Medical Genetics 2
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Transcript of 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…
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
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
Dystrophin
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)
A DMD pedigree
• II 1 had brothers with DMD
• She has 4 healthy sons
• Is she a carrier?
III 1 2 3 4
II 1
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
Bayesian calculation
II-1 Carrier II-1 Not Carrier
Pedigree Prior Risk 1/2 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
Biochemical evidence
• Creatine kinase in normal women and DMD carriers
Bayesian calculation (2)
II-1 Carrier II-1 Not Carrier
Pedigree Prior Risk 1/2 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
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)
Bayesian calculation (3)
II-1 Carrier II-1 Not Carrier
Pedigree Prior Risk 1/2 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
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
1,2
1
1
II 1
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