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Molecular Diagnostics - Gendia | Home Page

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  • 1. Molecular Diagnostics :Molecular Diagnostics : Hype or Hope ?Hype or Hope ? Patrick WillemsPatrick Willems GENDIA, Antwerp, BelgiumGENDIA, Antwerp, Belgium
  • 2. We now know how God wrote the book of life Bill Clinton
  • 3. But do we know how to read the book ?
  • 4. Genetic Diagnostics • Cytogenetic tests • FISH • Molecular tests
  • 5. Molecular Diagnostics - Diagnosis of infectious diseases - Genetic identification - Diagnosis of genetic diseases
  • 6. Diagnosis of infectious diseases HPV Chlamydia Hepatitis HIV Toxoplasmosis
  • 7. Genetic Identification - Paternity Testing - Forensics
  • 8. Paternity Testing
  • 9. Forensic testing
  • 10. Diagnosis of genetic diseases - Somatic rearrangements in cancer - Genetic risk factors - Pharmacogenetics - Mutations in monogenic diseases
  • 11. Rearrangements in Cancer Cells Chromosomal breaks produce fusion genes These cause leukemias and lymphomas Diagnosis determines treatment and prognosis
  • 12. Rearrangements in Cancer Cells Lymphocytic Leukemia t(9;22) : BCR - ABL t(12;21) : TEL - AML1 t(1;19) : E2A - PBX1 t(4;11) : MLL - AF4 Myeloid Leukemia Inv(16) : CBF - MYH11 t(8;22) : AML - ETO t(9;22) : BCR - ABL
  • 13. Diagnosis of genetic diseases - Somatic rearrangements in cancer - Genetic risk factors - Pharmacogenetics - Mutations in monogenic diseases
  • 14. Genetic Risk Factors Monogenic diseases are caused by a deleterious mutation in a single gene: Disease-causing mutations Multifactorial diseases are caused by a combination of variations in multiple genes: Genetic Risk Factors
  • 15. Genetic Risk Factors Deep venous thrombosis Cardiovascular disease Alzheimer disease Osteoporosis
  • 16. Genetic Risk Factors Most single risk factors have NO clinical significance in individual patients
  • 17. Genetic Risk Factors Deep venous thrombosis Factor V Factor II MTHFR
  • 18. Diagnosis of genetic diseases - Somatic rearrangements in cancer - Genetic risk factors - Pharmacogenetics - Mutations in monogenic diseases
  • 19. Pharmacogenetic tests • Drug specificity • Drug efficacity - toxicity
  • 20. Drug specificity Herceptin : HER2 Tyrosine kinase inhibitors BCR / ABL KIT PDGFR A/B EGFR
  • 21. Drug efficacity / toxicity Cytochromes CYP2D6 CYP2C9 CYP2C19
  • 22. Diagnosis of genetic diseases - Somatic rearrangements in cancer - Genetic risk factors - Pharmacogenetics - Mutations in monogenic diseases
  • 23. Diagnostic bottle necks • Number of diseasesNumber of diseases • Nature of disease mutationNature of disease mutation • Technology • Cost • Number of samples • Organisation
  • 24. Monogenic Diseases > 4.000 monogenic diseases > 2.000> 2.000 disease genes isolated
  • 25. Gene testing • Most countries : limited number (< 50 genes) • Few countries : large number (300-500 genes) • Nowhere : network complete availability (> 1000 genes)
  • 26. Diagnostic bottle necks • Number of diseasesNumber of diseases • Nature of disease mutationNature of disease mutation • Technology • Cost • Number of samples • Organisation
  • 27. Disease Mutations Easy tests : Single - common mutations Difficult tests : Private mutations
  • 28. Disease Mutations Single mutations Fragile X Sickle Cell Anemia Common mutations Deafness Hemochromatosis Panel of mutations Cystic Fibrosis Private mutations Breast Cancer Colorectal cancer
  • 29. Easy tests Disease Gene Mutation Fragile X FMR1 Repeat FRAXE FMR2 Repeat Friedreich ataxia FRDA Repeat Haw River DRPLA Repeat Huntington type 1 HD Repeat Kennedy AR Repeat Myotonic dystrophy type 1 DMPK Repeat Spinocerebellar ataxia SCA1,2, 3, 6, 7, 8,10, 12,17 Repeat Alpha 1 antitrypsin PI 2 common mutations Charcot-Marie-Tooth Type 1A PMP22 1 common mutation Cystic fibrosis CFTR Common mutations Deafness GJB2 1 common mutation Hemochromatosis type1 HFE 2 common mutations Hereditary neuropathy (HNPP) PMP22 1 common mutation Sickle cell anemia HBB 1 common mutation Spinal muscular atrophy SMN1 1 common mutation Beta thalassemia HBB 1 exon
  • 30. Difficult tests Disease Gene Mutation Breast cancer BRCA1 Private BRCA2 Private Colon cancer MLH1 Private MSH2 Private MSH6 Private
  • 31. BRCA testing BRCA1 : 23 exonen, 1863 AA, 6.200 bp BRCA2 : 28 exonen, 3418 AA, 10.300 bp Totaal : > 17.000 bp sequence
  • 32. Diagnostic bottle necks • Number of diseasesNumber of diseases • Nature of disease mutation • Technology • Cost • Number of samples • Organisation
  • 33. Mutation Detection 1. Point mutations, frame shifts : A. Sequencing B. WAVE 2. Deletions : MLPA
  • 34. Diagnostic bottle necks • Number of diseasesNumber of diseases • Nature of disease mutation • Technology • Cost • Number of samples • Organisation
  • 35. Cost Single mutations : cheap (200 E) Prevalent mutations : cheap (300 E) Panel of mutations : moderate (300 E) Private mutations : expensive (1000 E)
  • 36. Cost • Socioeconomic situation • Social security • Reimbursement by insurance
  • 37. Diagnostic bottle necks • Number of diseasesNumber of diseases • Nature of disease mutation • Technology • Cost • Number of samples • Organisation
  • 38. Common Genetic Diseases ?
