session one: risk assessment
TRANSCRIPT
Genomics for the Child Neurologist:
Genetic Risk Assessment
Facilitator(s)
Name• Expertise• Credentials
• Titles
Neurologic conditions are complex diseases
Spectrum of Genetic Contribution
GENEGENE
Frequency
Penetrance
GENEGENE
GENEGENE
Neurological conditions encompass all inheritance patterns
Autosomal Dominant
X-Linked
Workshop One:Genetics & Risk Assessment
Risk Assessment Learning Objectives
1. Take a family history with sufficient detail
2. Recognize genetic “red flags”
3. Analyze a detailed family history
4. Develop an appropriate evaluation plan based on personal and family history assessment
5. Communicate with families about genetic information
GENOMICrisk assessment
expands on the family history
Ask the right questions
Identify red flags
Identify patterns
Ask the right questions
3 yo maleDevelopmental delayFamHx: negative for ID/DD
Clinical Scenario: Joseph
HistoryBirth History: •normal
Developmental History: •hearing normal •gross motor milestones on time •cannot dress himself•speech delay •behavioral problems, such as hyperactivity and temper tantrums
Social History: •Joseph lives with his parents and his older sister•both English and Spanish are spoken in the home
Past Medical History: •unremarkable
What questions would you ask about Joseph’s family history?
Please check next to any condition that affects your child, parent, sibling, aunt/uncle or grandparent. For each checked box, explain below who is affected. Mental retardation Learning disabilities X Developmental delay Joseph has speech delay Early-onset deafness Early-onset blindness Birth defects
Neuromuscular Issues Seizures X Abnormal movements Mom’s uncle has a tremor, ataxia, and maybe
dementia Blood clotting or bleeding
disorder
Infant death Pregnancy losses Unexplained death Migraine
X Cancer Paternal grandmother had breast cancer
Family History Collection Demonstration
• Family structure
• Presence and extent of disease• Ages of onset and death• Chronic illness• Infertility, miscarriage
• Intellectual disability
• Birth defects
Questions for a targeted famhx include:
Medical and development information about your relatives can give us clues about what is going on with Joseph. Even a normal family history can help guide us.
“
”
When collecting family history, it is important to set expectations
Record family history so that it can be accessed, updated, and interpreted
Joseph3 y
ID, behavioral issues
2
D. 34 yBreast ca
High cholesterol
33 yMenopause dx 31
~60’sTremor, ?
dementia, ataxia
El SalvadorianIrish/German
FamHx: negative for ID/DD
Identify red flags
Red flags that alert you to genetic risk
• Multiple individuals with related conditions• Intellectual disability• Early age at onset• Less often affected sex• Absence of known risk factors• Severe manifestations• Ethnic predisposition• Consanguinity
What red flags do you see in Joseph’s family history?
Joseph3 y
ID, behavioral issues
2 Key
Intellectual disability
D. 34 yBreast ca
High cholesterol
33 yMenopause dx 31
~60’sTremor, ?
dementia, ataxia
El Salvadorian Irish/German
Movement disorder
Infertility
Joseph3 y
ID, behavioral issues
2 Key
Intellectual disability
D. 34 yBreast ca
High cholesterol
33 yMenopause dx 31
~60’sTremor, ?
dementia, ataxia
El Salvadorian Irish/German
Movement disorder
Infertility
Joseph’s red flags
Based on clinical guidelines for intellectual disability testing consider the
following diagnoses
a) Idiopathic intellectual disability
b) Chromosome abnormality
c) Micro-duplication/deletion syndrome
d) Fragile X syndrome
How would you focus testing based on family history and clinical guidelines?
• Intellectual disability• Early age at onset• Absence of known
risk factors
Joseph3 y
ID, behavioral issues
2 Key
Intellectual disability
D. 34 yBreast ca
High cholesterol
33 yMenopause dx 31
~60’sTremor, ?
dementia, ataxia
El SalvadorianIrish/German
Movement disorder
Infertility
Identify patterns to guide testing
Joseph3 y
ID, behavioral issues
2 Key
Intellectual disability
D. 34 yBreast ca
High cholesterol
33 yMenopause dx 31
~60’sTremor, ?
dementia, ataxia
El Salvadorian Irish/German
Movement disorder
Infertility
Autosomal Recessive
Complex Disease
X-Linked
Autosomal Dominant
Carrier
Idiopathic Intellectual Disability
Chromosome Abnormality
Intellectual disability
Intellectual disability
ID; Congenital heart defect;
Short
Micro-Duplication/Deletion Syndrome
Intellectual disability
Intellectual disability
Learning disability
Fragile X Syndrome
Intellectual disability
Intellectual disability
Infertility
Tremor, ataxia
Based on the red flags and patterns what is the most likely diagnosis?
