cardiovascular genetics

Question 1

how many deaths are there from CV diseases a year?

Answer 1

160,000

Question 2

how many deaths are there per year from coronary heart disease?

Answer 2

73,000

Question 3

what are coronary heart disease deaths associated with?

Answer 3

deprivation

Question 4

congenital heart disease?

Answer 4

12 babies diagnosed per day and more later in life

Question 5

inherited cardiac conditions

Answer 5

12 young people under 35 die from these a week

Question 6

causes of cardiovascular disorders

Answer 6

sedentary lifestyle
smoking
diet
genetics - structural variation or single nucleotide variation
epigenetic variation

Question 7

chromosomal causes of CV disorders

Answer 7

trisomy 21
turner syndrome
DiGeorge syndrome

Question 8

downs syndrome and heart disease

Answer 8

high rate of congenital heart disease

most common = atrioventricular septal defect

Question 9

turner syndrome and heart disease

Answer 9

high rate of congenital heart disease

left ventricular outflow tract obstruction, coarctation, aortic dissection and dilatations

Question 10

DiGeorge syndrome and heart disease

Answer 10

congenital heart defects
teraology of fallot
transposition of the great arteries
trucus arteriosus

Question 11

chromosome tests

Answer 11

array CGH replacing standard karyotyping

less labour intensive and greater detail

Question 12

when are chromosome tests done?

Answer 12

when a recognised chromosomal disorder or syndrome suspected

considered when congenital heart defect present, a number of congenital defects and associated learning difficulties

Question 13

how are cardiac conditions inherited?

Answer 13

mostly autosomal dominant

often heterogenous

Question 14

variation in human genome can be

Answer 14

disease causing
susceptibility factor - increased risk of developing a condition
benign

Question 15

what does monogenic mean?

Answer 15

1 base change

1 gene change

Question 16

what is familial hypercholesterolaemia?

Answer 16

raised cholesterol
affects 1/500 
causes premature coronary artery disease
heterogenous
to do with LDL clearance

Question 17

how is familial hypercholesterolaemia diagnosed?

Answer 17

diagnosed primarily with clinical scores

genetic testing can help identify at-risk relatives

Question 18

mutations involved in hypercholesterolaemia

Answer 18

LDLR
APOB
PCSK9
LDLRAP1

Question 19

when to do gene testing?

Answer 19

when monogenic conditions are suspected

Question 20

what are the main outcomes of genetic testing?

Answer 20

1. nil found - matches the expected sequence
2. clear pathogenic change
3. variant of uncertain significance - missense

Question 21

problems with gene testing

Answer 21

probabilistic

lots of uncertainty if get variant of uncertain significance

Question 22

what are the types of gene variation?

Answer 22

deletion
premature stop codon - TAG
frameshift = insertion or deletion of non-multiple of 3 number of bases
single base changes

Question 23

what are the clues to an inherited condition?

Answer 23

early onset

several affected relatives

Question 24

aortopathies

Answer 24

aortic dissection

aneurysms

Question 25

marfan syndrome

Answer 25

affects 1/5000 high risk of aortic dissection caused by FBN1 gene

Question 26

diagnosis of Marfan syndrome

Answer 26

diagnosed primarily on clinical grounds features overlap with other conditions associated with aortic dissection so may consider panel test to differentiate once diagnosed need to be screened for aortic dissection so treatment can be implemented

Question 27

take home messages

Answer 27

genetic testing has limitations | not all gene changes are disease causing

Question 28

cardiomyopathies

Answer 28

due to changes in proteins that form cardiac cells - sarcomere

Question 29

prevalence of hypertrophic cardiomyopathy

Answer 29

1/500

Question 30

what is hypertrophic cardiomyopathy?

Answer 30

thickened heart muscle, not due loading | presents with sudden death

Question 31

inheritance of hypertrophic cardiomyopathy

Answer 31

most families have monogenic cause autosomal dominant inheritance screening for first degree relatives

Question 32

what causes hypertrophic cardiomyopathy?

Answer 32

caused by aortic stenosis | hypertension or over athletism and many genes involved

Question 33

what to consider if there is family history of sudden cardiac death or near death or inherited cardiac condition

Answer 33

family need screening | needs to be repeated as these conditions can develop over time

Question 34

age related penetrance

Answer 34

repeat family screening as not all gene changes are disease causing and as many families have unique mutations

Question 35

genetic testing in inherited cardiac conditions

Answer 35

needs to be initiated in an affected individual as it will be uncertain whether any changes found are pathogenic or not

Question 36

electrical conducting issues

Answer 36

can cause sudden cardiac death | channelopathies

Question 37

examples of electrical conducting issues

Answer 37

long QT syndrome catecholaminergic polymorphic ventricular tachycardia Brugada syndrome

Question 38

Mendelian cardiac disorders

Answer 38

rare | high penetrance

Question 39

multifactorial cardiac disorders

Answer 39

common low penetrance multifactorial -environmental and polygenic factors many different gene loci normal distribution usually requires a build up of factors to cause the phenotypic expression

Question 40

what are the 2 different types of inherited cardiac disorders?

Answer 40

mendelian | multifactorial

Question 41

polygenic risk scores in clinical practice

Answer 41

can be calculated if no clear pathogenic variant in gene causing familial hypercholesterolaemia less concern for close relatives if cause is polygenic

Question 42

what do polygenic risk scores involve?

Answer 42

analysis of a number of relatively common SNPs which each contribute to modestly raised cholesterol those with high score - many SNPs are more likely to have a polygenic cause, not monogenic

Question 43

how do statins work?

Answer 43

inhibit rate-limiting enzyme so less cholesterol is formed in liver and increases clearance of lipids major treatment but has side effects

Question 44

pharmacogenomics of statins

Answer 44

can cause myopathy or rhabdomyolysis SNPs in SCLO1B1 gene are associated with risk of myopathy if this SNP is present may use lower dose and follow up more regularly testing for SNPs is beginning to be incorporated into routine care

Question 45

what is myopathy?

Answer 45

muscle pain

Question 46

what is rhabdomyolysis?

Answer 46

destruction of striated muscle cells | releases myoglobin which causes kidney failure