Testing Children for Carrier Detection and Adult-Onset Disorders

1. Testing Children for Carrier Detection and Adult-Onset Disorders Lainie Friedman Ross, MD, PhD Carolyn and Matthew Bucksbaum Professor Associate Director, MacLean Center for Clinical Medical Ethics Depts. of Pediatrics, Medicine and Surgery University of Chicago

2. Current Policy and Practice: The Genetic Testing and Screening of Children • Newborn screening (NBS) as a mandatory program • Diagnostic genetic testing as a routine medical test • Predictive genetic testing is considered taboo • Carrier testing is considered taboo • Growing acceptance of adolescents consenting to predictive genetic testing and carrier testing for themselves

3. Current Policies & Practices Re: Predictive Genetic Testing of Children • Predictive Testing is taboo • Rule of earliest onset • Kodish ED. Testing children for cancer genes: the rule of earliest onset. J Pediatr. 1999 Sep;135(3):390-5. • What the rule fails to consider: • Conditions that present in childhood versus conditions that present in adulthood. • Conditions that are treatable (or have treatments that can reduce morbidity if begun early) versus those that are not.

4. Predictive Genetic Testing • Presents in early childhood. • Curable: Retinoblastoma • Incurable: Duchenne Muscular Dystrophy [DMD] • Presents in adolescence • Curable: Familial Adenomatous Polyposi [FAP] • Incurable: Charcot-Marie Tooth [CMT] (although some variants present in early childhood and others do not present until adulthood) • Presents in adulthood • Curable: Breast Cancer [BrCa] • Incurable: Huntington Disease

5. Predictive Genetic Testing for Childhood Onset Conditions Retinoblastoma Duchenne Muscular Dystrophy [DMD] Familial Adenomatous Polyposi [FAP]

6. Retinoblastoma • Retinoblastoma can occur as a new mutation or as an Autosomal dominant inheritance. • If diagnosed early, Retinoblastoma is treatable although the eye(s) may not be salvageable. • Frequent ophthalmologic exams (every three months) are the appropriate screening technique for children at risk. • Prior to genetic testing, all children born to parents with Retinoblastoma were considered high-risk.

7. Genetic Testing in “High Risk” Family RB is a well-appearing six-week-old boy who you are meeting for the first time. The family history is remarkable for paternal retinoblastoma. Dad’s left eye was enucleated as an infant. You recommend genetic testing to determine if the child is at-risk. The mother states that they were offered such testing in-utero and they refused. They now refuse post-natal testing. 1. Why might the parents refuse genetic testing? 2. If the parents refuse genetic testing now, what should you do?

8. Retinoblastoma • Can parents refuse testing prenatally? • YES • Can parents refuse testing of their newborn? • If the parents are willing to get frequent ophthalmologic examinations for the child, the risk of not knowing genetic status is decreased: • If the child is positive, would get these exams and so care is unchanged. • If the child is negative, could avoid such exams, but they are relatively benign. • If the parents are unwilling to get frequent ophthalmologic examinations, this is medical neglect. Get court involved.

9. DMD Parents request testing of their 6 week old son for DMD. Maternal nephew recently diagnosed at 6 years of age and mom was found to be a carrier. • What are the pros and cons of testing at 6 weeks from the child’s perspective? • What are the pros and cons of testing at 6 weeks from the family’s perspective?

10. DMD • Can parents refuse testing prenatally? • YES • Can parents refuse testing of their newborn? • YES • Can parents demand testing of their newborn? • Should be able to particularly if member of high risk family • Are we screening infants for DMD? • Yes in several countries around the world (e.g., Wales, Belgium) • Currently two research pilot studies funded by CDC • NBS for DMD in Ohio • Screening boys at 6-15 months in Georgia

11. Retinoblastoma vs DMD • When early-onset condition is treatable, diagnosis is viewed as medically imperative; and refusal as neglect. • When early-onset condition is not curable, diagnosis is viewed as elective. • Once symptoms appear, diagnosis becomes medically imperative (in part to rule out treatable conditions)

12. FAP • Autosomal dominant condition with complete penetrance • Presents in adolescence to young adulthood with multiple polyps. • Polyps are pre-cancerous so at some point the treatment is total colectomy.

