cardiovascular genetics Flashcards
how many deaths are there from CV diseases a year?
160,000
how many deaths are there per year from coronary heart disease?
73,000
what are coronary heart disease deaths associated with?
deprivation
congenital heart disease?
12 babies diagnosed per day and more later in life
inherited cardiac conditions
12 young people under 35 die from these a week
causes of cardiovascular disorders
sedentary lifestyle smoking diet genetics - structural variation or single nucleotide variation epigenetic variation
chromosomal causes of CV disorders
trisomy 21
turner syndrome
DiGeorge syndrome
downs syndrome and heart disease
high rate of congenital heart disease
most common = atrioventricular septal defect
turner syndrome and heart disease
high rate of congenital heart disease
left ventricular outflow tract obstruction, coarctation, aortic dissection and dilatations
DiGeorge syndrome and heart disease
congenital heart defects
teraology of fallot
transposition of the great arteries
trucus arteriosus
chromosome tests
array CGH replacing standard karyotyping
less labour intensive and greater detail
when are chromosome tests done?
when a recognised chromosomal disorder or syndrome suspected
considered when congenital heart defect present, a number of congenital defects and associated learning difficulties
how are cardiac conditions inherited?
mostly autosomal dominant
often heterogenous
variation in human genome can be
disease causing
susceptibility factor - increased risk of developing a condition
benign
what does monogenic mean?
1 base change
1 gene change
what is familial hypercholesterolaemia?
raised cholesterol affects 1/500 causes premature coronary artery disease heterogenous to do with LDL clearance
how is familial hypercholesterolaemia diagnosed?
diagnosed primarily with clinical scores
genetic testing can help identify at-risk relatives
mutations involved in hypercholesterolaemia
LDLR
APOB
PCSK9
LDLRAP1
when to do gene testing?
when monogenic conditions are suspected
what are the main outcomes of genetic testing?
- nil found - matches the expected sequence
- clear pathogenic change
- variant of uncertain significance - missense
problems with gene testing
probabilistic
lots of uncertainty if get variant of uncertain significance
what are the types of gene variation?
deletion
premature stop codon - TAG
frameshift = insertion or deletion of non-multiple of 3 number of bases
single base changes
what are the clues to an inherited condition?
early onset
several affected relatives
aortopathies
aortic dissection
aneurysms
marfan syndrome
affects 1/5000
high risk of aortic dissection
caused by FBN1 gene
diagnosis of Marfan syndrome
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
take home messages
genetic testing has limitations
not all gene changes are disease causing
cardiomyopathies
due to changes in proteins that form cardiac cells - sarcomere
prevalence of hypertrophic cardiomyopathy
1/500
what is hypertrophic cardiomyopathy?
thickened heart muscle, not due loading
presents with sudden death
inheritance of hypertrophic cardiomyopathy
most families have monogenic cause
autosomal dominant inheritance
screening for first degree relatives
what causes hypertrophic cardiomyopathy?
caused by aortic stenosis
hypertension or over athletism and many genes involved
what to consider if there is family history of sudden cardiac death or near death or inherited cardiac condition
family need screening
needs to be repeated as these conditions can develop over time
age related penetrance
repeat family screening as not all gene changes are disease causing and as many families have unique mutations
genetic testing in inherited cardiac conditions
needs to be initiated in an affected individual as it will be uncertain whether any changes found are pathogenic or not
electrical conducting issues
can cause sudden cardiac death
channelopathies
examples of electrical conducting issues
long QT syndrome
catecholaminergic polymorphic ventricular tachycardia
Brugada syndrome
Mendelian cardiac disorders
rare
high penetrance
multifactorial cardiac disorders
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
what are the 2 different types of inherited cardiac disorders?
mendelian
multifactorial
polygenic risk scores in clinical practice
can be calculated if no clear pathogenic variant in gene causing familial hypercholesterolaemia
less concern for close relatives if cause is polygenic
what do polygenic risk scores involve?
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
how do statins work?
inhibit rate-limiting enzyme so less cholesterol is formed in liver and increases clearance of lipids
major treatment but has side effects
pharmacogenomics of statins
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
what is myopathy?
muscle pain
what is rhabdomyolysis?
destruction of striated muscle cells
releases myoglobin which causes kidney failure
