Not What We Went Looking For

1. Not What We Went Looking For Arlene M. Davis, JD Ethical, Legal, and Social Issues in Identification of Sex Chromosome Variations Assistant Professor Department of Social Medicine Investigator Center for Genomics and Society University of North Carolina, Chapel Hill

2. Fellow CGS Researchers Nancy M.P. King, JD Department of Social Sciences and Health Policy Wake Forest University School of Medicine Cynthia M. Powell, MD Department of Pediatrics University of North Carolina, Chapel Hill Ian Whitmarsh, PhD Department of Anthropology University of Iowa

3. Overview of Presentation • Technologic and societal changes regarding screening and genetics • Intended or incidental • Identification of sex chromosome variations (SCVs) in genetic screening • Data from two interview studies • Implications

4. Changing Landscape 2006 Supplement to Pediatrics: A Look at Newborn Screening: Today and Tomorrow

5. Detected: incidentally during prenatal screening or when symptoms are identified Proposed NBS methodologies detecting X-linked conditions may also detect SCVs Early intervention & detection of medical problems may be beneficial Genotype vs. phenotype – wide variation in presentations People may do well, whether or not the SCV is ever identified Some struggle with life-long medical, learning, & behavioral issues Genetic Screening & SCVs

6. Turner (45,X) 1/4000-1/5000 girls Symptoms vary and may include: Short stature* (4’7”) Delayed puberty* Infertility* Hearing impairment, lymphedema, cardiac & kidney problems, learning disabilities Some never diagnosed Klinefelter (47,XXY) 1/1000 boys Symptoms vary and may include: Tall stature Low testosterone/puberty* Infertility Behavioral problems & learning disabilities* 60-70% never diagnosed Screening May Identify SCVs

7. Family Study 14 families of children with 45,X and 47,XXY Parents’ ages: 30s-50s Children: 1-16 years Families with KS: 6 Families with TS: 8 Questions: diagnosis & care for children and interest/concerns about NBS to identify SCVs New Mothers’ Study 28 mothers of infants Mothers’ ages:19-45 years Infants: 8-12 weeks Questions: views on expanding NBS to include specific SCVs Our Two Interview Studies

8. Family Study Results Inform Mothers’ Study Questions Family Study New Mothers’ Study Should SCV screening be offered? Would you accept? Would it matter that: Often no medical treatment until symptoms develop? Some show few symptoms while others have many? Some may live entire lives without diagnosis? • Parents embrace uncertainty about condition, focus on: • Individuality of child • Her accomplishments • Argue: w/o symptoms, syndrome doesn’t exist Whitmarsh, I. et al. (2007). A place for genetic uncertainty. SS&M, 65: 1082-1093.

9. Perceived BenefitsIdentifying SCVs with NBS Family Study Early intervention Have an explanation Might not be detected otherwise New Mothers’ Study Early intervention Gives an opportunity to: prepare financially prepare emotionally research resources before symptoms arise learn more about child Peace of mind if results are negative

10. Perceived Concerns Identifying SCVs with NBS Family Study Increase worry Increase sense of guilt Diagnosing all behaviors Some families: offer testing when symptoms arise Chromosomal diagnosis=“syndrome” New Mothers’ Study Parents might jump to conclusions about child’s prognosis Symptoms may never present Offer screening for older babies, not newborns Confidentiality breaches Accuracy and expense of screening

11. Views Family Study New Mothers’ Study New mothers regarding some have few symptoms while others have many: “I am interested in knowing if she has it, not in how severe it may be.” “That’s the one where it makes me wish that we just wait and get him screened if he had any symptoms.” Mother of son with KS on getting diagnosis: • “Well, you find out and then you don’t know any more than you did before you found out.… It’s just, you just know that he has an extra chromosome and that’s as far as it goes.”

12. Views Family Study New Mothers’ Study New mothers regarding some live their entire lives without a diagnosis: “If he does not have symptoms, and I do not have a reason to think he has it, there is no reason to do this test.” “The possibility that she would have severe symptoms [is] enough to make me want to know.” Grandmother of a teenager with Klinefelter: • “He’s really not a full blown Klinefelter, he’s just a borderline….You know, he’s just a little Klinefelter’s, he’s not a lot Klinefelter’s.” Father of girl with Turner: • “I don’t think Turner’s exists without some of the physical aspects of it.”

13. ConclusionsNew Mothers’ Study Most said they would want screening for SCVs. “If it’s there, you would want to know about it. Even if it’s mild or asymptomatic. I mean, I would still want to know about it.” They believed diagnosis would provide access to early intervention services they thought would be beneficial. Some viewed screening as peace of mind, assuming the results would be negative.

14. Implications Our Views of Screening and Genetic Variation Who Controls Meaning of Genetic Information?

15. One Presentation of Our Future

20. Thank You davisam@med.unc.edu

22. Enrollment of Children in a Study of Huntington's Disease Leon S. Dure, MD Bew White Professor of Pediatrics and Neurology The University of Alabama at Birmingham

23. Clinical Features of HD • Prevalence 4 – 10/100,000 • Inheritance Dominant High penetrance Expansion of htt gene • Age of onset 35 – 45 yrs (range 2 – 80) <10% under 18 yrs • Duration 15 – 30 yrs

24. HD Genetics • Expansion of translated CAGn, chromosome 4p • Polyglutamate motif (similar to MCD, SCA-1, etc.) • CAG > 39 correlated with clinical disease • Age of onset inversely related to CAG expansion • Testing easily done – not highly accessed

25. Clinical Presentation of HD • Initial signs and symptoms • Chorea, incoordination, personality changes • Psychiatric diagnoses common • Later signs and symptoms • Progressive chorea, dystonia • Dysarthria • Dementia, ongoing psychiatric disturbances • Early death

26. HSG - COHORT“Framingham study for HD” • Scientific rationale • Innovations • Inclusion of spouses and 1º relatives • Inclusion of minors • Biobank repository • Comprehensive environmental history

27. Concerns for COHORT • HD family attitudes • Clinical research in general • Research involving minors • Logistics of assent and consent • Departure for HSG • Age and development specific process • Practical question – what and how are children to be approached? • When do they know about HD? • What do they know? • What would be the effect of participation on children?