13. Pros and Cons of Predictive Testing for conditions that present in late childhood • Pros • 50% will test negative—relieves anxiety. • Relieves ambiguity. • Cons: • It takes away the child’s right NOT to know. • Does the child have this right in the case of FAP? If the child does not get “gene-tested”, the child will have to undergo colonoscopies. (Failure to do so would be medically neglectful.) • Parents may seek inappropriate colonoscopies

14. Revising Genetic Testing Policiesfor conditions that present in childhood • Statements say very little about conditions that present in childhood. • Retinoblastoma • Predictive genetic testing in high risk families should be encouraged • Routine screening of general population not available (but would be acceptable) • DMD • Predictive genetic testing in infancy should not be routine • Testing in high risk families with extensive counseling

15. Revising Genetic Testing Policiesfor conditions that present in childhood • FAP • Although the consensus position is to wait until the child is 10 years of age, and to let the child have a role in the decision making process, it is not clear whether the child has the right to refuse. • (Even if the child can refuse the genetic test, his parents could still authorize a colonoscopy. In fact, it would be neglectful for them not to do so.)

16. Predictive Genetic Testing for Late Onset Conditions Breast Cancer Gene [BRCA] Huntington Disease [HD]

17. Current Positions of Various Medical Societies

18. The Genetic Testing of Children Report of a Working Party of the Clinical Genetics Society, U.K. J Med Genet 1994; 31: 785-97.

19. Conclusions & Recommendations • …the working party believes that predictive testing for an adult onset disorder should generally not be undertaken if the child is healthy and there are no medical interventions established as useful that can be offered in the event of a positive test result. • Of note, Genetics Interest Group [U.K. umbrella organization for parent-advocacy groups] supported this conclusion.

20. ASHG/ACMG Report: Points to Consider: Ethical, Legal and Psychosocial Implications of Genetic Testing in Children and Adolescents The American Society of Human Genetics Board of Directors and the American College of Medical Genetics Board of Directors (Amer J Hum Genet 1995; 57: 1233-41.)

21. ASHG/ACMG Report: The Impact of Potential Benefits and Harms on Decisions about Testing • If the medical or psychosocial benefits of a genetic test will not accrue until adulthood, as in the case of carrier status or adult-onset diseases, genetic testing generally should be deferred. • If the balance of benefits and harms is uncertain, the provider should respect the decision of competent adolescents and their families.

22. ASHG/ACMG Report: Assessing requests for tests • Until more information is available regarding the risks and benefits of genetic testing, the provider’s guiding principle continues to be primum non nocere—first do no harm. Thus, when faced with uncertainty, the provider may be obligated to avoid the possibility of harm, rather than to provide unclear benefits. There may be rebuttable presumption to defer testing unless the risk/benefit ratio is favorable.

23. Ethical Issues with Genetic Testing in Pediatrics American Academy of Pediatrics (AAP) Committee on Bioethics Pediatrics 2001; 107: 1451-1455.

24. AAP Recommendations • Genetic Testing for adult-onset conditions generally should be deferred until adulthood or until an adolescent interested in testing has developed mature decision-making capacities. The AAP believes that genetic testing of children and adolescents to predict late-onset disorders is inappropriate when the genetic information has not been shown to reduce morbidity and mortality through interventions initiated in childhood.

25. The consensus position holds that in general, predictive genetic testing of children and adolescents for adult-onset conditions should be deferred. Is this position justified?

26. BRCA and HD • Age of onset is similar (30s and 40s) • Gender: M/F ratio is equal in HD; mostly women in BRCA, although men and women have an equal reproductive risk (50% of their children) • Presymptomatic (HD) versus Predispositional (BRCA). • Untreatable (HD) versus Treatable via screening (mammograms) or prophylactic surgery (BRCA) • Percent of “at risk” community that seeks testing is much higher in BRCA (50%) versus HD (<15%)

27. Pros and Cons of Predictive Testing for Adult-Onset Conditions • Pros • 50% will test negative—relieves anxiety. • Relieves ambiguity. • Ability to incorporate into life plans. • Cons • It takes away the child’s right NOT to know. • Parents may seek inappropriate screening or unproven and potentially harmful therapies. • Potential for employment and insurance discrimination. • Harmful to self-identity.

