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Medical Genetics 2 Prof Duncan Shaw. Risk calculations In genetic counselling, we want accurate risk assessment for families with genetic disease What.

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Presentation on theme: "Medical Genetics 2 Prof Duncan Shaw. Risk calculations In genetic counselling, we want accurate risk assessment for families with genetic disease What."— Presentation transcript:

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 A DMD pedigree II 1 had brothers with DMD She has 4 healthy sons Is she a carrier? III II 1

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 II-1 CarrierII-1 Not Carrier Pedigree Prior Risk1/2 Conditional information (4 healthy sons) (1/2) Joint Odds1/321/2 = 16/32 Final Odds JO / (JOC + JONC) 1/1716/17

10 Biochemical evidence Creatine kinase in normal women and DMD carriers

11 Bayesian calculation (2) II-1 CarrierII-1 Not Carrier Pedigree Prior Risk1/2 Conditional information (4 healthy sons, CK) (1/2) 4 x 1/31 4 x 1 Joint Odds1/961/2 = 48/96 Final Odds JO / (JOC + JONC) 1/4948/49

12 DNA evidence 60% of DMD mutations are deletions – easy to detect by DNA analysis If we dont have DNA from the affected family members, cant be sure if mutation in family is a deletion So if we test the DNA and it isnt deleted, there could still be a DMD mutation (such as a frame-shift)

13 Bayesian calculation (3) II-1 CarrierII-1 Not Carrier Pedigree Prior Risk1/2 Conditional information (4 healthy sons, CK, no DNA deletion) (1/2) 4 x 1/3 x 2/5 1 4 x 1 x 1 Joint Odds1/2401/2 = 120/240 Final Odds JO / (JOC + JONC) 1/121120/121

14 Using linked markers If you dont 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 1, II 1

15 Bayesian calculation (4) II-1 CarrierII-1 Not Carrier Prior Risk (DNA result) 1/2019/20 Conditional information (4 healthy sons) (1/2) Joint Odds1/32019/20 = 304/320 Final Odds JO / (JOC + JONC) 1/305304/305


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