Cardiovascular Genetics Flashcards
sinus node
specialized group of cells in RA that generates impulses to coordinate the pumping of blood
arrhythmia
abnormal heart beat
bradycardia
excessively slow heartbeat
tachycardia
fast heartbeat, >100bpm
V fib
ventricles beating too rapidly causing tachycardia, eventually leads to medical emergency where the ventricles quiver and are no longer pumping blood
ECG/EKG
study used to record electrical activity of the heart with probes attached to skin
p-wave
atrial activation
pr interval
time between atrial activation to ventricular activation
QRS complex
represents ventricular activation, large peak on EKG
STT wave
represents ventricular repolarization
QT interval
period of ventricular activation and recovery
Holter monitor
portable device that records cardiac activity over a period of time (at least 24h)
stress test
test measuring cardiac ability to respond to external stress (ex: drug, exercise); coupled with EKG in a controlled setting
echo
test that uses ultrasound waves to visualize heart
color doppler
can be used in echo to look for abnormal communication between the right and left sides of the heart
transthoracic echo
most common, non invasive echo
transesophageal echo
more invasive echo, but completed because of the pictures it can provide
EF
measurement of blood leaving LV with each heart beat; normally above 50%
cardiac catheterization
invasive test that involves insertion into the heart for evaluation or so another procedure may be completed
pulmonary arterial pressure
measurement of the pressure inside the pulmonary artery via cardiac catheterization
myocardial biopsy
heart tissue taken for microscopic study
PM
implanted device that provides electrical impulses for each heartbeat; used when people have conduction anomalies or slow heartbeats
ICD
electronic device implanted to monitor for and prevent arrhythmias; only device that delivers a shock to the body
syncope
fainting or brief loss of consciousness due to temporary loss of oxygenated blood
palpitations
feeling of pounding, racing, skipping stopping beats; can include or exclude an abnormal underlying heart rate
SCD
death due to an abrupt loss of heart function; natural, rapid, unexpected and occurs within one hour of onset of symptoms
- 25% occurs in people with no cardiac history, most due to underlying structural defects
- 8% survival rate
SCD symptoms
CP, palpitations, syncope, dizziness, lightheadedness
commotion cordis
blow to the chest at the right time in rhythm to cause death
coronary heart disease
multifactorial disease
- risk factors: family history, sedentary lifestyle, high fat diet, smoking
- GT not standard of care, but part of research
familial hypercholesterolemia (FH) phenotype
- total serum cholesterol and LDL are elevated
- xanthomas
- atheromas/plaques
- causes elevated risk for CAD and MI
xanthoma
yellowish cholesterol-rich material in tendons or other body parts
atheroma
accumulation of debris containing cholesterol in artery wall
FH genetics
-AD
+earlier age of onset and more severe disease seen in homozygotes
-genes: LDLR, ApoB-100 (100 is one of two gene isoforms), more being linked
benefits of GT for FH
- allows for early screening related to elevated cholesterol levels and risk factor modification prior to symptom onset
- identifies at risk family members and how to target interventions
predisposition testing
*not very commonly done
assessing susceptibility to multifactorial disorders
pharmacogenetic testing
goal is to identify better drugs for treatment with fewer side effects and greater efficacy based on the analysis of genes responsible for drug metabolism and activity
analytical validity
correctness/accuracy of result
clinical validity
chance of revealing a result that allows us to make medical interventions on patient
clinical utility
how will testing guide management and intervention; was testing completed for a clinically valid reason
locus heterogeneity
mutations in different genes cause similar phenotypes
allelic heterogeneity
mutations in the same gene cause similar phenotypes
phenotypic heterogeneity
different mutations within the same gene cause different phenotypes
challenges in CV GT
does not account for low penetrance of mutations, age-related penetrance, or premature death