28. Predictive Testing of Late-Onset Condition in Childhood and Adolescence • NOT clinically indicated. • More akin to an elective procedure. • There are psychosocial risks and benefits of knowing one’s status—both for the child and for the family. • Families, not clinicians, should decide whether the benefits outweigh the burdens. • Families should be encouraged to consider the child’s interest as paramount. However, this does not mean that the parents’ interests ought to be ignored. • Child’s status may impact parents’ reproductive plans. • Parents have a known 50% risk that this child and each subsequent child will be affected.

29. Predictive Testing: Similarities and Differences Between Early- and Late-Onset Conditions • Much greater concern regarding predictive testing for adult-onset conditions in healthcare community. • Unknown psychosocial impact given the time between testing and risk of disease-onset. • Possibly greater concerns for privacy • For childhood-onset conditions, parents would consent to predictive testing and would consent to testing of child when medically indicated. • For adult-onset conditions, parents (possibly with adolescent) would consent to predictive testing; but the child or adolescent would consent for him- or herself if testing deferred until adulthood. • As such, only predictive testing of late-onset conditions raises the issue of a child’s right to privacy.

30. Predictive Testing: Similarities and Differences Between Early- and Late-Onset Conditions • Parents may not differentiate so clearly between predictive testing for early vs late-onset conditions. • Families live with the ambiguity • This may persist after testing as a positive gene is often predispositional (BRCA) and not presymptomatic (HD) • Responsibility (guilt) about passing on the genes, regardless of timing of disease-onset. • Parents believe themselves responsible for their children, even after they reach majority. By testing, they can ensure that their grown children take advantage of clinical and research opportunities, even during the vulnerable young adult years (e.g. colonoscopies for FAP, mammograms for BRCA).

31. Recommendation: Predictive Genetic Testing • I agree that the presumption should be to discourage predictive testing of children and adolescents for (early and) late onset conditions. • I do not agree that uncertain benefit-burden calculations should be resolved against testing.

32. Uncertain Risk/Benefits: Who Decides? • Two options: • Physicians • Parents • Option #1 Physicians • Physicians know what is medically best for the child. • Physicians have a right to refuse that which is not “medically indicated”.

33. Uncertain Risk/Benefits: Who Decides? • Option #2: Parents • Parents have presumptive decision making authority. • Physicians should respect parental decisions because they are unable and unwilling to make the myriad of decisions that need to be made daily for a child. • Parents balance the child’s medical needs with the child’s psychosocial needs and the medical, psychosocial and reproductive needs of the family. • Physician interference may hinder the parents’ ability to make other decisions. As such, interference should be limited to cases in which parents are abusive or neglectful.

34. Carrier Testing is Considered Taboo

35. If carrier testing of children is taboo, then the carrier status of children should be unknown • Detection prenatally: • If prenatal testing is done to detect a child with a genetic condition, carrier information is given to parents so that their child’s carrier status is known. • Detection in NBS: • Institute of Medicine report, Assessing Genetic Risks: Implications for Health and Social Policy [Washington DC: National Academy Press, 1994] argued that if carrier status determined incidentally (example, sickle cell disease [SCD] through newborn screening), the information belonged to the parents. • And in fact, while we can choose to screen for cystic fibrosis via 2 tests of immunoreactive trypsinogen [IRT], most states choose to use IRT/DNA.

36. Genetic Testing for Carrier Status in Childhood: Yes we DO detect it, SHOULD we? • Assumption: Carrier status has no implication for the child’s own well-being • Does it matter that there are numerous exceptions… • Assumption: Reproductive implications of carrier information is not needed until adulthood.

37. PROS and CONS of Carrier Detection in Children • PRO • Ambiguity can be more harmful than many realize • Carriers have more implications that previously believed • In high-risk families, can serve to reassure parents that child does not have a condition • CONS • Information has reproductive implications that a child may not want to share with his or her parents • Labeling

38. Working Party Report (UK) vs the Genetic Interest Group (GIG) • Working Party and GIG both against genetic testing of adolescents for late onset conditions • Working Party: Against carrier testing of adolescents. • GIG argues in favor of parents being allowed to test their adolescents for carrier status. • Facts of life better absorbed slowly rather than during a crisis over pregnancy. • Carrier status information is less intrusive on adolescents’ autonomy and confidentiality. • Individuals can still choose whether or not to use this information.

