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Molecular Diagnostics :Molecular Diagnostics :
Hype or Hope ?Hype or Hope ?
Patrick WillemsPatrick Willems
GENDIA, Antwerp, BelgiumGENDIA, Antwerp, Belgium
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We now know how God wrote the book of life Bill Clinton
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But do we know how to read the book ?
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Genetic Diagnostics
• Cytogenetic tests
• FISH
• Molecular tests
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Molecular Diagnostics
- Diagnosis of infectious diseases
- Genetic identification
- Diagnosis of genetic diseases
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Diagnosis of infectious diseases
HPVChlamydia
Hepatitis
HIV
Toxoplasmosis
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Genetic Identification
- Paternity Testing
- Forensics
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Paternity Testing
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Forensic testing
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Diagnosis of genetic diseases
- Somatic rearrangements in cancer
- Genetic risk factors
- Pharmacogenetics
- Mutations in monogenic diseases
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Rearrangements in Cancer Cells
Chromosomal breaks produce fusion genes
These cause leukemias and lymphomas
Diagnosis determines treatment and prognosis
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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 LeukemiaInv(16) : CBF - MYH11
t(8;22) : AML - ETO
t(9;22) : BCR - ABL
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Diagnosis of genetic diseases
- Somatic rearrangements in cancer
- Genetic risk factors
- Pharmacogenetics
- Mutations in monogenic diseases
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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
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Genetic Risk Factors
Deep venous thrombosis
Cardiovascular disease
Alzheimer disease
Osteoporosis
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Genetic Risk Factors
Most single risk factors
have NO clinical significance
in individual patients
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Genetic Risk Factors
Deep venous thrombosis
Factor V
Factor II
MTHFR
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Diagnosis of genetic diseases
- Somatic rearrangements in cancer
- Genetic risk factors
- Pharmacogenetics
- Mutations in monogenic diseases
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Pharmacogenetic tests
• Drug specificity
• Drug efficacity - toxicity
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Drug specificity
Herceptin : HER2
Tyrosine kinase inhibitors
BCR / ABLKITPDGFR A/BEGFR
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Drug efficacity / toxicity
Cytochromes
CYP2D6
CYP2C9
CYP2C19
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Diagnosis of genetic diseases
- Somatic rearrangements in cancer
- Genetic risk factors
- Pharmacogenetics
- Mutations in monogenic diseases
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Diagnostic bottle necks
• Number of diseasesNumber of diseases
• Nature of disease mutationNature of disease mutation
• Technology
• Cost
• Number of samples
• Organisation
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Monogenic Diseases
> 4.000 monogenic diseases
> 2.000> 2.000 disease genes isolated
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Gene testing
• Most countries : limited number
(< 50 genes)
• Few countries : large number
(300-500 genes)
• Nowhere : network complete availability
(> 1000 genes)
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Diagnostic bottle necks
• Number of diseasesNumber of diseases
• Nature of disease mutationNature of disease mutation
• Technology
• Cost
• Number of samples
• Organisation
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Disease Mutations
Easy tests : Single - common mutations
Difficult tests : Private mutations
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Disease MutationsSingle mutations Fragile X
Sickle Cell Anemia
Common mutations Deafness Hemochromatosis
Panel of mutations Cystic Fibrosis
Private mutations Breast Cancer
Colorectal cancer
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Easy testsDisease 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
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Difficult tests
Disease Gene Mutation
Breast cancer BRCA1 Private
BRCA2 Private
Colon cancer MLH1 Private
MSH2 Private
MSH6 Private
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BRCA testing
BRCA1 : 23 exonen, 1863 AA, 6.200 bp
BRCA2 : 28 exonen, 3418 AA, 10.300 bp
Totaal : > 17.000 bp sequence
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Diagnostic bottle necks
• Number of diseasesNumber of diseases
• Nature of disease mutation
• Technology
• Cost
• Number of samples
• Organisation
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Mutation Detection
1. Point mutations, frame shifts :
A. Sequencing
B. WAVE
2. Deletions : MLPA
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Diagnostic bottle necks
• Number of diseasesNumber of diseases
• Nature of disease mutation
• Technology
• Cost
• Number of samples
• Organisation
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Cost
Single mutations : cheap (200 E)
Prevalent mutations : cheap (300 E)
Panel of mutations : moderate (300 E)
Private mutations : expensive (1000 E)
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Cost
• Socioeconomic situation
• Social security
• Reimbursement by insurance
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Diagnostic bottle necks
• Number of diseasesNumber of diseases
• Nature of disease mutation
• Technology
• Cost
• Number of samples
• Organisation
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Common Genetic Diseases
?
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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 exonsMutations 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
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Most frequent DNA tests
• Thalassemia
• Cystic fibrosis
• Breast cancer
• Colorectal cancer
• FRAXE• SCA
• F5 Leiden
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Usual portfolio of DNA tests
• Easy tests
• Common tests
• Research tests
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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
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Diagnostic bottle necks
• Number of diseasesNumber of diseases
• Nature of disease mutation
• Technology
• Cost
• Number of samples
• Organisation
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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
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Diagnostic bottle necks
• Number of diseasesNumber of diseases
• Nature of disease mutationNature of disease mutation
• Technology
• Cost
• Number of samples
• Organisation
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Gene testing
• Unreliable
• Expensive
• Slow
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Unreliable
10 % mistakes in easy tests such as CF
Nature Genetics 2000; 25: 259 - 260
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Expensive
RESEARCH DIAGNOSTICS
1 genome 1 gene
< 1000 USD 200 – 5.000 USD
Ratio : 25.000
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Slow
RESEARCH DIAGNOSTICS
100 genomes 1 gene
in 10 days in 100 days
Ratio 25 million
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Message in a bottle
• Many different tests
• Many uncommon tests
• Many esoteric tests
• Many expensive tests
• International network needed
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Mission
A global network of diagnostic labs
• Large portfolio
• Reliable
• Fast
• Affordable
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GENDIAGENDIA
GENGENeticetic DIADIAgnosticgnostic NetworkNetwork
www.GENDIA.netwww.GENDIA.net
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The GENDIA network
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GENDIA Network
1000 Referral labs
1 Central lab
100 Test labs
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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
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Looking into the future
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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
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DNA SequencingDNA SequencingDNA SequencingDNA Sequencing
1980-1990 1990-2005 > 2005
Radio - gel Fluorescent - capillary Next generation
Thousand bp / day Million bp / day Billion bp / day
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