13-10-22 – Genetics in Cardiology Flashcards
Learning outcomes
- Analyse a family tree to identify mode of inheritance
- Discriminate between locus heterogeneity and allelic heterogeneity
- Give examples of disorders arising from changes in gene dosage
- Define genetic penetrance
- Evaluate the pros and cons of cascade and population screening
What are 5 facial features of down syndrome?
- Facial features of down syndrome
1) Flattened face, especially in the bridge of the nose
2) Almond shaped eyes that slant up
3) Short neck
4) Thin upper lip
5) Smooth philtrum (area between nose and mouth
What % of people with down syndrome have heart defects?
What 4 heart defects can people with down syndrome commonly have?
- Around 50% of people born with down syndrome have heart defects
- 4 heart defects people with down syndrome commonly have:
1) Atrioventricular septal defect
2) Ventricular septal defect
3) Atrial septal defect
4) Patent ductus arteriosus
In cytogenetics, what alteration of chromosomes do we see in down syndrome?
What 2 ways can this appear?
What can this be used for?
- In cytogenetics (chromosome analysis technique), those with down syndrome have trisomy 21, meaning there are 3 copies of chromosome 21
- Sometimes, there is only a partial 3rd chromosome 21 that still results in down syndrome heart problems
- This can be used to find the particular genes that result in heart problems in those with down syndrome
What is a derivative chromosome?
What are the 2 ways they are generated?
What can fluorescent in situ hybridisation be used for?
How does gene location differ on normal and derivative chromosome 21?
What is the DS-CHD region? What happens if duplication is present in this region?
- A derivative chromosome is a structurally rearranged chromosome
- They are generated either by a chromosome rearrangement involving two or more chromosomes or by multiple chromosome aberrations within a single chromosome
- Fluorescent in situ hybridisation can be used to see how gene locations differ on a normal chromosome 21 and a derivative chromosome 21 associated with down syndrome
- It was found that genes next to each other on the normal chromosome 21 were far apart on the derivative chromosome 21
- The DS-CHD region is a region on the derivative chromosome 21
- If duplication is In this region, this leads to congenital heart disease in those with down syndrome
How were the genes associated with heart problems in down syndrome found?
What 2 genes were found to cause problems?
What 2 things were these 2 genes associated with?
How were the heart problems confirmed in mice?
- The genes associated with heart problems in down syndrome were found using mice
- They were found to be an overexpression of DSCAM and COL6A2
- These 2 genes were found to be associated with Cell migration and Cell adhesion (how cells stick to each other)
- These heart problems were confirmed in mice using agitated saline bubble echocardiography
- Bubbles of saline were injected into the hearts of the mice, and if the bubble appeared very quickly on the other side of the heart, it was clear that there was a heart defect
What is Catch 22 syndrome?
What is DiGeorge syndrome?
What 5 abnormalities is it associated with?
- Catch 22 syndrome is 22q11.2 deletion syndrome
- DiGeorge syndrome should be seen as the severe end of the clinical spectrum embraced by the acronym CATCH 22 syndrome
- Catch 22 syndrome is associated with abnormalities:
1) Cardiac abnormalities
* Interruption of aortic arch
* Tetralogy of Fallot
* Ventricular septal defect
2) Abnormal Facies
3) Thymic aplasia (underdeveloped or absent thymus)
4) Cleft palate
5) Hypothyroidism
What is the deletion associated with DiGeorge syndrome?
Why is this region more likely to be deleted?
What 2 ways can this deletion occur?
- The deletion associated with DiGeorge syndrome is 22q11.2 deletion
- This section is more likely to be deleted as it appears between 2 repeated regions
- This deletion can be:
1) Interchromosomal (2 separate strands of DNA)
* There are Repeated segments (A and D on the diagram) that are replicated in meiosis
* Due to being repeated segments, they align incorrectly with the other strand of DNA (as lots of recombination is happing during meiosis)
* This can lead to the 22q11.2 part of the chromosome being deleted
2) Intrachromosomal (same strand of DNA)
* Can end as ring chromosome, which can’t sustain life, or as deleted 22q11.2 gene
How are those with DiGeorge syndrome affected when there is no deletion?
Where is this also present?
What is a transcription factor?
What is the TBX1 gene?
What does it affect?
What is a person’s genotype?
What is a phenotype?
How does TBX1 gene affect the formation of the 4th pharyngeal arch arteries in mice?
- In those with DiGeorge syndrome without deletion, there is a mutation in the TBX1 gene, which is also present in those with the deletion
- Transcription factors are proteins that binds to specific sequences of DNA, which effects the transcription of the adjacent gene
- The TBX1 gene is a transcription factor which likely binds to specific genes responsible for the development of the heart
- Since it is a transcription factor, it can also affect other transcription pathways, not just heart development (as seen from the multiple defects in Catch 22)
- A person’s genotype is their unique sequence of DNA, more specifically, this term is used to refer to the two alleles a person has inherited for a particular gene
- Phenotype is the detectable expression of this genotype – a patient’s clinical presentation.
- How TBX1 gene affects the formation of the 4th pharyngeal arch arteries in mice:
1) 2 good copies (+/+) – normal formation
2) 1 good copy, 1 abnormal copy (+/-) – abnormal formation (heart problem)
3) 2 abnormal copies (-/-) – abnormal formation
4) 5x normal (over exaggeration) – abnormal formation
How do those with DiGeorge syndrome with no deletion appear?
- Those with DiGeorge syndrome with no deletion still appear with some morphological features
Since TBX1 is a transcription factor what will it often work with?
