Transcript 1) What are secondary findings?

Consenting for the Unexpected:
Empowering patient and
provider
Nasim Monfared, CGC
Centre for Genetic Medicine
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• What health care providers (HCPs) need to know about
secondary/predictive findings
• Informed consent
5) Potential
benefits and
drawbacks
1) What are
secondary
findings
• Practical tips for informed consent about
secondary/predictive findings
2) Which
secondary
findings will
be reported
4) Management
and treatment
options
• Resources and checklist for your practice
3) How likely
is it that a
secondary
finding is
identified
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Initial consultation
and phenotyping
“primary/diagnostic
variants”
Exome/Genome
analysis
“Secondary variants”
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Why do health care providers need to know
about consenting
• Single gene testing and microarray first
introduced in genetics clinics, now widely utilized
by many HCPs
• Exome sequencing used by cardiologists,
neurologists, ophthalmologists, neonatologists
and many other specialists
• More economical
• Expansion of databases lead to better interpretation
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1) What are secondary findings?
• Disease causing variants in known
genes
• Medically actionable
Genes without known health
effects
Drug kinetics
genes
Other genes known
to affect health
• AAP: Do not test children for adult onset
disease
• As of 2013:
• ACMG: 56 genes for 24 inherited
conditions with opt out option
• ESHG: Bioinformatic exclusion of
secondaries, return of childhood onset
disease risks
• CCMG: No obligation to search but can
do so based on patient choice
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Courtesy of Stephen Meyn
2) Which secondary variants to return?
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“ACMG 56” (56 genes; 24 conditions)
•Hereditary breast and ovarian cancer
•Li–Fraumeni syndrome
•Peutz–Jeghers syndrome
•Lynch syndrome
•Familial adenomatous polyposis
•MYH-associated polyposis
•Von Hippel–Lindau syndrome
•Multiple endocrine neoplasia type 1
•Multiple endocrine neoplasia type 2
•Familial medullary thyroid cancer
•PTEN hamartoma tumor syndrome
•Retinoblastoma
•Hereditary paraganglioma–
pheochromocytoma syndrome
•Tuberous sclerosis complex
•WT1-related Wilms tumor
•Neurofibromatosis type 2
•Ehlers–Danlos syndrome, vascular type
•Marfan syndrome, Loeys–Dietz syndromes, and
familial thoracic aortic aneurysms and dissections
•Hypertrophic cardiomyopathy, dilated
cardiomyopathy
•Catecholaminergic polymorphic ventricular
tachycardia
•Arrhythmogenic right-ventricular cardiomyopathy
•Romano–Ward long QT syndrome types 1, 2, and 3,
Brugada syndrome
•Familial hypercholesterolemia
•Malignant hyperthermia susceptibility
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Laboratory
Family choice
Secondary/predictive
finding
Actionable
Nonactionable
Pharmacogenetic
findings
Carrier
status
Baylor
Opt in
+
+
+
+
GeneDx
Opt out
ACMG
-
-
-
Emory
Opt in
+
+
+
+
SickKids
Opt in
ACMG
-
-
-
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Different labs have different approaches to consenting for
secondary findings
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Examples can be illustrative
• Breast/ ovarian/ colon cancer
• Heart function
• Autoimmune diseases
• Drug reactions
• Complex traits not good
examples
Types of actionable secondary
variants chosen (n=108)
Cancer
Heart disease and related
disorders
Neurological conditions
Other chronic conditions
Mental health conditions
No
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Yes
105
0
1
3
5
108
107
104
103
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3) How likely is it that a secondary finding will be
identified?
Primary
diagnostic
findings
Secondary/
additional
findings
Concern among health
care providers
Patient uptake:
60-80% uptake
Diagnostic rate
25-35%
Clinical labs report
3-5%
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Initial
consultation and
phenotyping
Exome/Genome
analysis
“primary/diagnostic
variants”
Re-evaluation
and family
history
4) Management
and treatment
“Secondary variants”
Other
diagnostic
investigation
Familial
testing
Management/
surveillance
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4) Management and treatment
• Rare conditions, not always well-understood
• No consensus on management for asymptomatic individuals
• Psychological impact
• Theoretical harm
• Health dollars spent on screening and follow-up
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5) Potential benefits and drawbacks of
learning about secondary findings
- May lead to medical uncertainty
- Additional consultations and test
- Possible life/disability insurance
discrimination
- Impact on other family members
- Opportunity for prevention
and/or early detection
- Impact on other family
members
- long-term health care savings
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Time and resources
• 90 min streamlined to 15-30 min
• Not feasible for a genetic counsellor or geneticist to be involved in
every case
• Preventive/predictive medicine
• Especially in children
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Family assessment of benefits and drawbacks
can be fluid
Original choice: Yes
Choice upon confirmation: No
73
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Original choice: No
Choice upon confirmation: Yes
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Example case
?
-
?
Disease causing change
Cardiac myosin gene
5 yr old girl with intellectual disability and
abdominal wall structural defect
No reported cardiac abnormalities
- Cardiology consult, ECG, echo
Sister reported “palpitations”
- Genetic status unknown
- Cardiology consult
Reported family history of:
- Paternal grandfather d. MI, ICD implantation
@40
- Genetic status unknown
Father could also be at risk
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6) Resources
http://www.sickkids.ca/CGM/education
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Check list:
• How might secondary/predictive findings be found?
• What are secondary/predictive finding?
• Give some examples of such findings
• What will be reported: childhood/adult onset, medically actionable, etc
• What will not be reported
• What will happen if a secondary/predictive finding is identified
• How will the family be told
• How will the risk be managed
• Explain options to know or not know
• Benefits and drawbacks of learning about secondary/predictive
finding
• Implications for other family members
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