1. Genetic Testing: The Clinician’s Perspective Roberta A. Pagon, MD Professor, Pediatrics University of Washington, Seattle Third Annual Short Course on Medical and Laboratory Applications of Genetics and Genomics Hangzhou, China November 1, 2007

2. Genetic Testing Molecular genetic testing in patient care GeneTests Essential elements of testing for clinicians

3. Genetic Testing Molecular genetic testing in patient care GeneTests Essential elements of testing for clinicians

4. Uses of Molecular Genetic Testing in the United States To help physicians provide the best medical care for a patient with an inherited disorder To help a person with an inherited disorder make informed personal decisions

5. Molecular Genetic Testing: Medical Care Diagnostic testing in symptomatic persons Predictive testing in asymptomatic persons when treatment is available

6. Medical Care: Symptomatic Person Establish a diagnosis (e.g., Huntington disease: HD gene testing is the only way to make the diagnosis with certainty) Confirm a diagnosis (e.g., HNPCC: MLH1/MSH2 testing in a person who does not quite meet Amsterdam criteria)

7. Medical Care: At-risk Asymptomatic Person Predictive testing: Identify family members who have the disease-causing mutation before symptoms appear so that they can be monitored for early signs of the disease and treated promptly to reduce morbidity and mortality (e.g., HNPCC)

8. 33 y 28 y 65 y Indeterminate risk 13 y12 y15 y 50% risk HNPCC 40 y Proband

9. Molecular Genetic Testing: Personal Decision-making* Carrier testing: Autosomal recessive disorders Predictive testing: No treatment available Prenatal diagnosis/Preimplantation genetic diagnosis (PGD) *Results of testing do not help medical care

10. Genetic Testing Molecular genetic testing in clinical practice: BASIC PRINCIPLES GeneTests Clinical testing: Essential elements for clinicians

11. Genetic Testing Molecular genetic testing in clinical practice: BASIC PRINCIPLES GeneTests Clinical testing: Essential elements for clinicians

12. www.genetests.org Funded by National Institutes of Health Located at University of Washington Seattle, WA Information resource for healthcare providers to help integrate genetic services into patient care

14.  1160 clinics GeneReviews: “User manual” for genetic testing for specific diseases  405 GeneReviews  One new Review added each week Laboratory Directory: “Yellow Pages” of genetics labs  ~610 Clinical and research laboratories  ~1460 Inherited diseases  ~1180 clinical tests ~280 research only Clinic Directory: “Yellow Pages” of genetic services Illustrated Glossary: Genetic counseling and testing terms

15. Molecular genetic testing: United States Testing used in patient care must be done in “clinical” laboratories, not research laboratories Clinical laboratories have to meet standards set by federal law (“CLIA”) Non-US laboratories are used when testing is not available in the US

16. Molecular genetic testing: China Testing for patient care is only available through research laboratories Laboratories outside of China cannot be used for testing yet

17. GeneTests Laboratory Directory Useful in US to identify US and non-US clinical laboratories testing for specific inherited diseases Not so useful yet in China

18. GeneReviews Useful to all clinicians regardless of availability of molecular genetic testing Provide to non-expert clinicians information on the diagnosis, management and genetic counseling of patients with inherited disorders and their families Expert-authored, peer-reviewed, updated regularly

19. GeneReviews: Search by Disease

20. HNPCC GeneReviews: Search by Disease

21. GeneReviews: Disease Search Result Clinical Testing Research Testing GeneReview Consumer Oriented Resources

22. GeneReviews: Search by Title

24. GeneReviews: HNPCC Disease search result: Select Reviews button Title search result: Select HNPCC from the list Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum Hereditary Neuropathy with Liability to Pressure Palsies Hereditary Non-Polyposis Colon Cancer Hereditary Sensory Neuropathy Type I Hereditary Spastic Paraplegia Overview

26. GeneReviews Content Summary Diagnosis Clinical Description Differential Diagnosis Management Genetic Counseling Molecular Genetics Resources References

