Genomics for the Child Neurologist:

Genetic Testing Process

Facilitator(s)

Name• Expertise• Credentials

• Titles

Re-Cap: Evaluation & Testing Decisions

Narrow the differential

Select appropriate tests

Develop a family testing strategy

Workshop Three:Genetic Testing Process

Identify benefits, limitations, risks

Provide informed consent

Order testing appropriately

Take time to prepare for outcomes of testing

Evaluation & Testing DecisionsLearning Objectives

1. Use data to identify limitations of genetic testing

2. Weigh the benefits and risks of testing in the patient’s individual scenario

3. Provide pre-test education and counseling

4. Develop a protocol for ordering appropriate testing

2 yo male

History of febrile and afebrile seizures

Clinical Scenario: James

James2 y

Seizures

Key

Seizures

SeizuresD. 10

accident

James Family History

Evaluations and unique features point toward Dravet syndrome

Differential Diagnosis includes:

•Severe myoclonic epilepsy of infancy (SMEI, or Dravet syndrome)•Pyridoxine, B6 and Folic acid related seizures•Biotinidase deficiency

•Autosomal dominant nocturnal frontal lobe epilepsy

•Simple febrile seizures

Overview Dravet Syndrome

Features:•Severe myoclonic epilepsy of infancy•Cognitive decline over time

Genetics: •30-80% cases associated with a variant in SCN1A gene

Inheritance: •Typically de novo (depends on phenotype)•When inherited, autosomal dominant with significant intra-familial variable expression

Management: •Difficult to control•Anticonvulsant drugs and ketogenic diet may reduce seizure frequency

Identify benefits, limitations, risks

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

SCN1A

Other, unknown

genes

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 significance?

Negative genetic test doesn’t rule out disease in a symptomatic individual

SCN1A

Other, unknown

genes

SCN1APortion of variants

missed by test•Technology limitations•Test selected

No variants detected

Not tested

Step 3: Anticipate other results

How would you use a negative result?

What would you do with a variant of uncertain significance?

A VUS is uninformative and shouldn’t be used clinically

Not seen in any previous patient

OR

Contradictory reports in other individuals

AND/OR

Unknown effect on gene function

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

• Discrimination

• Family impact and privacy• Psychosocial coping and adaptation

Genetics Information Non-discrimination Act

(GINA) affords some protections

How would you discuss the risks, benefits, and limitations of testing?

Balance benefits, limitations, and risks in the context of the patient and family

Benefits• End diagnostic odyssey• Clarify reproductive risk• Refine differential

Limitations• Variable expression limits predictions• Uninformative negative• Uninformative VUS

Risks • 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 outcomes

Step 3: Anticipate other results

Step 4: Identify benefits and risks

Provide Informed Consent

What do you do for pre-test counseling currently?

Informed consent paves the way for results disclosure

Small Group Practice

7 yo female

Developmental delayHypotoniaDysmorphic features

Clinical Scenario: Suzie

What are your initial counseling messages?

Step 1: Communicate goals of microarray testing

Keep initial messages simple

A genetic test

because… We’ll use it to…

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 guidance

Did I cause it?

What will the future hold?

Step 3: Set realistic expectations

What additional information does the family need to be prepared for the various possible outcomes?

Reinforce limitations and risks; and discuss the process

Uncertainty is possible…

You’ll get results in…

Unexpected results are possible….

We might need more

tests.

Genes are…

Did you adequately prepare the family for this outcome?

Patient Name: Suzie HubbardTest Performed: SNP Array AnalysisIndication: Developmental Delay

Result:Normal Dosage; Long contiguous regions of homozygosity, see interpretation.

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 Communication

• Step 1: Outline goals

• Step 2: Assess family motivations and aims

• Step 3: Set expectations

Consider referral or consult for pre-test counseling

When to consult/refer:

•Lack of time •Low-literacy•Emotional responses•Family undecided

•Data is weak with unclear benefits

Order Testing Appropriately

What is your experience with ordering genetic tests?

Genetic Testing Logistics

Finding a lab

Cost and insurance

Prepare the sample and forms

Reporting practices

Finding a Lab

Referral Lab

http://www.ncbi.nlm.nih.gov/gtr

Genetics Specialist

Some labs verify

insurance

Genetic testing is medically necessaryDr. Susan Smith

Insurance and Cost

Preparing the sample and forms

Genetic Testing Requisition

Clinical History_____________

Family History_____________

Reporting Practices Vary

Genetic testing can get complicated

Summary: 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

Next steps

• Refer or consult with genetics

• Interpret results in the clinical context• Communicate with families about the

results• Develop a management plan based on

the genetic data

To be discussed in workshop 4

Homework/Practice

•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.

www.nchpeg.org/neuro

Thank you!

[facilitator contact information]