Joseph3 y
ID, behavioral issues
2 Key
Intellectual disability
D. 34 yBreast ca
High cholesterol
33 yMenopause dx 31
~60’sTremor, ?
dementia, ataxia
El Salvadorian Irish/German
Movement disorder
Infertility
Fragile X
Joseph3 y
ID, behavioral issues
2 Key
Intellectual disability
D. 34 yBreast ca
High cholesterol
33 yMenopause dx 31
~60’sTremor, ?
dementia, ataxia
El Salvadorian Irish/German
Movement disorder
Infertility
What about other red flags?
Joseph3 y
ID, behavioral issues
2 Key
Intellectual disability
D. 34 yBreast ca
High cholesterol
33 yMenopause dx 31
~60’sTremor, ?
dementia, ataxia
El Salvadorian Irish/German
Movement disorder
Infertility
What does this mean?What does this mean?
What do we do next?
Why is this important?
Communicate your findings
What do we communicate about the risk assessment?
Communication about risk assessment
• Explain your findings
• Tie together the red flags and patterns • What is Fragile X syndrome• Why evaluating for this diagnosis is important
– Joseph– Family members
• Next steps in evaluation
Next steps
• Order Fragile X genetic testing
• Refer or consult with genetics
Small Group Practice
Soledad’s family history
3 3
Argentina Argentina
d. 60 yETOH
Liver Cancer
d. 75 yPneumonia
A/W
A/W Luis33 yA/W
Maria32 yA/W
A/W
Daniela7 y
A/W
Carlos5y
Severe HeadacheRegression
Soledad2y
Possible SZ
Pablo2moA/W
A/WA/W
HeterochromiaWhite forelock
Key
A/W Alive & Well
What red flags do you see in Soledad’s family history?
3 3
Argentina Argentina
d. 60 yETOH
Liver Cancer
d. 75 yPneumonia
A/W
A/W Luis33 yA/W
Maria32 yA/W
A/W
Daniela7 y
A/W
Carlos5y
Severe HeadacheRegression
Soledad2y
Possible SZ
Pablo2moA/W
A/WA/W
HeterochromiaWhite forelock
Key
A/W Alive & Well
Red Flags
3 3
Argentina Argentina
d. 60 yETOH
Liver Cancer
d. 75 yPneumonia
A/W
A/W Luis33 yA/W
Maria32 yA/W
A/W
Daniela7 y
A/W
Carlos5y
Severe HeadacheRegression
Soledad2y
Possible SZ
Pablo2moA/W
A/WA/W
HeterochromiaWhite forelock
Key
A/W Alive & Well
What inheritance pattern do you see in Soledad’s family history?
3 3
Argentina Argentina
d. 60 yETOH
Liver Cancer
d. 75 yPneumonia
A/W
A/W Luis33 yA/W
Maria32 yA/W
A/W
Daniela7 y
A/W
Carlos5y
Severe HeadacheRegression
Soledad2y
Possible SZ
Pablo2moA/W
A/WA/W
HeterochromiaWhite forelock
Key
A/W Alive & Well
Autosomal recessive
Luis33 yA/W
Maria32 yA/W
Daniela7 y
A/W
Carlos5y 1moSevere
HeadacheRegression
Soledad2y 3mo
Possible SZ
Also, autosomal dominant
d. 75 yPneumonia
HeterochromiaWhite forelock
How would you communicate about family history collection and interpretation?
What does this mean?What does this mean?
What do we do next?
Why is this important?
Communicate
• Why you are collecting the information and how it can be used
• That collecting family history information is an ongoing process
• Informative questions
• What your finding mean for the patient
• Risks to family members
Communicate in a patient centered way
• Ask about family’s perceptions of condition and risk
• Be sensitive to family reactions and emotions
• Put risk into perspective
Next steps
• Create differential diagnosis • Communicate interpretation and suspected
diagnosis • Genetic testing• Refer or consult with genetics
Risk assessment for complex diseases
Key Points in Genomic Risk Assessment
1. Collect history that indicates family structure and manifestations of disease
2. Assess patterns and red flags
3. Use risk to adapt plan for genetic testing, management, counseling etc.
4. Communicate with families about risk in a patient centered way
Homework/Practice
• Practice identifying red flags & inheritance patterns (Cardiomyopathy Case)
• High comfort level: Practice recurrence risk counseling (Spinal Muscular Atrophy & Duchenne Muscular Dystrophy)
Find the homework at http://www.nchpeg.org/neuro/
Thank you!
[facilitator contact information]