1. Consenting for the Unexpected: Empowering patient and provider
Nasim Monfared, CGC
Centre for Genetic Medicine

2. Resources and checklist for your practice
What health care providers (HCPs) need to know about secondary/predictive findings
Informed consent
Practical tips for informed consent about secondary/predictive findings
Resources and checklist for your practice
1) What are secondary findings
2) Which secondary findings will be reported
3) How likely is it that a secondary finding is identified
4) Management and treatment options
5) Potential benefits and drawbacks

3. Initial consultation and phenotyping Exome/Genome analysis
“primary/diagnostic variants”
“Secondary variants”
Phenotype: is essentially a genetic physician exam to determine if a patient is a good candidate for exome/genome
Primary/diagnostic finding: Pathogenic variant in gene related to presenting phenotype
Secondary finding: Pathogenic variant in gene unrelated to presenting phenotype BUT is medically significant (ie. can indicate risk of other known treatable disease)
When counselling patients about secondary findings, our aim is to provide sufficient, personally tailored information and an appropriate format for the patient/family.
Have to strike a balance between providing sufficinet information to faciliated informed consnet but not overwhelm family
We will talk about important topics to remember when counselling a fmaily about secondary finidngs

4. 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
When microarray testing was introduced in 2005, it was mainly utilized by genetics specialists. Today CMA is already ordered for many pts referred to genetics clinics
Rapid implementation of genomic technologies means that clinicians are required to have the knowledge and confidence to allow discussion of testing and its potential implications with parents and families.
Yet, from the experience of CMA implementation we know that many clinicians lack the knowledge and confidence to have this discussion
Confidence in describing genomic tests will improve with increasing familiarity, use and availability

5. 1) What are secondary findings?
Disease causing variants in known genes
Medically actionable
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
Genes without known health effects
Drug kinetics
genes
Other genes known
to affect health
These can included childhood, adult onset, PGX, carrier status
Still a controversial topic in the Genetics and Ethics community
Traditionally genetic testing was hypothesis driven and focused on one or a few genes related to the patient’s presenting features
AAP
Exome and genome sequencing are genome scanning technologies, meaning they are hypothesis-free. It became clear early on that in the course of genomic testing, we may identify information unrelated to the primary reason the test was ordered
ACMG (Green et al. Genetics in Medicine 2013) targeted analysis of a ‘minimum list’ of 56 genes for 24 inherited clinically actionable disorders, regardless of age or primary with opt out option
ESHG (van El et al. EJHG 2013) bioinformatic pipelines exclude genetic variants in genes unrelated to the primary indication in order to minimise discovery of incidental findings.. if an unsolicited genetic variant is detected despite the initial filtering of the data and is indicative of a serious health problem, either in the person tested or a close relative, health professionals should report such variants.
CCMG (Boycott et al. CCMG 2015) until the benefits of reporting incidental findings are established, the CCMG recommends a cautious approach; we do not endorse the intentional clinical analysis of disease genes unrelated to the primary indication, even if the results might be medically actionable. Thus, to minimise the discovery of incidental findings, bioinformatic analysis of genome-wide sequencing may be performed using selective filtering (in silico gene panels) that are highly specific to the primary indication (ie, comparable to a multigene panel often requested now for a specific clinical presentation). This will minimize unanticipated and potentially high-cost (dollar or emotional) impacts on the healthcare system, patients, and their families, and will result in faster analysis for variants that are relevant to the patient’s primary indication. However, we recognize that some clinical laboratories may wish to offer a broader genetic analysis that includes the assessment of genes that may be associated with diseases unrelated to the primary indication for testing. In this instance, the possibility of identifying incidental findings exists, and should such a finding be detected, then, in principle,
Courtesy of Stephen Meyn

6. 2) Which secondary variants to return?
At the moment, majority of exomes ordered by Canadian physicians are sent out to the US
In any case, most clinical labs offer patients the option of analyzing and returning variants in the ACMG56 genes.

7. “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
Strong evidence of serious implications for health, effective treatment/surveillance exists and can lead to improved clinical outcome

8. Secondary/predictive finding Pharmacogenetic findings
Laboratory
Family choice
Secondary/predictive finding
Pharmacogenetic findings
Carrier status
Actionable
Non-actionable
Baylor
Opt in +
GeneDx
Opt out
ACMG -
Emory
SickKids
Different laboratories have different approached to secondary variant analysis and reporting and we need to tailor the consent discussion based on the lab performing the test

9. Different labs have different approaches to consenting for secondary findings
Hcp is required to provide a statement

11. Examples can be illustrative
Types of actionable secondary variants chosen (n=108) No
Yes
Cancer 3
105
Heart disease and related disorders
108
Neurological conditions 1
107
Other chronic conditions
104
Mental health conditions 5
103
Breast/ ovarian/ colon cancer
Heart function
Autoimmune diseases
Drug reactions
Complex traits not good examples
Depending on what laboratory we are using this discussion will be tailored especially in terms of drug rxns

12. 3) How likely is it that a secondary finding will be identified?
Diagnostic rate 25-35%
Primary diagnostic findings
Clinical labs report %
Secondary/ additional findings
Concern among health care providers
Patient uptake:
60-80% uptake
Correlates to 1 in 20 patients
Don’t say “uncommon”

13. 4) Management and treatment
Initial consultation and phenotyping
Exome/Genome analysis
“primary/diagnostic variants”
“Secondary variants”
Other diagnostic investigation
Familial testing
Re-evaluation and family history
Management/surveillance
Priamry/diagnostic finding: Pathogenic variant in gene related to presenting phenotype
Secondary finding: Pathogenic variant in gene unrelated to presenting phenotype BUT is medically significant (ie. can indicate risk of other known treatable disease)

14. 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
Health dollars – can be compounded because genes are inherited and diseases can run in families
By testing one member of a family, we can discover unanticipated information about other family members

15. 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
- long-term health care savings
In terms of benefits, identifying sec findigns offers the opportunity for prevention/prophylaxis/early detection thus impacting not only the individual but other family members who many be at risk
This can lead to long-term health care savings
limitations

16. 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
Time to consent 90min --- it can be streamlined to a min discussion
As we’ve heard all morning, Predictive and precision medicine are topical themes right now. I hope by the end of this day we convince you that secondary findings are an essential part of the practice of predictive medicine. Add “predictive medicine and improving health” in overall theme

17. Family assessment of benefits and drawbacks can be fluid
Original choice: Yes
Choice upon confirmation: No 73 4
Original choice: No
Choice upon confirmation: Yes 28 5

18. Example case
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
Genetic status unknown
Father could also be at risk ?
Disease causing change Cardiac myosin gene

19. 6) Resources

20. 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