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)

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))

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)

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

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

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

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

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

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

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

Sample Research Report

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.

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

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