Session Four: Results Interpretation & Application
-
Upload
nchpeg -
Category
Technology
-
view
176 -
download
4
Transcript of Session Four: Results Interpretation & Application
![Page 1: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/1.jpg)
Genomics for the
Child Neurologist:
Results Interpretation & Application
![Page 2: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/2.jpg)
Facilitator(s)
Name
• Expertise
• Credentials
• Titles
![Page 3: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/3.jpg)
Re-Cap: Genetic Testing Process
Identify benefits, limitations, risks
Provide informed consent
Order testing appropriately
![Page 4: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/4.jpg)
Workshop Four:
Genetic Result Interpretation & Application
![Page 5: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/5.jpg)
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
![Page 6: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/6.jpg)
12 month-old male
Family history of
optic glioma
Clinical Scenario: Alex
![Page 7: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/7.jpg)
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
![Page 8: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/8.jpg)
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
![Page 9: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/9.jpg)
Assessment: Alex’s Physical Exam
• Generalized freckling
• 3 café au lait < 5mm
• Height 25%tile
• Weight 25%tile
• Head Circ 75%tile
![Page 10: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/10.jpg)
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…
![Page 11: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/11.jpg)
Select the appropriate test:
NF1 testing should start with sequencing
![Page 12: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/12.jpg)
Interpret results in the
context of the clinical situation
![Page 13: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/13.jpg)
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?
![Page 14: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/14.jpg)
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
![Page 15: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/15.jpg)
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?
![Page 16: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/16.jpg)
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
![Page 17: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/17.jpg)
Predicted effect on
gene function?
Seen in previous
patients?
Other possible results:
Variant of Uncertain Significant (VUS)
![Page 18: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/18.jpg)
Negative PositiveVariant of Unknown
Significance
Significance
Unknown
Suspected
Benign
Suspected
Pathogenic
Range of VUS
![Page 19: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/19.jpg)
Communicate with families
about the results
![Page 20: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/20.jpg)
What is your experience with genetic
results disclosure?
![Page 21: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/21.jpg)
Genetic results may impact families
differently
Guilt & Shame
Privacy
Stigma & Discrimination
Relief from uncertainty
![Page 22: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/22.jpg)
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.
![Page 23: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/23.jpg)
Frame communication on family’s
needs and concerns
A malignant tumor is unlikely…
…but we’ll keep checking to be sure.
![Page 24: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/24.jpg)
Develop a management plan
based on genetic data
![Page 25: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/25.jpg)
Are management decisions
different for genetic conditions?
![Page 26: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/26.jpg)
Genetic results may have broader
implications
Multi-system Whole Family Cognitive Profiles
![Page 27: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/27.jpg)
What resources do you use for
management of genetic conditions?
![Page 28: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/28.jpg)
Tools are available for management
of a genetic diagnosis
![Page 29: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/29.jpg)
Testing of family members
Step-wise
multi-gene panels:
ATXN2 mutation found
$ 13,330
Targeted ATXN2
analysis:
$ 790
![Page 30: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/30.jpg)
Management: Clinical diagnosis
without molecular confirmation
Clinical diagnosis trumps
genetic testing…
![Page 31: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/31.jpg)
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.
![Page 32: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/32.jpg)
Individuals with uninformative results
still need screening
• Annual screening for
features until past the
average age of onset
![Page 33: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/33.jpg)
At-risk family members should have
screening
![Page 34: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/34.jpg)
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
![Page 35: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/35.jpg)
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
![Page 36: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/36.jpg)
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
![Page 37: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/37.jpg)
In retrospect, what do you think about
the utility of testing for Alex?
![Page 38: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/38.jpg)
Psychosocial concerns may justify testing,
but aware of remaining uncertainty
![Page 39: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/39.jpg)
Small Group Practice
![Page 40: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/40.jpg)
What is the bottom line for Lily?
![Page 41: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/41.jpg)
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
![Page 42: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/42.jpg)
What is the bottom line for Lily’s
family?
![Page 43: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/43.jpg)
Risk assessment is limited, but
non-genetic screening may be indicated
✔
![Page 44: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/44.jpg)
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
![Page 45: Session Four: Results Interpretation & Application](https://reader034.fdocuments.us/reader034/viewer/2022052623/559b558f1a28ab16298b4579/html5/thumbnails/45.jpg)
Homework/Practice
• Practice interpreting and communicating results
– Interpreting results case study (Soledad)
www.nchpeg.org/neuro