

For more detailed information about chromosomal microarray in general, see the following resource:

o NCHPEG The ABCs of CMA

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

http://www.ncbi.nlm.nih.gov/books/NBK1109/


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2598063/



http://www.ctf.org/

http://www.ctf.org/

http://www.nchpeg.org/microarray/




http://www.ctf.org/





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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: Neurofibromatosis type 1 fact sheet (2 pages)

Results Interpretation & Application Toolkit (6 pages)

Testing of children handout (1 page)

Lily 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 final in a four-part series on genomics in the Child Neurologist’s practice.

The overall goal of this program is to improve the integration of genomics into the child neurologist’s 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 final session focuses on the interpretation and application of genetic testing results, which builds on the

concepts of risk assessment, evaluation and testing decisions, and the genetic testing process that we discussed

in the last sessions.

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.

o Others can handle all aspects of ordering, interpreting, and acting on results.

o 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.

o We have tried to address all of these different perspectives.



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o 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.

o And that balance may be different for each individual.

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

other’s 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 Lily, a case that we will be working through.

You have handouts on Neurofibromatosis, chromosome microarray, and testing of children, which we will be

referencing during the cases.

*And you have an evaluation survey. You can job down notes during the session, and I’ll give you a few minutes

to fill it out when we finish.]

Any questions? Let’s get started!

1.2 Recap from Session 3 and introduction to the results interpretation and application:

Key Points from Session 3:

1. Use data to identify and weigh benefits, risks, and limitations of genetic testing

2. Provide pre-test education and counseling to families

3. Anticipate potential results and how you will use them

4. Develop a protocol for ordering appropriate testing

Learning objectives for this session:

1. Interpret results within the context of the clinical situation

2. Communicate with families about the significance and impact of results

3. Develop a management plan that incorporates results, family history, and other data

1.3 Interpret results in the context of the clinical situation1. The first part of interpreting genetic testing results is to examine the results in the context of the patient’s

personal and family histories.

2. Large group activity: Alex



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Alex is healthy and has a family history of optic glioma in his recently deceased father.

His father’s history is suggestive, but not diagnostic, for NF1. Alex has some features that could be

associated with NF1 on physical exam (café au lait spots and freckling), but are not diagnostic.

NF1 is an autosomal dominant condition with variable expression and is characterized by skin, nerve, and

bone manifestations.

Explore with the group whether or not Alex meets clinical criteria (see handout; he does not) and if his lack

of meeting criteria rules out NF1 (it does not). Assume that the steps in evaluating the utility of a test and pre-test counseling (sessions 2 and 3) were

completed, and you have decided to offer molecular NF1 testing for Alex.

3. Genetic testing results may be positive for a mutation, negative, or identify a variant of uncertain significance.

4. Large group activity: Discuss how the interpretation of a negative result changes depending on the clinical

scenario.

Scenario 1: How do you interpret a negative result in Alex, when his father’s NF1 mutation status is

unknown?

o Debrief: In the absence of a known familial genetic variant, a negative gene test significantly reduces the

possibility of NF1, but is not completely informative.

Additional (optional) scenario: How would you interpret a negative result in Alex if he met clinical criteria

for NF1 based on his features?

o Debrief: Clinical diagnosis trumps negative testing results, so the diagnosis of NF1 stands and Alex

should be managed accordingly.

Scenario 2: How do you interpret a negative result in Alex, when his father is known to have a NF1

mutation?

o Debrief: A “true” negative result for a known familial variant rules out disease.

5. Another potential outcome of genetic testing is a variant of uncertain significance (VUS).

A VUS is a change from the reference sequence that has not previously been associated with disease.

There is a range of “uncertainty” in VUS based on the specific type of mutation and its predicted effect on

gene function.

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.

1.4 Communicate with families about results1. Large group activity: Discuss the participants’ experience with disclosing genetic testing results to families.

2. Debrief and make sure to emphasize these points:

Personal, family, social and cultural beliefs about the meaning of “genetic” influence family responses.

The inheritance pattern of a genetic condition influences reproductive risks and anxiety, as well as privacy

issues within the family.

3. Large group activity: Using Alex’s case (original presentation in Scenario 1), discuss the strategies participants

use to discuss uncertainty with families.


Focus and frame the communication about the test results and uncertainty to the family’s needs and

concerns.



