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Genomics for the
Child Neurologist:
Results Interpretation & Application
Facilitator(s)
Name
• Expertise
• Credentials
• Titles
Re-Cap: Genetic Testing Process
Identify benefits, limitations, risks
Provide informed consent
Order testing appropriately
Workshop Four:
Genetic Result Interpretation & Application
Interpret results in the context of
the clinical situation
Communicate with families
about genetic test results
Develop a management plan
based on genetic data
Interpretation & Application
Learning Objectives
12 month-old male
Family history of
optic glioma
Clinical Scenario: Alex
Alex’s Family History
75 y
45 y
58 y
Alex
12 mo
d. 50, accident
optic glioma
skin lesions
36 y
d. 70
Heart attack
58 y
29 y
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
Assessment: Alex’s Physical Exam
• Generalized freckling
• 3 café au lait < 5mm
• Height 25%tile
• Weight 25%tile
• Head Circ 75%tile
Deciding to Test:
Given the level of family concern, you decide to
test Alex for NF1.
There are some limitations, but
testing might clarify things…
Select the appropriate test:
NF1 testing should start with sequencing
Interpret results in the
context of the clinical situation
Scenario 1:
NF1 Suspected but Unconfirmed in Alex’s Father.
Alex
18 mo
d. 50, accident
Optic glioma
Skin lesions
No testing
36 y
3 small café au lait
No NF1 variants identified
How do you interpret
a negative result in Alex?
Scenario 1:
NF1 Suspected but Unconfirmed in Alex’s Father.
Alex
18 mo
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.
A negative result reduces likelihood,
but is not completely informative
Scenario 2:
A pathologic variant in NF1
was identified in Alex’s father.
Alex
18 mo
d. 50, accident
Optic glioma
Skin lesions
Pathologic NF1 variant found
36 y
3 small café au lait
No NF1 variants identified
How do you interpret
a negative result in Alex now?
A “true negative” rules out disease
Scenario 2:
A pathologic variant in NF1
was identified in Alex’s father.
Alex
18 mo
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
Predicted effect on
gene function?
Seen in previous
patients?
Other possible results:
Variant of Uncertain Significant (VUS)
Negative PositiveVariant of Unknown
Significance
Significance
Unknown
Suspected
Benign
Suspected
Pathogenic
Range of VUS
Communicate with families
about the results
What is your experience with genetic
results disclosure?
Genetic results may impact families
differently
Guilt & Shame
Privacy
Stigma & Discrimination
Relief from uncertainty
What strategies do you use to discuss
uncertainty?
Alex
18 mo
d. 50, accident
Optic glioma
Skin lesions
No testing
36 y
3 small café au lait
No NF1 variants found
NF1 less likely, but not
ruled out.
Frame communication on family’s
needs and concerns
A malignant tumor is unlikely…
…but we’ll keep checking to be sure.
Develop a management plan
based on genetic data
Are management decisions
different for genetic conditions?
Genetic results may have broader
implications
Multi-system Whole Family Cognitive Profiles
What resources do you use for
management of genetic conditions?
Tools are available for management
of a genetic diagnosis
Testing of family members
Step-wise
multi-gene panels:
ATXN2 mutation found
$ 13,330
Targeted ATXN2
analysis:
$ 790
Management: Clinical diagnosis
without molecular confirmation
Clinical diagnosis trumps
genetic testing…
How would you manage Alex given the
negative result in this scenario?
Alex
18 mo
d. 50, accident
Optic glioma
Skin lesions
No testing
36 y
3 small café au lait
No NF1 variants found
NF1 less likely, but not
ruled out.
Individuals with uninformative results
still need screening
• Annual screening for
features until past the
average age of onset
At-risk family members should have
screening
How would you manage a VUS
result?
Alex
18 mo
d. 50, accident
Optic glioma
Skin lesions
No testing
36 y
3 small café au lait
VUS in NF1 found
Treat a VUS like an uninformative
negative
• Annual screening for
features until past the
average age of onset
• Classification of VUS may
change over time
Summary of testing outcomes
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
In retrospect, what do you think about
the utility of testing for Alex?
Psychosocial concerns may justify testing,
but aware of remaining uncertainty
Small Group Practice
What is the bottom line for Lily?
The variant is a probable cause of
ASD in Lily, but uncertainty remains
Lily
6 y
Speech Delay
Autistic Behaviors
15q11.2 del
A/WAsperger
Syndrome
15q11.2 del
What is the bottom line for Lily’s
family?
Risk assessment is limited, but
non-genetic screening may be indicated
✔
Summary: Interpretation and Application
• 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
Homework/Practice
• Practice interpreting and communicating results
– Interpreting results case study (Soledad)
www.nchpeg.org/neuro