28. Dataset Development • Pilot Internet survey targeting HD families • HDSA website • HSG website • Advantages • Inexpensive • Anonymous • Disadvantages • How representative are responses? • Limited information

29. HD Parent Survey • 6 months duration • 249 respondents • Survey design • Basic demographics • Gene status • Family information – children, risk, understanding • Attitudes regarding research for adults and children

30. Respondent Characteristics • Gender – 81% female • Mean Age – 42 yrs (F = 40y, M = 48y) • Gene status • 42% not at risk/gene negative • 37% at risk • 18% gene positive • Clinical research • 84% never participated in HD clinical research • Children of respondents • 225 reported from 75% of respondents • Mean age 11yrs

31. Informing Children • 62% had provided information of some type • Average age of respondent = 47y • < 50% of AR parents had informed • Age of children • Current average = 14y • Age informed = 12y

32. Uninformed Children • Average age = 7y • Gene status of parents • AR = 47% • NEG = 35% • POS = 18% • Reasons for not informing • Age • Sparing distress • Appropriate age to inform • Wait until adulthood – 8% • 15-18y – 44% • 10-14y – 26% • 5-9y – 16%

33. Attitudes Towards Research • Adults regarding themselves • 88% Agree/Strongly agree that symptomatic and at-risk persons should participate • No major differences regarding gene status • Adults regarding children • 55% agree that children should participate • 35% neutral • 10% disagree with participation • Age for participation • 51% greater than 14yrs • 29% 10-14yrs • 20% less than 10yrs

34. Adult/Parental Concerns • Adult participation • Insurance • Confidentiality • Child participation • Child’s understanding of the study • Most commonly cited – “psychological effect of participation”

35. Clinical Activities in COHORT • Yearly neurologic examination • 63% supportive • Age – 47% 15-18y • Blood specimen for research and “DNA testing” • 49% supportive • Age – 45% 15-18y • Statistically, AR group was least likely to be supportive of examination/blood specimen

36. Summary/Conclusions • Parental support for inclusion of children in COHORT • Older children • Informed children • Importance of family composition/gene status/symptom presence • Not all families inform children at the same time • Clinical activities of COHORT will need to be tailored to parental concerns • Need to develop strategies to assess childhood understanding of HD

38. Genetic Screening in CVID: Kristen Hayward, MD What are we looking for? Fellow, Pediatric Rheumatology Seattle Children’s Hospital

39. the Case 16 m.o. F presents for immune work-up Past Medical History: term, healthy 2 infections treated with oral antibiotics mild eczema Family History: Dad: immunodeficiency syndrome (CVID) sepsis, anemia, thrombocytopenia splenectomy, steroids, IV immunoglobulin

40. the Case(continued) Physical Exam: • normal growth & development • normal exam Labs: • mild anemia • normal vaccine responses • normal antibody levels Mom’s concern: • Should we send a genetic test for CVID?

41. What is CVID? Common Variable Immunodeficiency Incidence: 1/10,000 – 50,000 in U.S. Presents in 2nd – 3rd decade of life recurrent bacterial infections chronic lung disease autoimmune phenomena malignancies Inheritance: 90% sporadic

42. What is CVID? • Treatment: • replacement immunoglobulins (IVIG) • timely antibiotics • Prognosis: • mortality 20-30% over 30 years • Diagnosis: • clinical and laboratory criteria So what about genetic testing?

43. Genetic Testing in CVID? TACI gene: • mutation in 7-10% of CVID cases • good biologic plausibility • same change found in asymptomatic family members Father’s TACI gene analysis: • single amino acid substitution • described on OMIM, not validated mutation or variation?

44. Back to the CASE… Should we test our patient for a TACI mutation?

45. How do we decide? Burke, Pinsky & Press framework Effective treatment available? Clinical Validity? No Yes High CVID Low Burke, Pinsky, Press, American Journal of Medical Genetics106 (2001), pp. 233–240

46. “Positive” result - Unclear if causative - Unclear penetrance - Unclear age of onset “Negative” result - Unclear if causative - Baseline risk based on family history Clinical Validity? Genetic test for CVID Indeterminant clinical validity

47. Effective Treatmentfor CVID? • No preventative therapies • No cure • Supportive care: - Timely antibiotics can be life saving - IVIg may improve outcomes

48. What are the issues? Health Outcomes Labeling Effects Closer follow-up? Earlier detection? Vulnerable child? Future insurability?

49. What would YOU do? ?

50. the CaseWhat happened? Patient underwent genetic testing: • same TACI sequence as her father 26 months: • developed arthritis in multiple joints • started treatment within 8 weeks 36 months: • low WBC, low antibodies • started replacement IVIG