Yoo Han-Wook M.D., Ph.D “Role and Limitation of Legal Regulation for the Development of Quality Genetic Testing Services”

Overview of Genetic Testing in Korea: Current Status and Problematic Issues

Han-Wook Yoo, M.D., Ph.D.,

Medical Genetics Clinic & Laboratory, Department of Pediatrics, Asan Medical Center,

University of Ulsan College of Medicine, Seoul, Korea

Company Logo

Outlines of Presentation

Genetic testing: definition, classification

Prerequisite for clinical DNA testing

Current status of genetic testing in Korea

DNA testing in single gene disorders

DNA profiling

Susceptibility DNA testing in Polygenic disorders

Pharmacogenomic DNA testing

Current issues of genetic testing in Korea

Regulatory process of genetic testing in Korea

Conclusion

Company Logo

Classification & Definition of Genetic Testing

Maternal serum screening

Cancer, DM, Alzheimer disease, Hypertension, Drug response

Disease prediction(susceptibility &resistance)

Inborn error of metabolism

Chromosomenumerical &structural disorder

Micro-deletion & duplication syndrome

Monogenic Mendelian disease, Mitochondrial disease

Disease diagnosis (prenatal, presymptomatic, carrier testing)

Paternity testing, Forensic investigation

DNA profiling

Biochemicalgenetic test

ing

Cytogenetic testing

Molecular cyto-genetictesting

DNA testingTesting

Purpose

Company Logo

Classification & Definition of Genetic Testing

Clinical test: diagnostic testing, predictive testing, carrier testing, prenatal testing, preimplantation testing, newborn screening

Investigational test

Research test

Company Logo

Prerequisite for clinically applicable DNA testing

Preferably single gene disorderKnown gene structure & functionAppropriate marker linked to morbid geneLimited locus heterogeneity and genetic heterogeneityAvailability of genetic epidemiological dataReplacing or complementary for preexisting diagnostic testLess cost-higher benefitSensitivity, specificity, positive & negative predictive valuesPre- & Post- test genetic counselingMaintenance of privacy and confidentiality

Company Logo

DNA testing for single gene disorders in Korea

Number of laboratories 5 Commercial laboratories >10 Institutional laboratories

Number of testing diseases 3 to more than 50 monogenic diseases

Methods Medical DNA sequencing, DHPLC, PCR-RFLP, methyl

ation specific PCR, ASO hybridization, PCR-Southern, genomic Southern, MLPA, real time PCR, linkage analysis....

Reimbursement by national insurance (As of Jan-2008) Reimbursed in 17 tests (13 monogenic diseases,

3 familial cancer syndrome, 1 predictive testing) Regulated by price of ceiling in 62 tests (4

2 monogenic diseases, 12 oncogenes or tumor suppressor genes, 8 pharmacogenetic testings)

Company Logo

Single Gene (Monogenic) Disorder

Victor A. Mckusilk: Mendelian Inheritance in Man

Online version of Mendelian Inheritance in Man(OMIM) > 10,000 diseases or trait >2,500 human disease relate

d >2,000 loci mapped - mutatio

n (7% of total 29,000 genes) > 1500 genetic tests are avail

able.

Company Logo

DNA testing for single gene disorders in Korea

Inherited metabolic disorders: urea cycle defects, Gaucherdisease, GSD Ia, Fabry disease, Wilson disase

Skeletal dysplasia: achondroplasia, osteogenesis imperfecta, craniosynostosis

Neuromuscular disorders: DMD/BMD, spinal muscular atrophy

Triplet repeat expansion disorders: spinocerebellar ataxia,fragile-X syndrome, myotonic dystrophy, Kennedy disease,Huntington’s disease, DRPLA

Neurogenetic disorders: adrenoleukodystrophy, CADASIL,dystonia

Hematologic disorders: hemophilia, factor V Leiden

Company Logo

DNA testing for single gene disorders

Familial cancer syndromes: BRCA1, BRCA2, APC, Rb

Endocrine genetic disorder: MEN, congenital adrenal hyperplasia

Monogenic renal disorder: familial hyperuricemic nephropathy, nephrogenic DI

Monogenic eye disorder: corneal dystrophy

Dysmorphic syndromes: Prader-Willi/Angelman syndrome,Rett syndrome, Holt-Oram syndrome, Marfan sydnrome

Mitochondrial disorders: MFLAS, MERRF, LHON, Kearn-Sayers syndrome, Leigh disease

Company Logo

DNA testing for DNA profiling in Korea

Forensic Medicine: National Institute of ScientificInvestigation, Department of Forensic Medicine in Medical Schools (>2)

