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