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Molecular Diagnostics : Hype or Hope ? Patrick Willems GENDIA, Antwerp, Belgium

Molecular Diagnostics : Hype or Hope ? Patrick Willems GENDIA, Antwerp, Belgium. We now know how God wrote the book of life Bill Clinton. But do we know how to read the book ?. Cytogenetic tests FISH Molecular tests. Genetic Diagnostics. Molecular Diagnostics.

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Molecular Diagnostics : Hype or Hope ? Patrick Willems GENDIA, Antwerp, Belgium

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  1. Molecular Diagnostics : • Hype or Hope ? • Patrick Willems • GENDIA, Antwerp, Belgium

  2. We now know how God wrote the book of lifeBill Clinton

  3. But do we know how to read the book ?

  4. Cytogenetic tests FISH Molecular tests Genetic Diagnostics

  5. Molecular Diagnostics • Diagnosis of infectious diseases • Genetic identification • Diagnosis of genetic diseases

  6. HPV Chlamydia Hepatitis HIV Toxoplasmosis Diagnosis of infectious diseases

  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 diseases • Nature of disease mutation • Technology • Cost • Number of samples • Organisation

  24. Monogenic Diseases > 4.000 monogenic diseases > 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 diseases • Nature 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 mutationsFragile X Sickle Cell Anemia Common mutationsDeafness Hemochromatosis Panel of mutationsCystic Fibrosis Private mutationsBreast Cancer Colorectal cancer

  29. Easy tests

  30. Difficult tests

  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 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 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 diseases • Nature of disease mutation • Technology • Cost • Number of samples • Organisation

  38. Common Genetic Diseases ?

  39. Common genetic diseases

  40. Most frequent DNA tests • Thalassemia • Cystic fibrosis • Breast cancer • Colorectal cancer • FRAXE • SCA • F5 Leiden

  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 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 diseases • Nature of disease mutation • Technology • Cost • Number of samples • Organisation

  46. Unreliable Expensive Slow Gene testing

  47. Unreliable 10 % mistakes in easy tests such as CF Nature Genetics 2000; 25: 259 - 260

  48. RESEARCH DIAGNOSTICS 1 genome 1 gene < 1000 USD 200 – 5.000 USD Ratio : 25.000 Expensive

  49. RESEARCH DIAGNOSTICS 100 genomes 1 gene in 10 days in 100 days Ratio 25 million Slow

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