-“negative family history” may not mean investigation is not warranted (genetic basis not necessarily excluded)
cardiomyopathy
disease of the heart muscle that can lead to heart failure, arrhythmia, stroke, SCD
signs of heart failure
SOB/dyspnea, lower extremity swelling
DCM phenotype
-most common CM, usually occurring in adults
-causes stretching of the left ventricular muscle, leading to thinning
+muscular weakness can move to RV and atria
-dilated/weakened LV muscle can no longer effectively pump blood called systolic dysfunction
-can present with or without conduction system disease
systolic dysfunction
EF <50%
HCM
- can effect people of all ages, including children
- less common than DCM, but greater understanding of genetics
- (idiopathic) left ventricular hypertrophy without another predisposing condition such as aortic stenosis or long standing HTN
restrictive CM
- typically occurs in older adults
- scar tissue replaces normal heart tissue and causes stiffening, rigidity of the ventricles
- blood flow in the heart is reduced and arrhythmias and heart failure can occur
- less commonly of primary genetic cause, though can often be secondary to other multi systemic genetic conditions
arrhythmogenic right ventricular dysplasia (ARVD)
- often affects children, teens and young adults
- right ventricular tissue dies and is replaced by scar or other abnormal tissue, disrupting the electrical signals of the heart and causing arrhythmia
- palpitations and fainting after physical activity are commons symptoms
DCM inheritance
-greater than 30 genes implicated
+panels are the best approach for molecular diagnosis
+these genes only explain about half of all familial cases
-nearly all (80-90%) of identified genes are AD, though some cases of mito, AR, and XL have been reported
DCM genes
- TTN responsible for most known cases
- many gene defects affect the sarcomeric proteins and ability of the heart to effectively pump blood/contractile apparatus
- geno-pheno is still being correlated, some studies have show TNNT2 mutations may indicate an earlier age of onset with more aggressive disease
LMNA
-mutations can cause DCM with conduction system disease causing arrhythmia; including Afib
+increased risk for SCD
+affected individuals often require a PM
-gene also implicated in Emery-Dreifuss MD, so there is some overlap in phenotype and skeletal myopathy can also be seen isolated or in association to CM with these mutations
*example of phenotypic heterogeneity
SCN5A
mutations can cause DCM with conduction system disease
DMD
example of X-linked DCM where certain mutations cause a severe cardiac phenotype and subclinical skeletal muscle effects
Barth syndrome
- caused by mutations in TAZ
- phenotype includes congenital CM, underdeveloped skeletal musculature and muscle weakness, short stature and neutropenia
HCM pathogenesis
- causes stiffening and thickening of ventricular walls due to muscle cell enlargement and disarray
- ventricle becomes unable to effectively relax and fill with blood which can result in SCD, arrhythmia, CP, dizziness, syncope, fatigue, SOB
HCM symptoms and phenotype
- SOB, especially with exertion, CP, palpitations, syncope
- can sometimes be asymptomatic
- can lead to SCD and CHF
HCM diagnosis
- typically by echo, electrocardiogram, PE and family history
- heart sample from cardiac catheterization biopsy may also be helpful to visualize cell size, shape and organization
- genetic testing-detection not 100%
- still limited in predicting clinical course
HCM genetics
-mostly AD inheritance in sarcomeric genes
+mutation causes myocyte hypertrophy and disarray
-5% individuals have multiple mutations (compound hets, double hets) and tend to have very severe phenotypes that often begin at birth
-MYH7, MYBPC3 most common and make up about 40% of HCM
MYH7
- mutations most associated with HCM
- correlation with younger onset age, more severe hypertrophy
- penetrance is near 100%, but survivability is variable
PRKAG2
- mutation tends to result in Wolff-Parkinson White (WPW) with or without HCM
- result in metabolic disease that can occur in the myocardium and mimic HCM
LAMP2
- tends to result in Danon disease
- mutations mimic HCM phenotype due to metabolic disease of the myocardial cells
Danon disease
X-linked disorder with CM, muscle weakness, and variable ID