How does TBX1 function at normal dose?
- Since TBX1 is a transcription factor, it probable doesn’t work alone, and has other partners
- At a normal dose of TBX1, it can find its partner, bind to DNA, and function as a transcription factor
- At low doses of TBX1, it can struggle to find its partners
- At high doses of TBX1, the system is overwhelmed, TBX1 can partner with the wrong factor, and the wrong factors can bind to DNA
How is a long QT interval on an ECG classified?
What causes this?
What channels lead to depolarisation and repolarisation?
What channels cause a longer QT interval?
What is this an example of?
- A long QT on an ECG is classified as exceeding the 99th percentile values
- A long QT interval is due to a delay in repolarisation
- Depolarisation occurs when the sodium channels open and sodium ions move in to the cell
- Repolarisation occurs when the potassium channels open and potassium ions move out of the cell
- Mutations in multiple different sodium and potassium channel genes is the cause of a lengthened QT interval in 60 – 70% of cases
- This is an example of locus heterogeneity, where mutations in different places can lead to the same phenotype
What are the loss of function mutations associated with a long QT interval?
Where can these mutations be found?
What is this an example of?
How do these mutations affect the functioning of K+ channels?
How does this affect repolarisation?
- The loss of function mutations associated with a long QT interval are to do with the KCNQ1 K+ channels
- The mutations can be found in many different places along the channels
- This is an example of allelic heterogeneity, where many different mutations in the same gene cause the same disease
- These mutations lead to the channels not being able to open very well
- This leads to not much potassium being able to move out of the cell, making it hard to repolarise the membrane, which creates a longer QT interval
What are the gain of function mutations associated with a long QT interval?
Where can these mutations be found?
How do these mutations affect the functioning of Na+ channels?
How does this affect repolarisation?
- The gain of function mutations associated with a long QT interval are to do with the SCN5A Na+ sodium channel
- These mutations are generally found in 1 place (red dot along the diagram)
- These mutations lead to the Na+ channels staying open
- This results in higher/constant depolarisation, which makes it hard for repolarisation to occur, leading to a longer QT interval
Why is it important to know the mutation that leads to a longer QT interval?
- It is important to know the mutation that leads to the longer QT interval as different medication needs to be used treat different mutations
- Beta blockers can’t be used to treat C-loop mutations of the KCNQ1 K+ channel
What is familial hypercholesterolaemia (FH)?
What 2 things can FH present with?
What is a 1st and 2nd degree relative?
What is the Simon Broome criteria used for?
Describe the Simon Broome Criteria.
- Familial hypercholesterolaemia (FH) is an inherited condition, where an altered gene causes high serum LDL cholesterol (>7.5mM total cholesterol)
- FH can present with xanthoma (raised yellowish lesions) and atherosclerosis
- A 1st degree relative is one which you share 50% of your NDA with e.g siblings, parents, children
- A 2nd degree relative is one which you share 25% of your DNA with e.g grandparents, aunts, uncles
- The Simon Broome criteria is used to differentiate between definite FH or possible FH
What is a compound heterozygote?
How are compound heterozygotes formed?
What condition can this occur in?
How does this affect the phenotype?
- A compound heterozygote is the presence of two different mutant alleles at a particular gene locus (fixed position on the chromosomes where a particular gene is located), one on each chromosome of a pair
- Compound heterozygotes can occur when 2 individuals that have the same condition caused by different mutations of genes have a child and pass on both these mutations to the child
- This can occur in familial hypercholesterolaemia
- This leads to the phenotype being much more severe
How is LDL cholesterol removed from our blood in 3 steps?
What 4 different types of mutations can occur in this LDL receptor pathway that can lead to FH?
- LDL is removed through the LDL receptor pathway:
1) LDL receptor binds LDL
2) The receptor with bound LDL is then brought into the cell and the LDL is broken down
3) The receptor can either be recycled or degraded - Mutations that can occur in the LDL receptor pathway that lead to FH:
1) LDL receptor >1000 different mutations
* Not synthesised
* Not transported properly to cell membrane
* Not bind LDL properly
* Not internalised properly
* Not recycled properly
2) ApoB - Arg3500Gln
3) LDL receptor associated protein - null mutations
4) PCSK9 - Asp374Ty
What medication can be used to treat FH?
Why can’t this always be used?
How do mutations on different sides of the PCSK9 gene affect LDL cholesterol levels?
What medication can be used to treat this?
- FH can be treated using statins
- Statins may not always be able to be used because of side effects
- Mutations on one side of the PCSK9 gene lead to PCSK9 being produced, which breaks down LDL receptors and raises LDL cholesterol levels
- Mutations on the other side of the PCSK9 gene lead to PCSK9 not being produced, meaning LDL receptors are recycled and LDL cholesterol levels are lowered
- Inclisiran is a drug that can be used to treat this
Describe the 5 steps in the mechanism of how Inclisiran works to reduce blood LDL cholesterol levels
- Steps in the mechanism of how Inclisiran works to reduce blood LDL cholesterol levels:
1) A small portion of PCSK9 gene is made
2) It is released into liver cells as double stranded DNA
3) Our natural processes due to viruses is to make an RNA version to induce silencing processes
4) The Antisense strand produced can bind on the normal PCSK9 gene and target it for degradation
5) Reduced PCSK9 gene results in increase LDL receptors recycling to the surface of liver cells, which increases the clearance of circulating LDL, and lowers blood LDL levels
What is cascade testing?
- Cascade testing is when we know an individual has a genetic disorder, and we go to screen the family
