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Slide 1

  1. 1. Plan for talk  Illustrate current practice in Clinical Genetics  Duchenne muscular dystrophy  Early onset Alzheimer’s disease  Colorectal cancer  Identify categories of staff involved  Genetics and pharmacology – hype or hope?
  2. 2. Kate 29 6 weeks Adam DMD
  3. 3. Genetic counsellor  Take a family tree  Confirm diagnosis in Adam  Information  Consent  Liaise with laboratory where diagnosis made
  4. 4. Kate 29 6 weeks Deleted Exons 48, 49, 50 How can Kate’s carrier risk be clarified?
  5. 5. Molecular genetics laboratory  Technologist  Extract DNA from Kate’s blood sample  Set up multiplex PCR  Run on sequencer  Clinical Scientist  Analysis of results  Issues report
  6. 6. Compare upper and lower traces to estimate dosage Amplified exons from Dystrophin Gene
  7. 7. Clinical geneticist  Discuss results  Offer prenatal diagnosis  Fetal sexing on free fetal DNA?  CVS?  Amniocentesis?  No further testing?  Discuss results of prenatal testing if appropriate
  8. 8. Duchenne Muscular Dystrophy PCR amplification of exons 35, 36, 39, 47, 48, 50, 48 36 50 47 39 35 Adam Prenatal
  9. 9. Neurology referral  Jim - 53 years  3 year history of cognitive impairment  1 year history of personality change, loss of impulse control  All investigations negative - diagnosis ofAlzheimer’s disease made  Brother and cousin also thought to be affected  Blood sent to research lab in Belgium- mutation identified in PSEN-1 gene  Referred to clinical genetics to discuss “family implications”
  10. 10. Dementiaonset less than 60 yrs of age
  11. 11. What are the “family implications”  Testing theoretically possible for other affected family members  Possibility of pre-symptomatic testing of at risk relatives  Age of onset of dementia 35-55 years  Duration of illness 6-7 years  No treatment available to modify affect of disease
  12. 12. Difference between research and service  Research innovative and driven by need to publish original research  Funding related to specific objectives – results may be a by-product rather than primary goal  Research labs not quality assured  Tests not performed under standardised conditions
  13. 13. Utilising research findings  Need to get hold of report from research lab  In order to understand the report from the research lab need to understand:  What do they mean by “mutation”?  How do we predict the effect of the mutation?  Can we confirm result in our own laboratory?
  14. 14. Mutation consequences • Substitution mutations can – Leave protein unchanged (silent) – Change amino acid (missense) – Put in new “stop” signal (nonsense) • Insertions (or deletions) • Change all subsequent amino acids (frameshift) – Unless multiples of three • Add (or remove) one or more amino acids • May also change 1 or 2 amino acids • Often put in new “stop”
  15. 15. Mutation – substitution Control sequence Patient sequence – change G to A
  16. 16. What is the mutation in Jim’s family? • Substitution mutation gene changing CGC to TGC • Replaces cysteine with arginine in the PSEN-1 protein • Polar to basic amino acid • missense
  17. 17. How does the clinical scientist know if mutation is pathogenic?  Look at the literature - has the mutation been described in other families with early onset dementia?  Look at an unaffected population cohort from the same ethnic group as the patient to see if the mutation is a rare variant  Run computer programme to look for sequence conservation across species
  18. 18.  Not in literature  Not present in 98 early onset dementia patients from Scotland and Iceland  Not present in 425 unaffected Scots  Sequence highly conserved across species
  19. 19. How can a genetic counsellor help?  Look at other affected family members and see if they carry the same mutation
  20. 20. Evidence  All affected individuals carry the mutation  No evidence that it is found incidentally in Scottish population  Wild type sequence conserved across species  Sufficient evidence to offer pre-symptomatic testing
  21. 21. Opted for testing
  22. 22. Colorectal cancer (CRC) Mary died age 43 CRC John age 35 CRC Jane 30 Jane wants to know her risk of CRC and whether any testing is available
  23. 23. Why look at gene expression in tumours?  Identification of “genetic” tumours  DNA sequencing of blood from affected individual  Cascade testing of relatives if mutation found  Targeting of treatment  ? Resistance to 5FU with mismatch repair deficient CRC  Gefitinib in lung cancer
  24. 24. Thank you for listening!  For further material based on cases go to  www.scotgen.org.uk

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