WPW
- abnormal/accessory pathway allows bypass of the AV node in the heart and causing more rapid movement of electrical conduction activity and causes tachycardia
- symptoms can include dizziness, syncope, palpitations, SOB and can increase the risk for SCD and MI related to the arrhythmia
GLA
-gene mutated in Fabry
+X-linked and can be associated with left ventricular hypertrophy
-sometimes mutation symptoms can be isolated to the heart
Noonan cardio effects
- mutations in RAS MAPK genes
- 20% of affected individuals develop HCM
familial HCM screening
- <12y: only if family history shows condition related death, early LVH, etc, child is a competitive athlete in intense training, child is symptomatic
- 12-18: EKG & echo every 12-18mo
- > 18-21y: EKG/echo regimen reduced to every 3-5y or altered in response to a change in symptoms
- can be tailored for families with later onset phenotype or additional issues
HCM activity guidelines
- moderation of all physical activity
- avoidance of competitive endurance training and burst activities, like sprinting
- avoidance of intense isometric exercise such as heavy weight lifting
non-compaction CM
- most commonly seen as LVNC
- caused by failure of complete packing of the spongy myocardium between weeks 5-8 of gestation
LVNC
-70% inherited with a wide range of onset
+adult onset with avg age of 40y
+congenital form with avg age of onset at 6y
NCCM clinical presentation
- thromboembolic events
- Afib
- ventricular tachycardia
- heart failure
NCCM diagnosis
- ECG and echo findings
- sometimes also have cardiac MRI
NCCM genetics
-AD inheritance, except TAZ (XLD)
+MYH7 most common, then LDB3, ACTC, TNNT2
Long QT onset
can be inherited or acquired
- medication induced
- metabolic abnormalities
- bradycardia
- genetics
Long QT diagnosis and findings
- prolonged QT interval on EKG
- torsades de points-characteristic polymorphic Vtach
effects of Vtach
- syncope
- Vfib
- MI
- SCD
Romano-Ward syndrome
- LQTS phenotype
- usually AD inheritance
- 4% risk for SCD in 3 most common subtypes between birth and 40yo
Jervell and Lange-Nielsen syndrome
-LQTS phenotype + SNHL
-AR inheritance of KCNQ1 and KCNE1 mutations
+1/3 individuals are compound hets
LQTS RWS genetics
-at least 12 genes clinically tested
+KCNQ1 (30-35%), KCNH2 (25-40%), SCN5A (5-10%) most common
Anderson-Tawil syndrome
-LQTS phenotype caused by mutation of KCNJ2
+exacerbation through hypokalemia
-also causes skeletal anomalies, periodic paralysis
Timothy syndrome
-LQTS phenotype due to mutation of CACNA1c
+arrhythmias
-also see syndactly, dysmorphic features
-ID, autism
trend variability in LQTS
- common triggers: exercise-1, emotion-2, rest or sleep-3
- age of onset: before age 10-1, after in 2 and 3
- incidence of cardiac events: decreases with type
- beta blocker prevention: helpful in type 1, not in 2 and 3
- shows us how genetic testing may alter management and prognosis for patients
LQTS diagnosis
-can see reduced penetrance of symptoms and EKG anomalies
-multigene panel best option
+when using most common genes (KCNQ1, KCNH2 and SCN5A) detection rate is ~75%
-Schwartz score for clinical diagnosis based on symptoms
+EKG findings
+clinical history-syncope, deafness
+family history
LQTS avoid list
- drugs that prolong interval
- competitive sports/activities associated with intense physical activity and/or emotional stress
SQTS
- less known about this syndrome
- heritable conduction syndrome abnormality
- shortened EKG QT interval with tall peaked T waves
- increased risk for SCD and Afib
- clinically indistinguishable from LQTS by symptoms
SQTS genetics
-rare and may account for some cases of SIDS; unknown detection rate
-variable penetrance of AD inheritance
+KCNH2
+KCNQ1
+KCNJ2
*allelic heterogeneity
Brugada presentation
-conduction system anomaly
-characterized by abnormal EKG with increased risk for SCD
+syncope or MI while sleeping or at rest are common; can present as SIDS or SUNDS
sudden unexplained nocturnal death syndrome (SUNDS)
seen in SE Asia where young, apparently healthy males die of MI; different name for Brugada
Brugada management
- ICD placement is only known effective therapy
- treatment of fever, electrolyte disturbances
- avoidance of cocaine use, drugs that could induce arrhythmia
Brugada EKG
