Lecture 9 - Clinical Genetics Flashcards Preview

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Flashcards in Lecture 9 - Clinical Genetics Deck (40):
1

What is the pattern of inheritance of CF?

Autosomal recessive

2

Which ethnicity is most affected by CF?

Caucasian, mostly northern european

3

What is the incidence of CF?

1 in 2500-3000

4

Why is CF important?

Most common single genetic condition causing premature death in children of northern European descent

5

What is a possible selective advantage of heterozygotes for CF?

Postulated protection from cholera, typhus, asthma.

6

Describe the interaction between Salmonella and CF

The CF bacterium uses CFTR protein to gain entry to gut epithelial cells

7

In which ethnicities is CF prevalence very low?

Japanese population

8

What is often seen in CF pedigrees?

Absence of prior family history
'suddenly appears'
This is because it is autosomal recessive

9

Describe the genotype-phenotype correlations in CF

Not as strong as one might think
• Pancreatic insufficiency in Class I-III mutations has strong correlation

10

What are class I-III mutations usually correlated with?

• Pancreatic insufficiency; very strong correlation

Also, to a certain degree,
• More severe lung disease

11

What are class IV-V mutations usually correlated with?

• Pancreatic Sufficiency (PS)
• Milder lung disease

12

Describe the interaction of the R117H mutation and other genotypes

Depending on the n° of T's in cis to this mutation, the clinical penetrance is variable
R117H + 5T: will likely have disease causing mutation
R117H + 7T: unlikely to be a disease causing mutation
R117H + 9T: highly unlikely to act as a disease causing mutation

13

Describe Steven's genotype and phenotype

Homozygous F508del
Less severe phenotype than Sean

14

What is the best way to do studies that want to determine environmental and genetic modifiers?

Monozygotic twin studies

15

What are the effects of genes and environment on lung function in CF?

50-50 genes and environment

16

What is meconium ileus?
To what degree is it affected by genes and environment

• Blockage in ileum of babies in utero by sticky, black faeces
• almost completely determined by genes

17

Why is it important to identify genetic modifiers of CF?

• new targets for therapies
• understanding of disease variability
etc.

18

How does one identify genetic modifiers of CF?

• Linkage studies: track markers with specific phenotypes
• Candidate gene association
• Genome wide association studies

19

What are GWAS?

What information can they deliver?

Genome wide association studies

1. Sequence entire genome

2. Look for:
• Disease associated SNPs
• Nondisease associated SNPs

20

What are limitations of GWAS?

Need a large sample size

21

What is EDNRA?

Encodes Endothelin receptor - A

Normally:
1. Endothelin binds EDNRA
2. Induction of vasoconstriction and bronchoconstriction

If there is a variation in this receptor, they may be decreased constriction in the lungs; thus, less severe lung disease.

• A genetic modifier of lung disease in CF

22

What is MBL2?

Encodes mannose binding lectin
• role in innate immunity (in lungs)
• important for P. aeruginosa immunity
• genetic modifier of lung disease in CF

23

What is TGFB1?

Gene encoding TGF-B
• genetic modifier of lung disease in CF
• role in regulating inflammation and tissue remodelling

24

What are some genetic modifiers of lung disease in CF?

• TGFB1
• MBL2
• EDNRA

25

What is an example of a genetic modifier of intestinal obstruction in CF?

MSRA

26

What is MSRA?

Encodes methionine sulphide reductase
• role in modifying intestinal enzymes
• variants may alter digestion

27

What is TCF7L2?

• encodes transcription factor 7-like 2
• genetic modifier of Diabetes in CF
• role in proliferation of B cells in pancreatic islets

28

What are some environmental modifiers of CF?

• being female: diet and therapy adherence
• lower socio-economic
• tobacco smoke exposure
• infectious exposure
• disease self-management

29

What are the various types of screening carried out for CF?

• Newborn screening
• Cascade testing
• Population carrier testing

30

Describe the various stages of newborn screening
Why is this testing carried out?

This is carried out to identify babies at risk of CF

1. IRT test in heel prick test onto Guthrie card
• Elevated IRT → further testing

2. DNA testing; 12 mutation panel
• two mutations → baby has CF
• heterozygous for mutation → need further testing
• no mutations → baby doesn't have CF

3. Sweat test
• elevated Cl- and Na+ in sweat → baby has CF
• equivocal result → child may / may not have CF
• normal sweat → normal CF, but baby is a carrier

31

Describe cascade testing

• Identification of carriers in wider family of the affected child
• Only 12% opt-in

32

Describe population carrier screening

• Identification of carriers in the general population
• Screening of pregnant couples etc.
• Very expensive
• Ethical issues
• Overseas companies offering this service also

33

Why is a sweat test carried out?

• In heterozygous newborns
• determines whether the baby requires treatment

34

What is PGD?

Pre-implantation genetic diagnosis
• During IVF
• Cells removed; unaffected embryos are implanted

35

Describe candidate gene association

Choose a gene as a candidate

• looks at the gene in two people
• compare the results

36

What is IRT?

Immunoreactive Trypsinogen

37

What happens if there is an 'equivocal result' from the sweat test?

The baby may or may not have CF
Further monitoring required

38

Which class of mutation is F508del?

Class II

39

Which parameter is being tested on the Guthrie card?

IRT levels in baby's serum

40

Compare the implication of the various results of the sweat test

>60 mmol/L → child has CF

30-60 mmol/L → equivocal result

<30 mmol /M → child does not have disease but it a carrier