27. GeneReviews Summary Disease characteristics Diagnosis/testing Management Genetic counseling One paragraph on:

28. GeneReviews Diagnosis Clinical Diagnosis Testing Molecular genetic testing Testing strategy (Order in which to use all the testing described above for diagnosis)

29. GeneReviews Clinical Description What are the clinical findings in this disorder? What happens over time to people who have this condition? How does the disease progress? Natural History

30. GeneReviews Differential Diagnosis What other conditions are similar to this condition?

31. GeneReviews Management Evaluations Following Initial Diagnosis Treatment of Manifestations Prevention of Primary Manifestations Prevention of Secondary Complications Surveillance Agents/Circumstances to Avoid Testing of Relatives at Risk Therapies Under Investigation

32. GeneReviews Genetic Counseling Risk to Family Members Parents of a proband Sibs of a proband Offspring of a proband Prenatal Testing

33. Genetic Testing Molecular genetic testing in clinical practice: BASIC PRINCIPLES GeneTests: EASY TO USE Essential elements of genetic testing for clinicians

34. Genetic Testing Molecular genetic testing in clinical practice: BASIC PRINCIPLES GeneTests: EASY TO USE Essential elements of genetic testing for clinicians

35. Genetic Testing: Essential Elements for Clinicians Educational materials about the disease and the test Test result report forms that explain the test and the patient’s test result Collection of data on phenotype and genotype

36. Genetic Testing: Essential Elements for Clinicians Sound easy, but are VERY hard to do In general, US laboratories do not provide the essential elements RECOMMEND: Have essential elements in place before offering clinical testing

37. Essential Elements: Educational Materials What is the test? What is the test used for? Who should be tested? What does a positive test result mean for the patient? What does a negative test result mean for the patient?

38. Essential Elements: Test Result Report Forms Clinical Indication: Why is the test being performed? Results: Normal, abnormal, uncertain Interpretation: What do results mean for this patient? Limitations: What can’t the test do? Suggestions for test result clarification: Testing other family members, other tests to do Test methods: How was this test performed? Resources: Links or citations to help the clinician understand more about the disease or test References: Literature citations

39. Genetic Testing: Data Collection A one page (electronic) phenotype data collection form to be filled in by the clinician at the time the test is ordered. Must be anonymous to protect the patient. Central database for phenotype data and genotype data when testing is completed

40. Genetic Testing: Essential Elements for Clinicians Being developed in the US by the Collaboration, Education, Test Translation (CETT) Program www.cettprogram.org

41. Genetic Testing Molecular genetic testing in clinical practice: BASIC PRINCIPLES GeneTests: EASY TO USE Essential elements of genetic testing for clinicians: HARD TO DO

42. Genetic Testing Molecular genetic testing in clinical practice: BASIC PRINCIPLES GeneTests: EASY TO USE Essential elements of genetic testing for clinicians: HARD TO DO

43. Thank you ! For your kind invitation to visit your beautiful city and to speak at this stimulating conference

44. Roberta A Pagon, MD Thomas D Bird, MD Cynthia R Dolan, MS Gerald L Feldman, MD, PhD Richard JH Smith, MD, PhD Karen Stephens, PhD Suzanne B Cassidy, MD Mary Beth P Dinulos, MD Amy Lawson Yuen, MD, PhD Monica Smersh Miriam Espeseth, MA Ellen Terry Carla Gifford Candace Street Editor-in-Chief Associate Editors Assistant Editors Managing Editor Online Production Editor Update Manager Editorial Assistants Genetic Counselors Laboratory Directory Coordinator Cynthia R Dolan, MS Roberta Spiro, MA Gina McCullough Grohs Database Administrator Systems Administrators Sergey Mikhaylov, MS Michael Kortas Brad Willson Staff GeneReviews Principal InvestigatorRoberta A Pagon, MD Directories Technical Support Resources Resources Liaison Kathi Marymee, MS