Genetics of Inherited CV Disease Flashcards
What are the three basic inheritance patterns in CV diseases?
Autosomal dominant
Autosomal recessive
X-linked recessive
If affected parents have a 50% chance of having an affected child, the inheritance pattern is…
Autosomal dominant
What is reduced penetrance?
Less than 100% of individuals with a certain genotype actually express signs or symptoms
What is variable expressivity?
The signs and symptoms of a genetic condition differ among affected individuals
What is genetic heterogeneity?
A genetic disorder can be caused by more than one mutation in an allele
What is pleiotropy?
Genetic variants in a particular allele can cause several signs or symptoms
What are the inherited CV diseases?
- Arrhythmias
- Cardiomyopathies
- Aneurysm syndromes
- Familial Hypercholesterolemia
- Pulmonary Arterial Hypertension
Arrhythmias are usually due to gene mutations in ___ _______
ion channels
What are common findings associated with Arrhythmias?
Syncope
SCD (Sudden cardiac death)
SIDS (Sudden infant death syndrome)
At what age are patients affected with arrhythmias?
Any age
Long QT syndrome (LQTS) is usually caused by mutations in _______ channels
potassium
LQTS is associated with what life threatening complication?
Torsades de pointes (TdP)
Syncopal episodes of LQTS usually occur during ______ or ______ _______
exercise; high emotions
What are the congenital causes of LQTS?
Romano Ward syndrome (RWS)
Jervell and Lange-Nielson syndrome
What are some acquired causes of LQTS?
- Primary myocardial problems (infarction/cardiomyopathy)
- Electrolyte abnormalities
- Autonomic influences
- Drug effects
- Hypothermia
What QT intervals are indicative of positive certainty for RWS (68% of affected individuals) in males? females?
males: >470
females: >480
QT intervals which cause uncertainty of RWS diagnosis are between what two values for males and what two values for females?
males: 400-450
females: 400-470
What type of inheritance is shown by RWS?
___ of individuals with RWS mutation will not show symptoms (reduced penetrance)
Autosomal dominant; 50% (half)
How many genes are known to be associated with RWS?
13
What are the three most common genes associated with RWS?
KCNQ1
KCHN2 (HERG)
SCN5A
What events can trigger RWS in genetically susceptible individuals?
- Exercise
- Sudden emotion
- Swimming
- Postpartum
- Sleep
How is LQTS treated?
- Avoidance of strenuous exercise (triggers)
- Beta blockers
- Pacemakers
- Access to defibrillators
- ICD
What clinical defects are associated with Jervell and Lange-Nielson syndrome (JLNS)?
Congenital, proofound, bilateral sensorineural deafness and QT prolongation often > 500ms
Infants with JLNS have increased risk for _____ and > 50% of untreated children with JLNS die prior to age ___
SIDS (sudden infant death syndrome); 15
In genetic testing for RWS, what is the current detection rate?
75%
Why does a negative genetic test not rule out LQTS?
5-12% of patients with normal sequencing of the most common LQTS genes had large genomic rearrangements
Brugada syndrome presents as ______, _______ or ______
Syncope, SIDS, SUNDS (sudden unexpected nocturnal death syndrome)
What genetic defect is most likely to be seen in Brugada syndrome?
SCN5A (alpha subunity of cardiac sodium channel)
What is CPVT?
Cathelominergic polymorphic ventricular tachycardia
- Syncope caused by exercise or acute emotion in an individual without structural heart disease
- Tachycardia that can degenerate into ventricular fibrillation and cause sudden death
For CPVT, gene mutations in ______ are inherited in an autosomal dominant manner while gene mutations in _____ are inherited in an autosomal recessive manner
RYR2 (Cardiac ryanodine receptor channel); CASQ2 (calsequestrin - calcium binding protein of the sarcoplasmic reticulum)
What is the difference between single gene analysis and gene panels?
Single gene analysis allows for coding exon sequencing to evaluate the mutation in one gene
Gene panels perform massive parallel sequencing of the coding exons within multiple genes
What are the main proteins involved in cardiomyopathies?
- Cytoskeletal proteins
- Sarcomeres
- Nuclear envelope proteins
- Desmosomes
Which cardiomyopathy is a major cause of sudden cardiac death (SCD) in the young and the most common cause of SCD in young athletes
Hypertrophic cardiomyopathy
How do patients with HCM present clinically?
- Typically includes chest pain, exertion related dyspnea or syncope
- Majority of individuals remain asymptomatic
HCM is a disease of the ______
sarcomere
What is the inheritance pattern of HCM?
What are the 3 most common gene mutations and how do they present?
Autosomal dominant inheritance
- MYH7: classic presentation
- MYBPC3: later age of onset
- TNNT2: mild or absent LVH; higher risk for arrhythmia
Why are 6% of individuals with HCM more severely affected, showing earlier age of onset, more severe LVH and more frequent and rapid progression?
Most likely HCM caused by multiple mutations
Which cardiomyopathy is the primary indication for cardiac transplantation?
Dilated Cardiomyopathy
Dilated cardiomyopathy usually occurs in what age group?
Adult years (30s to 50s) - but varies widely
What are the clinical features of DCM?
Congestive heart failure
Reduced cardiac output
Arrhythmias and/or conduction system disease
Thromboembolic disease
(Some patients may have muscle weakness or dystrophy)
What would prompt genetic testing to rule out an idiopathic cause to DCM?
Two or more closely related family members that meet the criteria for idiopathic DCM (non-aquired type)
What pattern of inheritance is associated with DCM?
What genes are often involved?
Most cases show autosomal dominant inheritance
Genes involved in sarcomere, Z-disk, nuclear lamina, intermediate filaments, desmosomes, dystrophin…
What gene mutation is associated with DCM, muscular dystrophy, Hutchinson-Gilford progeria syndrome (Benjamin Button disease) and bracydactyly?
What is it called when a gene mutation has multiple manifestations?
LMNA (nuclear envelope gene)
Pleiotrophy
If an LMNA mutation is detected, patients may benefit from a ___ _________ before EF<35%
ICD implantation
Clinical screening for cardiomyopathy is recommended for….
- Asymptomatic first degree relatives
- At-risk relatives who are know to carry the disease causing mutation
- Asymptomatic at-risk first degree relatives when genetic testing has not been performed or has not identified a disease-causing mutation
How is Cardiomyopathy managed pharmacologically? Non-pharmacologically?
Pharm: ACE inhibitors and diuretics
- Lifestyle modifications
- Pacemakers, ICD
- Surgical intervention (alcohol ablation)
- Cardiac transplantation
What are complications of Familial hypercholesterolemia?
Xanthomas: yellowish cholesterol rich material in tendons or other body parts
Atheromas: Accumulation of debris containing cholesterol in the artery walls (plaques)
LDL and cholesterol levels in FH for…
Untreated adults?
Untreated children?
Untreated adults: LDL-C> 190 or total cholesterol >310
Untreated children: LDL-C > 160 or total cholesterol > 230
What are the genes affected in FH?
LDLR (low density lipoprotein receptor)
APOB (apolipoprotein B)
PCSK9
What two patterns of inheritance are associated with FH?
Autosomal dominant (HeFH) and autosomal recessive (HoFH) inheritance
What are the benefits of genetic testing for FH?
- Risk factor modification before onset of disease
- Pharmacotherapy : statins (HoFH not responsive)
- Early screening and therapy for elevated cholesterol levels
What did GINA (2008) do to affect genetic testing?
Prevents insurance discrimination based on genetic testing results
