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Medical Genetics 2

Medical Genetics 2. Prof Duncan Shaw. Risk calculations. In genetic counselling, we want accurate risk assessment for families with genetic disease What kinds of information can be used? Pedigree Biochemical DNA Using X-linked recessive inheritance as an example….

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Medical Genetics 2

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  1. Medical Genetics 2 Prof Duncan Shaw

  2. Risk calculations • In genetic counselling, we want accurate risk assessment for families with genetic disease • What kinds of information can be used? • Pedigree • Biochemical • DNA • Using X-linked recessive inheritance as an example…

  3. X-linked recessive inheritance • Usually affects males • Usually born to asymptomatic carrier mothers who may have other affected male relatives • Females may be affected if the father affected and mother a carrier • Females may be affected due to non-random X inactivation • No male to male transmission

  4. Duchenne Muscular Dystrophy • DMD is a relatively common (1/3000 births) and fatal genetic disorder • Major symptom is progressive muscle weakness • Incurable • Affected boys are in wheelchairs by age 10-12, and die by early 20s of heart or respiratory failure • Caused by mutation in the dystrophin gene on Xp21 From USA Muscular Dystrophy Association

  5. Dystrophin

  6. Genetics of DMD • 1/3 of DMD cases are new mutations (so no LD) • 2/3 have carrier mothers, 1/3 of which are new mutations themselves • About 60% of mutations are deletions • DMD is a big gene – over 2Mb • Other mutations in this gene cause a milder phenotype - Becker Muscular Dystrophy (BMD)

  7. II 1 III 1 2 3 4 A DMD pedigree • II 1 had brothers with DMD • She has 4 healthy sons • Is she a carrier?

  8. Evidence for carrier risk calculation • Pedigree evidence - her mother is a carrier so her prior risk is 50% - but has 4 healthy sons • Biochemical evidence - because of X inactivation some muscle cells have mutant X active and release creatine kinase (CK) so 2/3 carrier females have increased CK levels • DNA evidence: • Deletions of the DMD gene could be tested for (60% of DMD caused by deletion mutations) • Linked markers • None of the above is necessarily definitive

  9. Bayesian calculation

  10. Biochemical evidence • Creatine kinase in normal women and DMD carriers

  11. Bayesian calculation (2)

  12. DNA evidence • 60% of DMD mutations are deletions – easy to detect by DNA analysis • If we don’t have DNA from the affected family members, can’t be sure if mutation in family is a deletion • So if we test the DNA and it isn’t deleted, there could still be a DMD mutation (such as a frame-shift)

  13. Bayesian calculation (3)

  14. 1 1,2 II 1 1,2 1 1 Using linked markers • If you don’t know what the mutation is (or even what the disease gene is) but have closely linked markers, can use these to modify risk • Marker shown is linked to disease with 5% recombination • Mother has not received the same allele as affected brothers

  15. Bayesian calculation (4)

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