- three different signs for three different types
- RBBB and ST elevation in leads V1-V3 with coved morphology
- can occur spontaneously or be induced by medication
Brugada diagnosis
-clinical criteria
+EKG abnormality combined with personal symptoms or family history
+type 1 abnormality more impactful in scoring
Brugada genetics
- AD with variable expressivity and male sex bias
- SCN5A mutations most common (15-30%), other mutations only makeup less than 5%
PAH
widespread obstruction and obliteration of the smallest pulmonary arteries causes resistance of blood flow to lungs
+RV tries to compensate and pump with higher pressure, leading to heart failure
PAH symptoms
SOB, Reynaud’s phenomenon in females, fatigue, syncope or near syncope, CP, palpitations, lower limb edema
PAH diagnosis and prognosis
- mean survival is 2.8y post diagnosis
- mean pulmonary arterial pressure during catheterization of >25mmHg at rest or >30mmHg when exercising is diagnostic
- be sure to rule out advanced stage lung and heart disease, CTD, cirrhosis, HIV, and PE or large pulmonary vessel disease
- diagnosis in two or more family members or if a disease causing mutation has been identified
PAH genetics
-BMPR2 mutation accounts for 75% of the cases
+25% of simplex cases (one affected person in family)
+only about 20% penetrance
-other genes are less than 1% cases
-female: male sex bias of 2.5
HHT symptoms
presence of many arteriovenous malformations (AVMs) that bleed with slight trauma when close to skin surface; recurrent nose bleeds, GI bleeding and AVM complications in brain liver and lungs
PAH and HHT joint phenotype genes
- ACVRL1 most common
- rarely ENG, SMAD8 or BMPR2
ARVD/ARVCM
progressive fibrofatty replacement of the myocardium predisposing to ventricular tachycardia and sudden death
ARVD phases
1-concealed phase when no clinical manifestations have occurred, but SCD risk exists
2-electrical disorder with symptomatic arrhythmia
3-RV failure
4-biventricular pump failure that resembles DCM
ARVD diagnosis
-made or supported non-invasively
+24h holter monitor and EKG
-invasive testing also useful-looking for tissue replacement or hypertrophy of myocardium
+RV angiography
+RV endocardial bx
-clinical diagnosis made by meeting certain major and minor criteria related to global v. regional dysfunction and structural anomalies, depolarization, depolarization and conduction anomalies, arrhythmic anomalies, and family history
-genetic testing
ARVD genetics
-AD inheritance with variable expressivity and reduced penetrance
-DSP, PKP2, DSG2 most commonly mutated
+note great deal of overlap with other conditions
catecholaminergic polymorphic v tach (CPVT)
-cardiac electrical instability triggered by acute activation of adrenergic nervous system (epi, norepi, dopamine)
-rapid heart beat originating in ventricles
+causes rapid change and morphology to QRS complexes
*normal resting EKG
CPVT symptoms
-brought on by acute emotional changes, exercise, etc
-syncope occurs in 80% individuals
+can see bidirectional or polymorphic v tach during this time
+arrhythmias may terminate themselves or persist and result in SCD or MI
-cardiac arrest occurs in 30% of affected individuals
CPVT incidence and prognosis
-mean onset is between 7-9y
+can have onset up to 4th decade and could explain some cases of SIDS
-lower prevalence than other arrhythmogenic disorders
CPVT genetics
- AD RYR2 (50-55%)
- AR CASQ2 (1-2%)
cardiac amyloidosis
deposit of abnormal amyloid protein in heart tissue-replacement of normal tissues may affect electrical signaling
transthyretin (TTR) amyloidosis
- group of diseases caused by accumulation abnormal protein in the body
- clinical presentation can include peripheral and autonomic sensorimotor neuropathy, CM, vitreous opacities and CNS protein buildup
TTR amyloidosis genetics
-caused by mutation of AD TTR mutations
+2/3 cases de novo
-sequencing most useful
+most mutations are single BP substitutions causing missense changes
-two common mutations-V30M (Portuguese, Japanese, Swedish), V122I (AA)
Alagille syndrome
- AD mutations of JAG1, less so NOTCH2
- 90% individuals with CHD (pulmonic stenosis)
- also have jaundice, paucity of intrahepatic bile ducts, butterfly vertebral anomalies, renal anomalies
- dysmorphic features: broad forehead, deep set eyes, pointed chin