Paternity testing: More than 10 commercial laboratories

Company Logo

SNP-based DNA testing for susceptibility genesin polygenic disorders in Korea

Thrombophilia panel : Factor V Leiden in Caucacians, prothrombin(factor II), MTHFR (methylenetetrahydrofolate reductase)

Coronary heart disease panel: lipoprotein (Lp(a), apoE), coagulation factor, MTHFR

Hypertension : ACEInsulin dependent diabetes mellitus : HLACancer disease (non-familial) : tumor suppressor genes, on

cogenes (n-myc gene, breakpoint cluster region (bcr) (BCR-ABL), breast cancer, colon cancer

Hemochromatosis : population screening for CaucaciansAlzheimer disease : familial vs sporadic (APOE genotyping)Neural tube defect : MTHFR gene

Company Logo

Pharmacogenetic variants that have been significantly associated with drug re

sponse in at least two studies (Nat Rev Genet 2003;4:937-947)

Pharmacogenomic DNA testing in Korea

Company Logo

Company Logo

Warfarin genotyping: CYP2C9 & VKORC1

Company Logo

Current Issues of Genetic Testing in Korea (I)

DTC (direct to consumer) or “Over the Counter” DNA testing More than 15 laboratories Advertised and sold over the Internet Limited oversight of the analytic & clinical validity of ge

netic tests No pre & post test genetic counseling

Implementation of legislation Oversight of genetic testing laboratories Approval of diagnostic kits & methods Biomedical ethical-legal-social issues

Company Logo

6. 유전자건강정보센터 (www.9191114.com/gene) – 검사종목

Company Logo

Regulatory process of genetic testing (I)

Initiated by Korean Society of Medical Genetics by reviewing mostcommonly sold DTC tests on web sites Clinical validity evaluation by literature review and meta-analy

sis Publication of reports

Implemented by the Ministry of Health & Welfare Funding a grant for research Organizing advisory committee of genetic testing composed of

expert physicians, geneticist, scientists, expert of bioethics, lawyer, representative from NGO

Holding a conference for public hearing Enhancing legislation by National Advisory Committee of “Bioe

thics & Security”

Company Logo

Regulatory process of genetic testing (II)

Since 2007-Jan, 14 DNA-based genetic tests are banned as a clinical test and 6 tests are limitedly allowed in specific clinical situation Prohibited DNA tests for clinical diagnostic purpose

Hyperlipidemia related gene: LPL Hypertension related gene: Angiotensinogen Osteoporosis related genes: VDR, ER Diabete mellitus related genes: IRS-2. Mt16189 Obesity related genes: UCP-1, Leptin, PPAR-gamma, ADRB3(B3AR) Alcoholism related gene: ALDH2 Depression related gene: 5-HTT Longevity related gene: Mt5178A Intelligence related genes: IGF2R, CALLAsthma related genes: IL-4, beta2-AREndurance related gene: ACELung cancer related gene: CYP1A1Violence related gene: SLC6A4Curiosity related gene: DRD2. DRD4

Company Logo

Regulatory process of genetic testing (III)

limitedly allowed in specific clinical situation Ankylosing spondylitis related gene: HLA-B27 Leukemia related genes: BCR/ABL Short stature related gene: SHOX Cancer related gene: P53 Breast cancer genes: BRCA1, BRCA2 Alzheimer related gene: Apolipoprotein E

Any genetic tests for trait identification are prohibited. The banned genetic test will be reviewed and updated on a regular basis. Protection of genetic information privacy and informed consent should be

ensured. The DTC tests are strictly prohibited except DNA profiling for paternity test

ing. Pre & post-test genetic counseling and request for diagnostic DNA testing

should be offered exclusively by medical doctor. DNA-diagnostic kit is regulated by KFDA and law related medical practice. The introduction of positive system is currently being considered.

Company Logo

Current Issues of Genetic Testing in Korea (II)

Establishment of “Korea Institute of Genetic Testing Evaluation” in2005 Evaluation of clinical validity of genetic testing Quality assurance of genetic testing

Enhancement of public & medical professionals’ awareness of pros& cons of genetic testing by education

Accreditation of genetic testing laboratories and personnel by Korean Society of Medical Genetics

Issues of insurance reimbursement Issues of certification & training program of medical geneticist as

a medical specialty Issues of oversight and regulation of DTC DNA testings

Company Logo

Genetic Testing in Korea

“Medicalization”

“Subspecialization”

“Professionalization”

“Molecularization”

“Commercialization”

“Cosumerization”

SNP-based susceptibility genetic testing in polygenicdisorders

Unproven clinical & analytical validities

Unresolved ethical, legal, and social issues

Conclusion