Genetics in the CVS

Question 1

What are common cardiac defects in Down Syndrome ?

Answer 1

AVSD
VSD
ASD
PDA

Question 2

What are the defective genes for cardiac disease in Down Syndrome ? What function are the genes associated with ?

Answer 2

DSCAM (overexpressed) and COL6A2 (deleted)

Associated with cell adhesion and migration

Question 3

Describe 22q11.2 deletion syndrome.

Answer 3

Also known as DiGeorge Syndrome, associated with:

• Cardiac abnormalities
• Abnormal faces
• Thymic aplasia
• Cleft palate
• Hypothyroidism

Question 4

What are common cardiac defects in 22q11.2 deletion syndrome ?

Answer 4

Interruption of aortic arch
TOF
VSD

Question 5

How does the deletion of part of the chromosome occur in 22q11.2 deletion syndrome ?

Answer 5

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).

Question 6

Can DiGeorge Syndrome occur without deletions ? In such a situation, what genetic changes are occurring ?

Answer 6

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.

Question 7

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) ?

Answer 7

TBX-1 is a transcription factor, so it’s necessary for the process of transcription.

Question 8

Why does under and over-expression of TBX-1 result in cardiac/vascular problems ?

Answer 8

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.

Question 9

Define pleiotropic effects, giving an example.

Answer 9

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

Question 10

What are the main phenotypic features of hypertrophic cardiomyopathy ?

Answer 10

• Increased muscle thickness
• Disorganised myocytes
• Fibrosis

Question 11

Define locus heterogeneity. Give an example of a defect associated with locus heterogeneity.

Answer 11

Defects in more than one gene can cause phenotype.

Hypertrophic cardiomyopathy, long QT syndrome have locus heterogeneity.

Question 12

What are possible defective genes in hypertrophic cardiomyopathy ?

Answer 12

Mutations in Beta myosin heavy chain or Myosin binding protein C.

Question 13

What is the right treatment for high risk hypertrophic cardiomyopathy patients ?

Answer 13

Implantable defibrillator

Question 14

Which imaging techniques can be used to detect a hypertrophic cardiomyopathy ?

Answer 14

ECG + Echo

Question 15

Is long QT syndrome associated with exercise ?

Answer 15

Not necessarily

Question 16

What symptoms is long QT potentially associated with ?

Answer 16

Sudden death

Question 17

What is the main problem in long QT syndromes ?

Answer 17

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).

Question 18

What genetic defects is the delay in repolariastion, in long QT syndrome, due to ?

Answer 18

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).

Question 19

What is the mode of inheritence of long QT syndrome ?

Answer 19

Autosomal dominant

Question 20

Define variant of unknown significance.

Answer 20

an allele, which has been identified through genetic testing, but whose significance to the function or health of an organism is not known

Question 21

Differentiate penetrance and variable expression.

Answer 21

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.

Question 22

Give an example of condition with variable expression.

Answer 22

Marfan’s

Question 23

Describe the effect of beta blocker treatment on long QT syndrome patients with, and without C loop mutations.

Answer 23

Patients with C loop - much reduced mortality, because beta blockers reduce depolarisation

Patient with non-C-loop - no effect on mortality

Question 24

What is the concentration of cholesterol above which one is considered to have hypercholesterolaemia ?

Answer 24

Total cholesterol > 7.5 mM

Question 25

What are possible consequences of hypercholesterolaemia ?

Answer 25

Atherosclerosis

Xanthomas

Question 26

Describe the Simon Broome criteria.

Answer 26

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

Question 27

Define compound heterozygous.

Give an example.

Answer 27

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

Question 28

What genes are affected in hypercholesterolaemia ? How do currrent drugs address this , and how can we improve hypercholesterolaemia treatment ?

Answer 28

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.

Question 29

Define cascade testing.

Answer 29

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.