1. Direct-To-Consumer Genetic Testing Developed by Dr. Judith Allanson, Ms. Shawna Morrison and Dr. June Carroll Last updated November 2015

2. Disclaimer This presentation is for educational purposes only and should not be used as a substitute for clinical judgement. GEC-KO aims to aid the practicing clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evidence-based manner. Physicians must use their own clinical judgement in addition to published articles and the information presented herein. GEC-KO assumes no responsibility or liability resulting from the use of information contained herein.

3. Objectives Following this session the learner will be able to: – Refer to their local genetics centre and/or order genetic testing appropriately regarding direct-to-consumer genetic testing (DTC GT) – Discuss and address patient concerns regarding DTC GT – Find high quality genomics educational resources appropriate for primary care

4. Case 1: Jenny Jenny, 33yo female in good health 6 months ago she found out that her paternal aunt, who is dying from ovarian cancer, was found to carry a mutation in the BRCA1 gene She didn’t feel this was the best time to approach the family to inquire further, so she purchased a DTC-GT kit online which tests the BRCA1 gene with the hope of being proactive, like Angelina Jolie

5. Case 2: Clark Clark, 50yo male in good health Recently purchased a DTC-GT kit out of curiosity after reading a news article MI AD dx 80 88 8690 75 50 80 d.87 d.85 arthritisIDDM A&W

6. Case 3: Jane and Jack Jane and her partner, Jack, are corporate lawyers, both in excellent health Their law firm strongly encourages employees to access the local executive health centre The couple had preconception counselling through the local executive health centre and purchased a carrier screening panel (screening for carrier status of 100+ recessive diseases) Although genetic counselling is available through this clinic, Jane always bring her results to review with you Neither she nor Jack was a carrier of the same recessive condition

7. Case 3: Jane and Jack Jane has just delivered a healthy baby boy by uncomplicated vaginal delivery As you commonly do, you anticipate prescribing Jane a combination codeine and acetaminophen after birth for episiotomy pain, however you recall Jane had also had pharmacogenomic testing (her predicted response to certain medication based on her genotype)

8. What is direct-to-consumer genetic testing? Direct-to-consumer genetic testing (DTC-GT), also referred to as personal genome testing, refers to genetic testing available for ‘over- the-counter’ purchase without health care provider involvement

9. What is direct-to-consumer genetic testing? Companies use data generated from genome-wide association studies (GWAS) – These are case-control studies which examine single nucleotide polymorphisms [SNPs] – SNPs (pronounced ‘snips’) are the most common type of genetic variation – Each SNP represents a difference in a single DNA building block, a nucleotide – GWAS compare large groups of individuals (unaffected controls versus individuals with symptoms of a specific disease) in an attempt to distinguish between non-harmful changes in the DNA code and pathogenic, disease-causing/predisposing changes

10. What is direct-to-consumer genetic testing? For complex health conditions (e.g. heart disease, diabetes) and traits (e.g. eye colour) individuals are generally categorized using SNP data as at increased risk (higher than average), average, or at decreased risk (lower than average) Pharmacogenomics uses SNP data to assess the kinetics and dynamics of specific drugs in the hope of avoiding adverse drug effects and to improve efficiency

11. What is direct-to-consumer genetic testing? For Mendelian inherited conditions companies will look for common gene mutations, generally ethnicity based – BRCA1 and BRCA2 3 Ashkenazi Jewish founder mutations (5382insC, 185delAG, 6174delT) are generally offered – CFTR (mutations in this gene cause cystic fibrosis) A core panel of 23 mutations is generally offered

12. What is direct-to-consumer genetic testing? Marketed with the promise of providing: – Predictive genetic risk assessment for a variety of health conditions (i.e. diabetes, cancer, obesity) – Information regarding response to and/or side-effect risk of certain pharmaceuticals (i.e. clopidogrel, statins) – Carrier status of single gene disorders (e.g. cystic fibrosis, Tay Sachs disease) – Ancestry information and link to relatives – Medically irrelevant information such as bitter taste perception, ear wax type, curly hair

13. Who can obtain direct-to-consumer genetic testing? Generally, direct-to-consumer (DTC) genetic testing is available online to anyone for a cost Genetic testing for DTC genetic testing is usually performed on a saliva sample

