Lecture 9 - Clinical Genetics of Cystic Fibrosis Flashcards Preview

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Flashcards in Lecture 9 - Clinical Genetics of Cystic Fibrosis Deck (48):
1

Incidence of CF

~1/2500 - 3000 live births

2

Carrier frequency of CF

~1/25 in northern Europe

3

How strong is the genotype-phenotype correlation in CF?

Strong in some areas (pancreatic insufficiency)
Less strong in other areas (lung blockage)

4

Which mutation classes correlate with pancreatic insufficiency?

Class I, II and III

5

Which mutation classes correlate with more severe lung disease?

Classes I, II and III

6

Which mutation classes correlate with less severe lung disease and pancreatic sufficiency?

Classes IV and V

7

Example of a mutation in CFTR with reduced penetrance

R117H

8

What determines R117H penetrance?

A poly-T tract (5, 7 or 9 T's) exists on same intron (intron 8) as R117H.
Establishes which mutations are in phase, in cis

5 T's means R117H will likely cause disease
7 T's means R117H is unlikely to cause disease
9 T's means R117H is highly unlikely to cause disease

9

Why might being heterozygous for CF be advantageous for cholera infection?

If 50% of CFTR channels have impaired function, less water might be lost into the gut lumen

10

Why might being heterozygous for CF be advantageous for S. typhi infection?

S. typhi can bind to CFTR.
If 50% of CFTR proteins are misshapen, might reduce bacterial adherence

11

How can environmental vs genetic modifiers be studied for CF?

Compare disease for monozygotic, dizygotic twins, and siblings

12

How genetically-determined is lung function in CF?

50% genetic, 50% environmental

13

How genetically-determined is meconium ileus in CF?

Completely genetically determined

14

How genetically-determined is diabetes in CF?

Mostly genetic

15

Why identify genetic modifiers of CF?
1)
2)
3)
4)

1) New targets for therapies
2) Better understand disease variability
3) Expect mutations to be minimally-penetrant in normal people, but effects unmasked in CF
4) Mutations might have modifying effects on other diseases

16

Do many de novo mutations cause CF?

No
Few de novo mutations leading to CF

17

Ways to identify genetic modifiers of CF
1)
2)
3)

1) Linkage studies
2) Candidate gene association
3) Genome-wide association studies

18

Linkage studies

Track genes or markers associated with a specific phenotype in individuals or families with CF

19

Candidate gene association

Look at genes with a known function (which correlates with CF symptoms)
Correlate variations in gene with different CF phenotypes

20

Genome-wide association studies

Look at DNA markers across whole genome in people with CF and without CF

Look for SNPs which are prevalent more in affected populations than unaffected populations

21

Drawbacks of genome-wide association studies
1)
2)
3)

1) For genes with reduced penetrance, need greater sample size
2) Need to replicate studies for validation
3) Need to demonstrate cause, not just correlation. This requires research on specific mechanisms, which GWAS don't do

22

CF genetic modifiers which affect lung function
1)
2)
3)

1) EDNRA
2) MBL2
3) TGFb1

23

Which aspect of CF phenotype do EDNRA, MBL2 and TGFb1 affect?

Lung function (FEV1)

24

What does EDNRA encode?

Endothelin receptor type A

25

Correlation between endothelin receptor type A and CF phenotype

Variants in EDNRA alter smooth muscle tone and vasculature in airways

26

What does MBL encode?

Mannose binding lectin

27

How is mannose binding lectin implicated in CF phenotype?

Defective MBL results in reduced innate immunity, and more severe bacterial infections in lungs

Pseudomonas aeruginosa main bacterial threat

28

How is TGFb1 implicated in CF phenotype?

TGFb1 involved in inflammation and tissue remodelling
Higher levels correlate with worse phenotype

29

Which aspect of CF phenotype does MSRA exacerbate?

GIT blockage

30

Which mutation correlates with worse GIT blockage in CF?

MSRA (methionine sulphoxide reductase)

31

How does MSRA correlate with CF phenotype?

MSRA encodes methionine sulphoxide reductase
Methionine sulphoxide reductase modifies intestinal enzymes, EG: alpha-1 antitrypsin

Modification can lead to intestinal blockage, modified digestion

32

Which mutation correlates with diabetes in CF?

TCF7L2

33

Which phenotype correlates with TCF7L2 in CF?

Diabetes

34

How does TCF7L2 correlate with diabetes in CF?

TCF7L2 (transcription factor 7-like 2) plays role in proliferation and function of beta-cells in pancreatic islets

35

Which environmental factors correlate with worse CF outcomes?
1)
2)
3)
4)

1) Being female
2) Lower socio-economic status
3) Exposure to tobacco smoke
4) Disease exposure

36

Why mightn't being female be merely a genetic predisposition to worse CF phenotype?

CF requires a high-fat, high-salt diet.
Young women more likely to care about weight, therefore maybe less likely to follow diet

37

Cascade testing

Test relatives of newborn with CF

38

Newborn screening for CF
1)
2)
3)

1) Immunoreactive trypsinogen test
2) If in top 1% of IRT levels, DNA testing on 12 mutation panel
3) Heterozygotes have sweat test of NaCl concentration

39

Immunoreactive trypsinogen test

If baby has CF, levels of immunoreactive trypsinogen will probably be high
If baby has [IRT] in top 1%, given DNA testing

40

DNA testing for CF

Initial screen is for 12 mutations
If 2 mutations aren't detected, extended DNA test is used

41

Positive result for sweat test

Over 60mmol/L of NaCl

42

Equivocal result for sweat test

30-60mmol/L of NaCl

43

Negative result for sweat test

Under 30 mmol/L of NaCl

44

Procedure for sweat test

1) Pilocarpine (ionophore) placed on arm to produce sweat
2) Sweat is collected, sent to a lab

45

When is the sweat test performed?

At 6 weeks of age

If a baby has scored in the top 1% of [IRT], hasn't been found to be homozygous for a CF mutation

46

Carrier testing offered by doctors in Victoria

$200
12 mutations, tested from a cheek swab
Can test for more mutations

47

VCCS reproductive carrier screen

Includes CF, fragile X syndrome, PKU
Costs $385
From a blood sample

48

Options for carrier parents

Pre-implantation genetic diagnosis
Implant unaffected embryos