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 Carrier II-1 Not Carrier Pedigree Prior Risk
1/2
Conditional information (4 healthy sons)
(1/2)4 14
Joint Odds
1/32
1/2 = 16/32
Final Odds
JO / (JOC + JONC)
1/17
16/17

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

11. Bayesian calculation (2)
II-1 Carrier
II-1 Not Carrier
Pedigree Prior Risk
1/2
Conditional information (4 healthy sons, CK)
(1/2)4 x 1/3
14 x 1
Joint Odds
1/96
1/2 = 48/96
Final Odds
JO / (JOC + JONC)
1/49
48/49

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)
II-1 Carrier
II-1 Not Carrier
Pedigree Prior Risk
1/2
Conditional information (4 healthy sons, CK, no DNA deletion)
(1/2)4 x 1/3 x 2/5
14 x 1 x 1
Joint Odds
1/240
1/2 = 120/240
Final Odds
JO / (JOC + JONC)
1/121
120/121

14. 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
1,2 1
II 1

15. Bayesian calculation (4)
II-1 Carrier
II-1 Not Carrier
Prior Risk (DNA result)
1/20
19/20
Conditional information (4 healthy sons)
(1/2)4 14
Joint Odds
1/320
19/20 = 304/320
Final Odds
JO / (JOC + JONC)
1/305
304/305