14. How will direct-to-consumer genetic testing help you and your patient? While there are limited data to support the clinical validity (ability to predict clinical outcome) and utility (the likelihood of improving patient outcome), some consumers might benefit from direct-to-consumer genetic testing as results may: – Encourage positive behaviour modifications (e.g. increase exercise, smoking cessation) – Provide useful information for medication choice and/or dose, or management – Provide information to individuals who have no or limited information about their family history (e.g. an individual who was adopted) – Reveal carrier status of a genetic condition that could have implications for family planning or medical management

15. Are there harms/limitations of direct-to- consumer genetic testing? Caution when interpreting direct-to-consumer (DTC) genetic testing should be exercised as: – DTC genetic testing does not take into account numerous factors important when interpreting genetic test results such as age, family history, lifestyle (e.g. smoking, obesity) and other environmental factors that are a significant contribution to common complex disease development – Clinical utility of some of reported results is questionable – Family health history-based risk assessment is still the gold standard in the initial assessment for heritable conditions

16. Privacy No testing regulation Discrepant results between companies, different studies may be used for result interpretation Concerns re downstream testing and costs as result of direct-to- consumer (DTC) results Truth in advertising ( potential for consumers to be misled about the benefits versus risks and limitations ) “misattributed equivalence” – if a DTC test indicates a lower than average lifetime risk for a certain condition, when FH indicated a much higher risk, a consumer could be falsely reassured and not be as vigilant about medical interventions indicated by FH – This phenomenon speaks to the need for knowledgeable healthcare provider involvement in pre- and post-test counselling Are there harms/limitations of direct-to- consumer genetic testing?

17. Back to case 1: Jenny Purchased DTC testing to know her BRCA1 mutation carrier status She receives her results and tells you that she is very relieved because she does not have a mutation in BRCA1 What are your next steps? Review the report DTC-GT testing companies generally only screen for a few founder mutations Need to confirm that Jenny was tested for the familial mutation – still need the familial mutation report If she truly is negative for the familial mutation, this is reassuring, should still confirm result in a clinical lab

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20. Back to case 2: Clark Purchased DTC for curiosity He brings in his laptop to show you his results He is distraught to learn that he has an increased genetic risk for Alzheimer disease, he had thought that he could stave off the disease by healthy lifestyle choices MI AD dx 80 88 8690 75 50 80 d.87 d.85 arthritisIDDM A&W

22. How do you counsel Clark? APOE is a susceptibility gene and is not a predictive test. Thus, individuals with no copies of the  4 allele still face about a 2x increased lifetime risk of developing AD if they have a first-degree relative with AD. Regardless of his DTC result, based on Clark’s family history, his AD risk is about 20-25% because of an affected FDR (actually higher than the risk estimate) He should still continue with his healthy lifestyle as AD develops from a complex interaction between genetic and environmental factors

23. Back to case 3: Jane and Jack Jane and her partner, Jack, had preconception counselling through the local executive health centre Jane has just delivered a healthy baby boy by uncomplicated vaginal delivery As you commonly do, you anticipate prescribing Jane a combination codeine and acetaminophen after birth for episiotomy pain, however you recall Jane had also had some pharmacogenomic testing (her predicted response to certain medication based on her genotype)

25. Jane’s result Codeine Gene tested - CYP 2D6 Result - Ultrametabolizer Functional duplications of CYP 2D6, lead to enhanced codeine to morphine metabolism (ultra-rapid metabolism - UM) and associated adverse events

26. What action can you take? Women who are ultra-rapid metabolizers of codeine will have significantly higher than normal levels of morphine in breast milk which could consequently cause problematic or lethal levels in the newborn. It is recommended that analgesics other than codeine be used by nursing mothers See GECKO on the run on Codeine metabolism and breastfeeding

27. Pearls – Direct-to-consumer (DTC) genetic testing is over-the- counter genetic testing available online to consumers through private companies – Generally, results report an individual’s probabilistic risk to develop a medical condition based on genome wide association studies (GWAS) – Interpret DTC results with caution – Family health history-based risk assessment is still the gold standard in initial assessment for heritable conditions

28. Resources See www.geneticseducation.ca for more details and how to connect to your local genetics centrewww.geneticseducation.ca To learn more about Canadian ethnicity-based carrier screening recommendations see the point of care toolthe point of care tool For a recent review on DTC-GT see Scott Roberts et al. Direct-to-Consumer genetic testing and personal genomics services: a review of recent empirical studies. Curr Genet Med Rep. 2013; 1(3): 182–200