Genetics in Cardiology Flashcards
What percentage of people with Down’s Syndrome also have heart defects?
~50%
What are the common cardiac defects associated with Down’s Syndrome?
- Atrioventricular septal defect
- Ventricular septal defect
- Atrial septal defect
- Patent ductus arteriosus
- Setpal defects - large hole which affects the entire septum and therefore all chambers.
- Problems are also caused because DS patients with congenital heart defects tend to have only a single valve causing major problems.
- Oxygenated blood and deoxygenated blood mix, putting extra pressure on the heart.
Describe the chromosomal changes which indicate congenital heart defects associated with Down’s Syndrome.
- Not every patient has 3 copies of the ENTIRE chromosome 21 - they can have 3 copies of part of the chromosome.
- Use FISH to map the specific chromosomes and pinpoint where the rearrangements are.
- Many rearrangements and duplications - larger G band sizes.
- Some banding can be rearranged and duplicated / added onto the p arm.
- Able to map which regions common to partial trisomy 21 with congenital heart defects. Then able to map the specific genes to the region.
What are the roles of DSCAM and COL6A2 in Down’s Syndrome?
- Overexpression of DSCAM and COL6A2 gives phenotype of cardiac defect in child with DS.
- These cause defects in cell migration and cell adhesion.
- DSCAM = Down’s Syndrome Cell Adhesion Molecule.
- COL6A2 = Collagen type VI alpha 2 chain.
What is 22Q11.2 deletion syndrome?
- ‘DiGeorge Syndrome’.
- Caused by deletion of a small segment of chromosome 22.
- Signs include:
- Cardiac abnormalities
- Abnormal faces (difficult to distinguish due to natural variation)
- Thymic aplasia
- Cleft palate
- Hypothyroidism
- Prognosis is good.
- One of the most common microdeletions.
- 1/4000 births.
- 25-30 genes.
Which cardiac abnormalities are common in patients with DiGeorge Sydrome?
- Interruption of aortic arch
- Tetralogy of Fallot
- Ventricular Septal Defect
Describe what happens to the heart in Tetralogy of Fallot.
- Deoxygenated blood that is returning to the heart from the body (SVC/IVC) is supposed to be re-oxygenated by the lungs via the pulmonary artery.
- Pulmonary stenosis prevents this.
- De-oxygenated blood is re-routed back to the body through the displaced aorta.
- This causes cyanosis in the tissue and this means the tissue can shut down the cells - the patient will become symptomatic with syncope.
- VSD causes mixing/shunting of the deoxygenated blood and oxygenated blood.
- RV hypertrophy occurs due to the pulmonary stenosis, and the force required to push the blood through the pulmonary valve into the pulmonary artery so that it can get to the lungs to become oxygenated.
Describe low copr repeats (LCR).
- Non-allelic homologous recombination.
- Mostly de novo rearrangements but can be inherited.
- Diversity of phenotype can mean non-diagnosis in a parent can be passed in autosomal dominant manner.
- In DiGeorge syndrome, LCR are separated by 3mb.
What happens in DiGeorge Syndrome without deletion?
Pleiotropic effects (one particular gene influencing several different tissues).
What percentage of the global population have hypertrophic cardiomyopathy?
~0.2%
What is the most common cause of sudden death in under 35s?
Hypertrophic cardiomyopathy
Describe the pathophysiology of hypertrophic cardiomyopathy.
- Both the septum and heart wall are thickened.
- Can be due to over exerting the heart, or can be a congenital condition.
- Phenotype:
- Increased muscle thickness.
- Disorganised myocytes.
- Fibrosis-scarring on cells.
- Autosomal dominant.
What gene defects are associated with hypertrophic cardiomyopathy?
- Defects in more than one gene can cause phenotype - locus heterogeneity.
- 11 or more genes.
- In 75% of cases, the beta myosin heavy chain or myosin binding protein C are implicated.
- No single mutation.
- Difficult to test for genetically.
What interventions can be carried out to prevent sudden death due to hypertrophic cardiomyopathy?
Implantable defibrillator is most effective as patients can go into cardiac arrest during exercise.
Describe long QT syndrome.
- Delay in repolarisation of the cardiac muscle after the AP has triggered.
- QT length has to have exceeded the 99th percentile values.
- Not necessarily associated with exercise.
- Can be excessive depolarisation or that the channels responsible for the depolarisation are not working correctly - channelopathy.
Describe loss of function mutations in long QT syndrome.
- In the KCNQ1 potassium channel.
- Dots represent the sites where mutations have been reported.
- Many different sites within the same protein, same gene - allelic heterogeneity.
- Majority of mutations are on the inside of the cell.
- Not enough potassium leaving the cell therefore there is delayed repolarisation.
Describe gain of function mutations in long QT syndrome.
- SCN5A sodium channel.
- Too much Na2+ as the channel remains open too long; initially causing increased constant depolarisation which makes it difficult to repolarise.
Describe the Simon Broome criteria for assessing risk of familial hypercholesterolaemia.
- 1st degree relative = parents, siblings, children.
- 2nd degree relative = grandparents, grandchildren, aunts, uncles, nephews, nieces.
Which genes are affected in familial hypercholesterolaemia?
- Mutations in LDL-receptor pathway:
- LDL receptor >1000 different mutations
- Not synthesised
- Not transported properly to the cell membrane
- Don’t bind LDL properly
- Not internalised properly
- Not recycled correctly
- ApoB - Arg3500Gin
- LDL receptor associated protein - null mutations
- PCSK9 - Asp374Tyr
- LDL receptor >1000 different mutations
