Lecture 9 - Clinical Genetics Flashcards
What is the pattern of inheritance of CF?
Autosomal recessive
Which ethnicity is most affected by CF?
Caucasian, mostly northern european
What is the incidence of CF?
1 in 2500-3000
Why is CF important?
Most common single genetic condition causing premature death in children of northern European descent
What is a possible selective advantage of heterozygotes for CF?
Postulated protection from cholera, typhus, asthma.
Describe the interaction between Salmonella and CF
The CF bacterium uses CFTR protein to gain entry to gut epithelial cells
In which ethnicities is CF prevalence very low?
Japanese population
What is often seen in CF pedigrees?
Absence of prior family history
‘suddenly appears’
This is because it is autosomal recessive
Describe the genotype-phenotype correlations in CF
Not as strong as one might think
• Pancreatic insufficiency in Class I-III mutations has strong correlation
What are class I-III mutations usually correlated with?
• Pancreatic insufficiency; very strong correlation
Also, to a certain degree,
• More severe lung disease
What are class IV-V mutations usually correlated with?
- Pancreatic Sufficiency (PS)
* Milder lung disease
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
Describe Steven’s genotype and phenotype
Homozygous F508del
Less severe phenotype than Sean
What is the best way to do studies that want to determine environmental and genetic modifiers?
Monozygotic twin studies
What are the effects of genes and environment on lung function in CF?
50-50 genes and environment
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
Why is it important to identify genetic modifiers of CF?
• new targets for therapies
• understanding of disease variability
etc.
How does one identify genetic modifiers of CF?
- Linkage studies: track markers with specific phenotypes
- Candidate gene association
- Genome wide association studies
What are GWAS?
What information can they deliver?
Genome wide association studies
- Sequence entire genome
- Look for:
• Disease associated SNPs
• Nondisease associated SNPs
What are limitations of GWAS?
Need a large sample size
What is EDNRA?
Encodes Endothelin receptor - A
Normally:
- Endothelin binds EDNRA
- 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
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
What is TGFB1?
Gene encoding TGF-B
• genetic modifier of lung disease in CF
• role in regulating inflammation and tissue remodelling
What are some genetic modifiers of lung disease in CF?
- TGFB1
- MBL2
- EDNRA
What is an example of a genetic modifier of intestinal obstruction in CF?
MSRA
What is MSRA?
Encodes methionine sulphide reductase
• role in modifying intestinal enzymes
• variants may alter digestion
What is TCF7L2?
- encodes transcription factor 7-like 2
- genetic modifier of Diabetes in CF
- role in proliferation of B cells in pancreatic islets
What are some environmental modifiers of CF?
- being female: diet and therapy adherence
- lower socio-economic
- tobacco smoke exposure
- infectious exposure
- disease self-management
What are the various types of screening carried out for CF?
- Newborn screening
- Cascade testing
- Population carrier testing
Describe the various stages of newborn screening
Why is this testing carried out?
This is carried out to identify babies at risk of CF
- IRT test in heel prick test onto Guthrie card
• Elevated IRT → further testing - DNA testing; 12 mutation panel
• two mutations → baby has CF
• heterozygous for mutation → need further testing
• no mutations → baby doesn’t have CF - 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
Describe cascade testing
- Identification of carriers in wider family of the affected child
- Only 12% opt-in
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
Why is a sweat test carried out?
- In heterozygous newborns
* determines whether the baby requires treatment
What is PGD?
Pre-implantation genetic diagnosis
• During IVF
• Cells removed; unaffected embryos are implanted
Describe candidate gene association
Choose a gene as a candidate
- looks at the gene in two people
* compare the results
What is IRT?
Immunoreactive Trypsinogen
What happens if there is an ‘equivocal result’ from the sweat test?
The baby may or may not have CF
Further monitoring required
Which class of mutation is F508del?
Class II
Which parameter is being tested on the Guthrie card?
IRT levels in baby’s serum
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
