1. Secondary findings from Genome-wide Testing
Patients and Families
Incidental findings, ethics
Clinical assessment
Diagnostics, Management and Therapy
Description of Phenotype
All roads start
and end
with the genome
blueprint
Neuroscience, cancer, precision
medicine
Population variation, statistical genetics
Understanding Molecular Pathobiology
Gene(s) Identification
Function, regulation and epigenetics
Patient/Family-Driven Research Cycle
(70% of admissions to SickKids have some ‘genetic’ link)

2. What is a secondary/incidental/ material incidental finding (MIF)?
TCPS2 article 3.4
*MIF= findings that have significant welfare implications for participant, whether health-related, psychological or social
Researchers have an obligation to disclose to participants any material incidental findings (MIF) discovered over the course of the research
TCP= Canadian Tri-council Agencies (Canadian Institutes of Health Research/CIHR, Natural Science and Engineering Research Council/NSERC, Social Sciences and Humanities Council/ SSHRC))

3. The friction/challenge/problem is…..
We’re finally right where we want to be!
Genomics can now
be part part of everyone’s
diagnosis/medicine
No clue what is, or will be, wrong with this chap-
wish I had some genetic clues
-WGS/technology is not disruptive because it is ahead of its time...it is disruptive because it is late to medicine
-We need to get on with it and do the best we can to make it work (do the best science/medicine that you can)

4. Information maps (or views) of the genome
Presented here are the three major genomic technologies used to study DNA not only in autism, but also in every other genetic disorder.
-turn to slide and present
Information maps (or views) of the genome
Increasingly more and more complicated information
High-resolution genome era is upon us!
Chromosomes and
Alterations
Microscope/karyotype
CNVs: Unified genetic variation
maps of genome
i.e. genomics
Microarrays and whole
genome sequencing
Science 2003; Nature Genetics 2004;
Nature 2006, Nature 2010;
Nature Reviews Genetics 2006/2016
SNPs and gene
Mutations
Sequencing and microarrays 4 4 4

5. Molecular diagnostic yield of CMA and WES in Autism: complex data what to report back?
9.3% (24/258) of individuals received positive results from CMA and 8.4% (8/95) from WES, and more often than not these genes/CNVs were associated with disorders bearing other names (but can exhibit autism)
5% of participants had pathogenic mutations in 2 or more CNV/genes often associated with other OMIM diseases
Increased molecular diagnostic yield in the children with additional dysmorphic features and/or birth defects (37.5%)
Three points above: are these incidental findings to ASD, or ASD itself?
Genomic testing (preferably WGS) should be prioritized to complex group
JAMA, 2015

6. Courtesy of Dr. Michael Szego
Current clinical guidance on report secondary/incidental findings is conflicting
Currently, no agreement on what to report:
ACMG (Green et al., Genetics in Medicine 2013)
Pathogenic variants in 56 genes should always be reported following clinical WES/WGS
Updated, now requiring consent
American Acad. of Pediatrics/ACMG (Ross et al., Genetics in Medicine 2013)
Predictive testing children for adult onset disorders discouraged
Focus on medical best interests
ESHG (van El et al., EJHG 2013)
Filtering to avoid detection of secondary variants
ACMG: American college of medical genetics
ESHG: European Society of Human Genetics
AAP: American Academy of Pediatrics
CCMG: Canadian College of Medical Genetics
Courtesy of Dr. Michael Szego

7. Canadian College of Medical Genetics (CCMG) has a cautious stance on returning Incidental Findings
“we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication”
BUT in (paediatric) cases where labs want to report Ifs
When parents request disclosure AND
Disclosure could prevent serious harm to the health of parent or family member
No obligation to re-contact
Jen’s Notes: the concept of filtering (introduced in previous slide) / no intentional clinical analysis of disease-associated genes other than those linked to the primary indication – for ASD the complete gene list for those linked to the primary indication is not yet complete so by filtering or not looking at some genes we may be missing some that are involved ASD.  This was our argument for not filtering.
Boycott K et al. J Med Genet 2015

8. Rationale of ACMG’s permissive stance
Information may be relevant to the parent. If risk is previously unknown this information benefits the child “by potentially preventing a severe adverse health outcome in a parent.”
Policy does not contradict the AAP/ACMG policy against predictive genetic testing of children because the AAP/ACMG joint policy focused on high-risk families where there are expectations that the child will be offered testing as an adult
There may be psychosocial implications but “the ability to identify a significant medical risk for the child that could avoid future morbidity takes precedence over this possible risk”
These rationales are in keeping with the child’s best interests
Green et al., Genetics in Medicine 2013
Szego et al., American Journal of Bioethics 2014
Anderson et al., Clinical Genetics 2015

9. Presidential Commission for the Study of Biothical Issues: No obligation to hunt for secondary findings
“Anticipate and Communicate: Ethical Management of incidental and Secondary findings” Presidential Commission for the Study of Bioethical Issues, 2013

10. A tale of Two- WGS projects
The Personal Genome Project
Hundreds registered; 50 done
0 on cloud
The ASD Genomics Study;
7500 done;
5,200 on Google cloud

11. Sample Research Report

13. Approach to Secondary Findings in the Autism Genome Study
Jen’s notes: .  At the recommendation of Bartha we should amend this to any finding which is medically actionable during childhood WILL be reported; others they have the option of yes or no.  I have not submitted this to the REB yet so what Michael has here is what is in our current consent.
At the recommendation of Dr. Knoppers and team, we are in the process of amending this to any finding which is medically actionable during childhood WILL be reported; for others they have the option of yes or no.

14. Objectives for the meeting
Get you thinking, involved, and access to experts and their opinions and experiences.
Better understand the true nature of genetic disease. Think about medicine/research, and population health in a different way.
Predictions of common themes
Still early days, do WGS when there is a need (economic/medical) for it, or when embedded in a research project
When dealing with secondary findings, will there be a ‘one-size-fits’ approach? Probably not, but a common theme will be need for genetic counseling, continual re-annotation of sequence and re-annotation (amendment) of your REB, and multi-disciplinary decision making. 14

16. TCPS2 article 3.4
Researchers have an obligation to disclose to participants any material incidental findings (MIF) discovered over the course of the research
*MIF= findings that have significant welfare implications for participant, whether health-related, psychological or social
PARTICIPANT HAS CAPACITY TO CONSENT FOR SELF
(ANY AGE)
PARTICIPANT DOES NOT HAVE CAPACITY TO CONSENT:
Consent Is Provided By Parent Or Legal Guardian
OPTION 2**
MIF that is medically actionable during childhood -> RETURNED
Other MIF – returned if deemed significant & actionable by a locally delegated expert review committee.
MIF that is medically actionable during childhood -> participant has option of receiving results or not
Other MIF - participant has the option of receiving results or not
OPTION 1**
MIF that is medically actionable during childhood -> RETURNED
Other MIF – participant has the option of receiving results or not
*MIFs may be actively sought, or not, depending on the design of the research study or clinical diagnostic test
**option used as determined by approval by local ethics board