1. The Predictivity Concept Peter Propping Institute of Human Genetics University of Bonn, Germany CDBI Seminar on predictivity, genetic tests and insurance Strasbourg, 3-4 December 2007

2. Source: Dr. Ron Zimmern, Oxford Gene-environment Interaction: Cystic fibrosis Fragile X Duchenne muscular dystrophy Heart disease PKU Cancer Diabetes Multiple sclerosis Schizophrenia Asthma TB Obesity Alzheimer Autism Meningococcus Struck by lightning Motor vehicle accident Rheumatoid arthritis ‘Totally’ Genetic ‘Totally’ Environmental

3. The Human Genome 3,2 x 10 9 nucleotide pairs not a “unique” sequence, but appreciable interindividual variation any two genomes: 99,9% DNA sequence identity, thus, 0.1 % sequence differences (3 mio). Any individual (diploid, i. e. two genomes): 6 mio differences to the reference genome.

4. Modes of inheritance ? Autosomal dominant ? Autosomal recessive ? X-chromosomal

5. Two major groups of genetic diseases Monogenic (= Mendelian) disorders - monocausal - clear relationship between genotype and phenotype - about 2.000 disorders clarified - most disorders are rare - therapy mostly difficult Genetically complex (multifactorial) disorders - complicated genetic structure - many of them common in the population - may be influenced by exogenous factors - therapy frequently possible

6. Conceptual distinction -Prognosis: statement about the future course of a past or currently existing disorder -Prediction: probability of the onset of a disease that has not yet occurred

7. Methods of prediction and prognosis in a proband -medical history -medical examinations -family history -predictive genetic diagnosis -prediction based on lifestyle

8. Prediction on the basis of medical examinations Imaging techniques (CT, MRT, Ultrasound) -e.g.polycystic kidney disease hereditary brain tumors, e.g. tuberous sclerosis degenerative brain disorders Electrocardiogram -e.g.hereditary disturbance of conductivity (long QT-syndrome) Blood biochemistry -e.g.hypercholesterolemia hyperlipidemia

9. I:1 60 y I:2 58 y II:1 36 y II:2 34 y II:4 21 y II:3 34 y III:1 10 y III:2 8 y III:3 5 y Genetic diagnostics in familial adenomatous polyposis (FAP)

10. I:1 60 y I:2 58 y II:1 36 y II:2 34 y II:4 21 y II:3 34 y III:1 10 y III:2 8 y III:3 5 y Predictive diagnostics in familial adenomatous polyposis (FAP)

11. CRC, 56y CRC, 32y HNPCC? 30y28y ?? 2y Persons at risk for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC)

12. Cumulative risk in carriers of a mutation in the BRCA1 or BRCA2 gene Meta-analysis, King et al., Science 2003 BRCA1 BrCa BRCA2 BrCa BRCA1 OvCa BRCA2 OvCa Gen.pop. BrCa Gen.pop. OvCa X

13. Examples for Hereditary disorders with late onset for which predictive genetic diagnosis is possible (autosomal-dominant) Treatable: Hereditary tumor syndromes: -breast/ovarian cancer -colorectal cancer -familial adenomatous polyposis Polycystic kidney disease, type 1 Hereditary deafness, several late onset forms Untreatable: Huntington disease Myotonic dystrophy Alzheimer disease, autosomal-dominant forms Spinocerebellar ataxia, several forms Facio-scapulo-humeral muscular dystrophy Retinitis pigmentosa, several late onset forms

14. Concordance rates in identical (monozygotic, MZ) and fraternal (dizygotic, DZ) twins % MZDZ Coronary heart disease 4612 Hyperthyroidism47 7 Neurodermitis8328 Diabetes mellitus I45 5 Diabetes mellitus II9510 Lepra5920 Epilepsy („idiopathic“)86 4 Schizophrenia – narrow definition264-10 – wide definition4110-20

15. Genetic model of a complex (multifactorial) disease: Hypertension as an example „super-normal“ slightly predisposed slightly increased definitely increased severely ill

16. Relationship between genotype and phenotype in a complex disease -Predictive value of a genotype Positive Predictive Value (PPV) - Fraction of persons with a predisposing genotype who will develop the disease Negative Predictive Value (NPV) - Fraction of persons without the genotype who do not have the disease

17. Positive Predictive Value (PPV): Example: Crohn disease and association with NOD2 variant NOD2 GenotypePatientsControls Wildtype / Wildtype227248 Wildtype / Ins5723 Ins / Ins201 Positive predictive value: Homozygous 20 = 0,95 Heterozygous 57 = 0,71 20 21 57 80

18. Relationship between Genotype Frequency, Relative Risk and Positive Predictive Value DiseaseDiseaseGenotypeGenotypeRelative RiskPPVFrequency COPD + 0,05Pi ZZ0,000520,099,1% Narcolepsy0,0005DQB1*06020,02110,50,4% homozygosity + COPD = chronic obstructive pulmonary disease

19. Predictability of affection status in the carrier of a predisposing genotype -monogenic diseases up to 100% depending on penetrance - complex (multifactorial) diseases often low eventually higher after genotypic profiling

20. To what degree can multifactorial disorders be predicted ? Generally, the concordance rate of MZ twins is the upper limit of prediction; but: only cross-sectional information taken into account, no age correction possible; global concordance rates give only average data, in fact part of the cases higher degrees of heritability may exist.

21. Screening approaches: -Genetic population screening newborn screening for treatable diseases e. g. preconceptual thalassemia screening on Sardinia and Cyprus preconceptual screening in certain ethnic groups, e. g. for Tay-Sachs in Jews cascade screening, e. g. for hypercholesterolemia in the Netherlands

22. Screening approaches: -Ascertainment of persons at high risk through family history e. g. inherited breast/ovary cancer and Lynch syndrome (HNPCC) population-based for preconceptual testing in recessive diseases

23. The Future: The “1000 Dollar Genome” -nightmare of informed consent -nightmare of interpretation