Lecture 9 - Clinical Genetics

Question 1

What is the pattern of inheritance of CF?

Answer 1

Autosomal recessive

Question 2

Which ethnicity is most affected by CF?

Answer 2

Caucasian, mostly northern european

Question 3

What is the incidence of CF?

Answer 3

1 in 2500-3000

Question 4

Why is CF important?

Answer 4

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

Question 5

What is a possible selective advantage of heterozygotes for CF?

Answer 5

Postulated protection from cholera, typhus, asthma.

Question 6

Describe the interaction between Salmonella and CF

Answer 6

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

Question 7

In which ethnicities is CF prevalence very low?

Answer 7

Japanese population

Question 8

What is often seen in CF pedigrees?

Answer 8

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

Question 9

Describe the genotype-phenotype correlations in CF

Answer 9

Not as strong as one might think

• Pancreatic insufficiency in Class I-III mutations has strong correlation

Question 10

What are class I-III mutations usually correlated with?

Answer 10

• Pancreatic insufficiency; very strong correlation

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

Question 11

What are class IV-V mutations usually correlated with?

Answer 11

• Pancreatic Sufficiency (PS)

* Milder lung disease

Question 12

Describe the interaction of the R117H mutation and other genotypes

Answer 12

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

Question 13

Describe Steven’s genotype and phenotype

Answer 13

Homozygous F508del

Less severe phenotype than Sean

Question 14

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

Answer 14

Monozygotic twin studies

Question 15

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

Answer 15

50-50 genes and environment

Question 16

What is meconium ileus?

To what degree is it affected by genes and environment

Answer 16

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

Question 17

Why is it important to identify genetic modifiers of CF?

Answer 17

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

Question 18

How does one identify genetic modifiers of CF?

Answer 18

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

Question 19

What are GWAS?

What information can they deliver?

Answer 19

Genome wide association studies

1. Sequence entire genome
2. Look for:
   • Disease associated SNPs
   • Nondisease associated SNPs

Question 20

What are limitations of GWAS?

Answer 20

Need a large sample size

Question 21

What is EDNRA?

Answer 21

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

Question 22

What is MBL2?

Answer 22

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

Question 23

What is TGFB1?

Answer 23

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

Question 24

What are some genetic modifiers of lung disease in CF?

Answer 24

• TGFB1
• MBL2
• EDNRA

Question 25

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

Answer 25

MSRA

Question 26

What is MSRA?

Answer 26

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

Question 27

What is TCF7L2?

Answer 27

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

Question 28

What are some environmental modifiers of CF?

Answer 28

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

Question 29

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

Answer 29

* Newborn screening * Cascade testing * Population carrier testing

Question 30

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

Answer 30

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

Question 31

Describe cascade testing

Answer 31

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

Question 32

Describe population carrier screening

Answer 32

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

Question 33

Why is a sweat test carried out?

Answer 33

* In heterozygous newborns | * determines whether the baby requires treatment

Question 34

What is PGD?

Answer 34

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

Question 35

Describe candidate gene association

Answer 35

# Choose a gene as a candidate * looks at the gene in two people | * compare the results

Question 36

What is IRT?

Answer 36

Immunoreactive Trypsinogen

Question 37

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

Answer 37

The baby may or may not have CF | Further monitoring required

Question 38

Which class of mutation is F508del?

Answer 38

Class II

Question 39

Which parameter is being tested on the Guthrie card?

Answer 39

IRT levels in baby's serum

Question 40

Compare the implication of the various results of the sweat test

Answer 40

>60 mmol/L → child has CF 30-60 mmol/L → equivocal result <30 mmol /M → child does not have disease but it a carrier