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One strategy to help families cope with uncertainty is to emphasize what is known.

Another strategy for managing uncertainty is to re-frame the situation as an opportunity.

Finally, communicating a clear plan may provide an increased sense of control and alleviate some anxiety.

5. Refer participants to the communication tool for additional information.

1.5 Develop a management plan based on genetic data1. Large group activity: Discuss how management of genetic conditions is similar or different to that of other

neurologic disorders.


A genetic diagnosis may impact referrals, family counseling, and even psych and educational interventions.

Genetic syndromes may require additional referrals, such as a condition that has cardiac, skeletal, and

neurologic manifestations.

In addition, inherited conditions may impact the family differently from non-genetic conditions.

Reproductive risk counseling and screening for at-risk family members may be indicated.

Finally, an increasing number of genetic conditions have been associated with distinct cognitive and

behavioral profiles that influence educational interventions.

3. Large group activity: Discuss what resources participants currently use help manage genetic conditions.


A number of tools have been developed to guide management of genetic conditions.

Participants have been provided with a handout listing the web addresses for these resources.

5. Management of genetic conditions involves discussion of risks and options for at-risk family members and

reproductive testing.

6. In an individual who meets clinical diagnostic criteria, but testing fails to identify a genetic variant, this person

should still be managed per their clinical diagnosis.

7. Large group activity: Discuss management for Alex and his relatives in different scenarios.

Using Alex’s original presentation (Scenario 1), how would you manage Alex given a negative result?o Debrief: At risk individuals with uninformative test results still need to be screened.

o Although NF1 is less likely in Alex, there is still a small chance he has the condition.

o The family history alone is indication for regular screening for emerging signs of disease.

With a syndrome but no know mutation in a family, at-risk relatives cannot use molecular testing to

determine individual risk. But they should also receive screening for disease manifestations.

If Alex was found to have a VUS on genetic testing, how would you manage Alex?

o Debrief: Treat a VUS like an uninformative negative; manage based on symptoms and family history.

o Family members should be screened like an uninformative negative result as well.

8. Summarize the clinical implications of positive, negative, and VUS results.

1.6 Reflect on clinical utility of testing1. Large group activity: Discuss the participants’ views of the utility of using molecular NF1 testing in Alex’s case.


Psychosocial concerns may be sufficient to justify testing, but be wary of residual uncertainty.



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Because severe 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.

In this case, residual uncertainty is the biggest risk of testing, which may be ameliorated by sufficient pre-

test counseling.

When testing asymptomatic children, it is important to consider the balance of risks and benefits. See the

handout on testing of children.

1.7 Small group practice and debrief • Break into groups of 3 – 5 and work together on the case for about 10 minutes.

• Have groups read through Lily’s history and then work through the discussion questions within the group.

• Have them refer to the toolkit to help interpret results and determine management recommendations.

• 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.

1. Debrief as a large group: Discuss the final interpretation of the result for Lily. Make sure to emphasize these

points:

Family information points toward the variant being pathologic, but uncertainty remains.

(Part 1 in handout) Initially, we had conflicting evidence about the significance of the variant. Without more

information, a VUS should be treated like an uninformative negative.

(Part 2) When we thought Lily’s father was asymptomatic, family testing pointed toward the variant being

benign.

(Part 3) 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.

2. Debrief as a large group: Discuss implications for Lily’s family. Make sure to emphasize these points:

Genetic testing for at-risk family is not recommended for a VUS, but other forms of screening may be

appropriate.

We can advise the family that there is a 50% chance for each child to inherit this variant. However, given the remaining uncertainty about the significance of the variant, family and reproductive

testing is not recommended.

Even if the deletion is pathogenic, it apparently has variable expression, making it difficult to predict

whether it will result in autism in other family members.



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Although genetic testing for at-risk family is not recommended, relatives may benefit from other types of

screening for subtle signs of autism to determine if they would benefit from intervention services.

1.8 Summary and reflections• 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

• Assign Homework

1. Additional practice exercise: visit www.nchpeg.org/neuro and click on Case Studies Menu, and select the

Soledad case study

1.9 Evaluation and follow-up

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

http://www.nchpeg.org/neuro




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Genomics for the Child Neurologist Facilitator Guide Session Four Results Intepretation and Application