Genetics in Cardiology

Question 1

What are the common defects in Down Syndrome?

Answer 1

1) Atrioventricular septal defect
2) Ventricular septal defect
3) Atrial septal defect
4) Patent ductus arteriosus

Question 2

Changes in what gene dosages cause cardiac defects? and why?

Answer 2

Over-expression of DSCAM and COL6A2 as these are important in heart development as there are involved in cell migration and cell adhesion.

Question 3

What is 22q11.2 deletion syndrome?

Answer 3

DiGeorge syndrome. Has good prognosis

Question 4

What are the symptoms of 22q11.2 deletion syndrome?

Answer 4

• Cardiac abnormalities,
• Abnormal facial features
• Thymic aplasia
• Cleft palate
• Hypothyroidism (CATCH-22)

Question 5

What are the cardiac abnormalities of 22q11.2 deletion syndrome?

Answer 5

• Tetralogy of Fallot,
• Interruption of aortic arch
• Ventricular septal defect

Question 6

Describe the types of mutations that can arise in TBX1 and what this results in?

Answer 6

Deletion - Nonsense or missense (change in amino acid) mutation. Normally TBX1 acts as transcription factor allowing for production of mRNA. Dose dependant mutation means either low or high dosages cause it not to function properly

Question 7

What is the difference between LQTS and hypertrophic cardiomyopathy but what do they both result in?

Answer 7

LQTS - Takes longer for heart to repolarise between beats.

HC - Abnormally thick heart muscle.

Both result in sudden cardiac death

Question 8

Define genetic penetrance

Answer 8

Proportion of people with genetic change that exhibit signs and symptoms of genetic disorder

Question 9

What is locus heterogenity?

Answer 9

Disease may be cause by mutations in one of several genes

Question 10

Describe features of autosomal dominant

Answer 10

• Disease seen in all generations.
• 50% risk of inheriting it.
• Males and females equally effected

Question 11

Describe features of autosomal recessive

Answer 11

• One generation affected.
• 25% risk of inheritance (1 in 4).
• Increased risk in consanguineous families

Question 12

Define allelic heterogenity

Answer 12

Different mutations in the same gene can cause the same disease

Question 13

Why is it important to identify mutations?

Answer 13

Depending on the mutation, it can effect how a patient will respond to treatment. Some mutations respond to certain treatments better than other.

Question 14

What is familial hypercholesterolemia?

Answer 14

High concentration of serum LDL cholesterol caused by inherited mutations.

Question 15

What can occur due to FH

Answer 15

Xanthoma and atherosclerosis - Increased risk of heart disease

Question 16

How much DNA do you share with 1st and 2nd degree relatives?

Answer 16

1st - 50%, eg, Parents, siblings, children.

2nd Degree - 25% eg, aunts or uncles, grandparents.

Question 17

What is compound heterozygote

Answer 17

condition of having two or more heterogeneous recessive alleles at a particular locus

Question 18

What can occur as a result of a mutation in the LDL receptor pathway?

Answer 18

Ldl receptor:

• Not synchronised
• Not transported to membrane,
• Not binding to LDL properly,
• Not internalised properly,
• Not recycled properly.

Question 19

A mutation in what gene can lead to changes in LDL?

Answer 19

PCSK9 gene:

Gain of function - high LDL-c,
Loss of function - Low LDL-c

Question 20

What happens in the liver in the presence of inclisiran?

Answer 20

PCSK9 is not produced so LDL receptors are not broken down and LDL can be removed. Promising treatment

Question 21

What is cascade testing?

Answer 21

If family member has a FH gene mutation then screen biological family members incase they have it too.

Question 22

What are the pros and cons of cascade testing vs whole population testing

Answer 22

CT - All family members who may be at risk are screen = early intervention however one family member first has to be symptomatic for them to be screened.

WP - Everyone gets tested but as there is 1 in 500 chance of having FH then it isn’t hugely efficient.