Download 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 nonrandom 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?
II 1
III
1
2
3
4
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)
Joint Odds
(1/2)4
14
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)
Joint Odds
(1/2)4 x 1/3
14 x 1
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)
Pedigree Prior Risk
II-1 Carrier
II-1 Not Carrier
1/2
1/2
Conditional
(1/2)4 x 1/3
information (4
x 2/5
healthy sons, CK, no
DNA deletion)
Joint Odds
1/240
14 x 1 x 1
Final Odds
JO / (JOC + JONC)
120/121
1/121
1/2 = 120/240
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
1,2
II 1
1,2
1
1
Bayesian calculation (4)
II-1 Carrier
II-1 Not Carrier
Prior Risk (DNA
result)
Conditional
information (4
healthy sons)
Joint Odds
1/20
19/20
(1/2)4
14
1/320
Final Odds
JO / (JOC + JONC)
1/305
19/20 =
304/320
304/305