39. Working Party Report (UK) vs the Genetic Interest Group (GIG) • Working Party and GIG against genetic testing of adolescents for late onset conditions, but differed about carrier testing (Working Party supported it; GIG did not) • Interpretation: I have a right to privacy about whether I am at risk for having a genetic condition that is life-threatening; but I don’t have a right to privacy about my risk of having an affected child. • Many of us would believe that our reproductive risks are more “personal” than our mortality… • By my actions I can keep you unaware of my reproductive risks (e.g., not have children, adopt, use PGD), but it is hard to hide one’s mortality.

40. Recommendation: Carrier Testing in Children and Adolescents • I agree that the presumption should be to discourage carrier detection in low-risk families. • I would not encourage carrier detection in high-risk families, but I would respect family requests. • I do not agree that uncertain benefit-burden calculations should be resolved against testing. • I do NOT support carrier screening programs in schools.

41. Growing Acceptance of Adolescents Consenting to predictive genetic testing and carrier testing for and by themselves

42. When the Adolescent Requests Testing • ASHG/ACMG: Ensure that the request comes from the adolescent. • “In the face of uncertain benefits and harms, an adolescent’s request for a test necessitates an individual assessment of competence and voluntariness.” • carrier status testing may fall under the specialized consent statutes; late onset conditions would not. • Mature minor/emancipated minor statutes may apply in some states.

43. When the Adolescent Requests Testing • Working Party: If > 16 years or Gillick competent, adolescent can consent on his or her own. • Canada and Australia have experimented on carrier status screening in high schools. • Data show that the majority understood what they were told, but that there were some significant misperceptions.

44. Arguments against Adolescent Autonomy • Competency is necessary but not sufficient for health care autonomy. • Moral arguments • Short-term autonomy versus life-time autonomy. • Child’s autonomous decisions will be based on limited world experience. • Parental rights and responsibilities. • Pragmatic arguments • No valid test for competency exists. • Parents should be encouraged to respect their child’s evolving capacity, but parents should not be legally compelled to do so. • Health care autonomy in perspective.

45. Additional Arguments against Adolescent Autonomy in Genetic Decision-Making • Genetic information is probabilistic and ambiguous. • Many health care providers are confused and are unable to counsel adequately. • Rapidly evolving state of knowledge means that misinformation and outdated information will be transmitted. • Genetic information has implications for third parties. • Parents have a right to privacy against their children prior to legal emancipation. • Genetic screening for carrier status in the schools is ethically problematic. • It ignores the impact of such a venue on voluntariness. • It implies a state interest in ensuring that its citizenry knows its carrier status when adults frequently choose not to be tested.

46. What legitimate interests do parents have in predictive genetic testing or carrier detection of their children? • Obligation to do what they perceive will promote their child’s interests. • Their obligation does not abruptly end when the child becomes an adult (although the expression of their obligation may be abruptly changed). • Right to consider familial interests (as long as the child is not “sacrificed” in the process).

47. What role for the adolescent? • Carrier Detection and Predictive genetic testing are akin to an elective medical procedure (e.g. cosmetic surgery). • While it is NOT wrong for parents to want this information even over the child’s objections, medical interventions require the participation of third-parties who are moral agents themselves. • Physicians may refuse to test a teen without assent.. • Parents can get this information when the child is younger or even prenatally. • As such, the requirement for adolescent assent is not too restrictive of parental autonomy and yet it gives adolescents some control over their lives. • In the reproductive context, adolescents may need to consent for themselves for carrier status info.

48. REVISIONS to Current Policy and Practice: Predictive Genetic Testing of Children • Predictive genetic testing is considered taboo • Parental discretion for predictive genetic testing for childhood onset conditions should be respected • (adolescent’s role described in separate recommendations) • Predictive genetic testing for late-onset conditions is akin to elective procedure • Presumption against testing • HOWEVER, families, not clinicians, should decide whether the benefits outweigh the burdens.

49. REVISIONS to Current Policy and Practice: Carrier Genetic Testing of Children • Carrier testing is considered taboo • Carrier testing is akin to elective procedure • Presumption against testing • HOWEVER, families, not clinicians, should decide whether the benefits outweigh the burdens.

50. REVISIONS to Current Policy and Practice: The Adolescent’s Role • Growing acceptance of adolescents consenting to predictive genetic testing and carrier testing for themselves • The adolescent’s consent alone is not sufficient for predictive testing. • The adolescent’s dissent should be taken seriously. • Parents may get around this by testing their younger children. • The adolescent’s consent alone may be sufficient for carrier testing in reproductive context, but this does not justify screening programs in schools.