Cardiovascular genetics

Question 1

Common cardiac disease with Down’s syndrome

Answer 1

Atrio-ventricular septal defects

Question 2

Common cardiac disease with Turner’s syndrome

Answer 2

Coarctation of aorta and bicuspid aortic valve disease

Question 3

Common cardiac defect with missing pieces of chromosomal 22

Answer 3

Conotruncal defects (tetralogy of Fallot, DORV, TGA, TA)

Question 4

Monogenic disorder

Answer 4

Mendelian disorders (dominant, recessive etc)

Question 5

Polygenic disorders

Answer 5

Multifactorial

Question 6

Examples of monogenic disorders

Answer 6

• Sickle cell disorder - single base substitution causing GLU to be replaced with VAL
• Cystic fibrosis - single gene mutated

Question 7

Example of heterogenous disorders

Answer 7

Hypertrophic cardiomyopathy

Question 8

Common cardiomyopathies

Answer 8

Hypertrophic cardiomyopathy
Dilated cardiomyopathy
Arrythmogenic cardiomyopathy

Question 9

Hypertrophic cardiomyopathy

Answer 9

• Thickened heart muscle, not due to loading
• Can present with sudden death
• Many genes involved
• Most families have monogenic cause
• AD inheritance
• Screen first degree relatives

Question 10

Electrical conducting tissue disorders

Answer 10

• Long QT syndrome
• Catecholaminergic polymorphic ventricular tachycardia
• Brugada syndrome
• Caused by mutations in genes coding for protein component of channel

Question 11

Circulation disorders

Answer 11

• Coronary arteries - familial hypercholesterolaemia

- Aorta - aortopathies - TAAD

Question 12

Hypercholesterolaemia

Answer 12

• Raised cholesterol
• Premature coronary artery disease
• Diagnosed primarily with clinical scres
• Gene testing to identify relatives at risk
• Heterogenous - LDLR, APOB, PCSK9 - all these genes normally clear LDL from circulation
• LDL receptors in liver clears LDL from circulation

Question 13

Genes for FH

Answer 13

LDLR, APOB, PCSK9, LDLRAP1

Question 14

What is VUS and how do we deal with it?

Answer 14

Variant of uncertain significance - not enough information to conclude
Test relatives with most significant phenotype. If two relatives with same condition share same variant, pathogenicity is supported

Question 15

Marfan syndrome

Answer 15

• High risk of aortic dissection - once diagnosed, screening is diagnosed so treatment can be implemented
• FBN1 gene
• Features overlap with other aortic conditions so consider panel test
• Symptoms: tall and slender, long arms and legs, high/arched palate, crowded teeth, heart murmurs, flat feet
• Marfan syndrome is disorder of connective tissues

Question 16

What is used to collate panels and what summarises eligibility?

Answer 16

Panel App and test directory

Question 17

Polygenic inheritance

Answer 17

• Expression of phenotype determined by many genes at different loci, each with small additive effect
• No one gene is dominant or recessive
• Many human characteristics show continuous distribution in population
• Spread of distribution about mean determined by SD

Question 18

What is threshold effect?

Answer 18

Condition occurs when threshold exceeded

Question 19

What is relative-curve shift?

Answer 19

Higher chance that threshold reached

Question 20

What is APOB?

Answer 20

On gene 2, used in panel testing

Question 21

Main treatment of FH

Answer 21

Statins

Question 22

Why are statins bad?

Answer 22

• Statin side effect = myopathy and muscle pain

- SNPs in SCLO1B1 associated with risk of myopathy - pt has these SNPs then lower dose of statin used

Question 23

Polygenic scores in FH

Answer 23

• Can be calculated if no pathogenic cause
• Analyse common single nucleotide polymorphisms which contribute to raised cholesterol
• Those with high score more likely to have polygenic cause

Question 24

Clinical score for Marfan’s

Answer 24

Ghent

Question 25

Clinical score for FH

Answer 25

Dutch lipid score