  • 39. Common genetic diseases Disease Frequency Mutation Genes Mutations Conclusion Hemochromatosis 1 / 600 1 / 400 HFE 2 common mutations Easy / cheap Breast Cancer 1 / 20 1 / 500 BRCA1 BRCA2 Mutations in 23 exons Mutations in 28 exons Complicated / expensive Hypercholesterolemia 1 / 500 1 / 750 LDLR Mutations in 16 exons Complicated / expensive Colorectal Cancer 1 / 25 1 / 1.000 MLH1 MSH2 MSH6 APC MUTYH Mutations in 19 exons Mutations in 16 exons Mutations in 10 exons Mutations in 15 exons Mutations in 16 exons Complicated / expensive Cystic fibrosis 1 / 2.500 1 / 2.500 CFTR Common mutations Easy / cheap Prelingual deafness 1 / 1.500 1 / 4.000 GJB2 1 common mutation Easy / cheap Fragile X syndrome 1 / 5.000 1 / 5.000 FMR1 Only 1 mutation Easy / cheap SMA 1 / 10.000 1 / 10.000 SMN1 Only 1 mutation Easy / cheap Beta Thalassemia variable variable HBB Only 1 exon Easy / cheap
  • 40. Most frequent DNA tests • Thalassemia • Cystic fibrosis • Breast cancer • Colorectal cancer • FRAXE • SCA
  • 41. Usual portfolio of DNA tests • Easy tests • Common tests • Research tests
  • 42. Genetic testing in Europe • inhabitants per country : 10 million • births per year : 100.000 • disease frequency : 1 on 10.000 • new patients per year : 10 • genetic labs : 10 New patients per lab per year: 1
  • 43. Diagnostic bottle necks • Number of diseasesNumber of diseases • Nature of disease mutation • Technology • Cost • Number of samples • Organisation
  • 44. Current Organisation • Small local labs : small portfolio’s ( < 50 tests ) • Same spectrum of tests : common + easy tests • Majority academic labs : research -diagnostic setting • Many academic labs give up diagnostic testing • No (inter)national network
  • 45. Diagnostic bottle necks • Number of diseasesNumber of diseases • Nature of disease mutationNature of disease mutation • Technology • Cost • Number of samples • Organisation
  • 46. Gene testing • Unreliable • Expensive • Slow
  • 47. Unreliable 10 % mistakes in easy tests such as CF Nature Genetics 2000; 25: 259 - 260
  • 48. Expensive RESEARCH DIAGNOSTICS 1 genome 1 gene < 1000 USD 200 – 5.000 USD Ratio : 25.000
  • 49. Slow RESEARCH DIAGNOSTICS 100 genomes 1 gene in 10 days in 100 days Ratio 25 million
  • 50. Message in a bottle • Many different tests • Many uncommon tests • Many esoteric tests • Many expensive tests • International network needed
  • 51. Mission A global network of diagnostic labs • Large portfolio • Reliable • Fast • Affordable
  • 52. GENDIAGENDIA GENGENeticetic DIADIAgnosticgnostic NetworkNetwork www.GENDIA.netwww.GENDIA.net
  • 53. The GENDIA network
  • 54. GENDIA Network 1000 Referral labs 1 Central lab
  • 55. Advantages GENDIA • 1 lab to send samples to • 1 lab to get results from • > 2.000 genetic tests • Large portfolio • Best first selection of test • Best Reflex testing
  • 56. Looking into the future
  • 57. Sequencing power : billion bp / day Will rapidly multiply Cost : 100.000 Euros Will rapidly decrease to 1000 Euro Whole genome sequencing of Watson and Venter Sequencing all patients Next generation sequencing
  • 58. DNA SequencingDNA Sequencing 1980-1990 1990-2005 > 2005 Radio - gel Fluorescent - capillary Next generation Thousand bp / day Million bp / day Billion bp / day