Genetics in the CVS Flashcards
What are common cardiac defects in Down Syndrome ?
AVSD
VSD
ASD
PDA
What are the defective genes for cardiac disease in Down Syndrome ? What function are the genes associated with ?
DSCAM (overexpressed) and COL6A2 (deleted)
Associated with cell adhesion and migration
Describe 22q11.2 deletion syndrome.
Also known as DiGeorge Syndrome, associated with:
- Cardiac abnormalities
- Abnormal faces
- Thymic aplasia
- Cleft palate
- Hypothyroidism
What are common cardiac defects in 22q11.2 deletion syndrome ?
Interruption of aortic arch
TOF
VSD
How does the deletion of part of the chromosome occur in 22q11.2 deletion syndrome ?
LCR22 is a repeated element which is separated by 3 MB. De novo rearrangements may result in deletion or duplication of that region (but can be inherited).
Can DiGeorge Syndrome occur without deletions ? In such a situation, what genetic changes are occurring ?
Yes!
Mutations in TBX-1 (located in 22q11.2), which can be frameshift non-sense mutations (i.e. deletions), whilst others can be missense mutations (i.e. base pair substitution).
As a result, either under-expression (either one or both copies disrupted) or over-expression of the TBX-1 gene will result in heart/vascular defects.
How doe the mutation of TBX-1 result in features of the 22q11.2 deletion syndrome (i.e. what is the function of TBX-1) ?
TBX-1 is a transcription factor, so it’s necessary for the process of transcription.
Why does under and over-expression of TBX-1 result in cardiac/vascular problems ?
Because TBX-1 works as a dimer so under-expression of it would result in difficulty finding its partner, and thus inability to bind to DNA.
Over-expression results in artificial dimerisation (i.e. it sticks to another molecule of itself) which results in no transcription being generated.
Define pleiotropic effects, giving an example.
One gene influences several seemingly unrelated traits (e.g. muscles and bones of face and neck, as well as larger arteries of the heart and low calcium).
For instance TBX-1
What are the main phenotypic features of hypertrophic cardiomyopathy ?
- Increased muscle thickness
- Disorganised myocytes
- Fibrosis
Define locus heterogeneity. Give an example of a defect associated with locus heterogeneity.
Defects in more than one gene can cause phenotype.
Hypertrophic cardiomyopathy, long QT syndrome have locus heterogeneity.
What are possible defective genes in hypertrophic cardiomyopathy ?
Mutations in Beta myosin heavy chain or Myosin binding protein C.
What is the right treatment for high risk hypertrophic cardiomyopathy patients ?
Implantable defibrillator
Which imaging techniques can be used to detect a hypertrophic cardiomyopathy ?
ECG + Echo
Is long QT syndrome associated with exercise ?
Not necessarily
What symptoms is long QT potentially associated with ?
Sudden death
What is the main problem in long QT syndromes ?
Delays in repolarisation, either due to excessive polarisation or just slow repolarisation due to channelopathies (in sodium and potassium channels, for instance not enough potassium leaving the cell).
What genetic defects is the delay in repolariastion, in long QT syndrome, due to ?
Both loss (i.e. mutations in K channel, not enough potassium leaving channel due to defect) and gain of function/activating (i.e. mutation in Na channel, too much sodium coming in due to defect) mutations.
If different mutations cause this within the same receptor (and thus, within the same gene) it’s allelic heterogeneity (same channel, different mutations)
Different mutations affecting different receptors and resulting in this condition, it’s locus heterogeneity (different genes can cause it).
What is the mode of inheritence of long QT syndrome ?
Autosomal dominant
Define variant of unknown significance.
an allele, which has been identified through genetic testing, but whose significance to the function or health of an organism is not known
Differentiate penetrance and variable expression.
Penetrance refers to having the phenotype or not so “incomplete” or ‘reduced’ penetrance means the genetic trait is expressed in only part of the population.
Variable expression, on the other hand, means all affected have the disease but to different severities.
Give an example of condition with variable expression.
Marfan’s
Describe the effect of beta blocker treatment on long QT syndrome patients with, and without C loop mutations.
Patients with C loop - much reduced mortality, because beta blockers reduce depolarisation
Patient with non-C-loop - no effect on mortality
What is the concentration of cholesterol above which one is considered to have hypercholesterolaemia ?
Total cholesterol > 7.5 mM
What are possible consequences of hypercholesterolaemia ?
Atherosclerosis
Xanthomas
Describe the Simon Broome criteria.
Definite FH: Cholesterol > 6.7 mM in children or > 7.5 in adults + either
1) first or second degree relative or tendon xanthoma
OR
2) DNA confirmation
Possible FH: Cholesterol > 6.7 mM in children or > 7.5 in adults + either
1) Family history of MI (<50 years in second degree relatives and < 60 years in first degree relatives)
2) Family history of cholesterol > 7.5 mM in first or second degree relative
Define compound heterozygous.
Give an example.
Organism has two recessive alleles for the same gene, but with those two alleles being different from each other (for example, both alleles might be mutated but at different locations).
Example: Cholesterol levels
What genes are affected in hypercholesterolaemia ? How do currrent drugs address this , and how can we improve hypercholesterolaemia treatment ?
Mutations in the LDL receptor:
- Not synthesised
- Not transported to cell membrane
- Not bind LDL properly
- Not internalised properly
- Not recycled properly
Including ApoB, LDL receptor associated protein (null mutation), PCSK9
Statins reduce cholesterol synthesis. Through drugs which increase LDL-R synthesis.
Define cascade testing.
A systematic process for the identification of individuals at risk for a hereditary condition.
Start with identifying someone with the condition and then extending genetic testing to biological relatives.
Repeat this process again.
