Cardio-Genetics Module-4

Cardio-Genetics

Module 4

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Learning Objectives

• Understand the genetics underlying hereditary cardiac conditions
• Learn about the characteristics of different cardio-genetic diseases
• Identify appropriate next steps and resources for patients with these conditions.

Cardio-genetics overview

Cardiomyopathies

Lipidemia

• ACMG Recommendations

• Dilated Cardiomyopathy
• Hypertrophic Cardiomyopathy

• Familial Hypercholesterolemia

Agenda

Syndromic conditions

Emerging cardio-genetics

Arrhythmias

• Pompe Disease
• Marfan Syndrome
• Ehlers Danlos Syndrome

• Resources

• Long QT Syndrome

CardioGenetics

4.1

What is cardio-genetics?

• Predisposition to cardiac abnormalities that impact structure, rhythm and function of the heart.
• Genetic risk factors for hereditary cardiac conditions, like:
• Cardiomyopathies.
• Arrhythmias.
• Familial hypercholesterolemia.
• Connective tissue disorders.

Quiz

The American College of Medical Genetics recommends secondary reporting of hereditary:

A Cardiomyopathy

B Arrhythmia

C Lipidemia

D All of the above

ACMG Cardiogenetic Conditions

ACMG recommends that findings in the following genes be reported to consented patients:

ACMG Cardiac Conditions

4.2

Cardiomyopathies

Dilated Cardiomyopathy

Clinical Features

• Left ventricular enlargement
• Identified by echocardiogram or cardiac MRI
• Systolic dysfunction
• Reduction in myocardial force of contraction
• Ejection fraction of less than 50%
• Measure left ventricular ejection fraction via two-dimensional echocardiogram or cardiac MRI
• Typical presentation in 40s-60s but can more rarely present prenatally, in infancy, childhood or adolescence
• Recommend pediatric assessment if suspicious of DCM
• Often asymptomatic for years with presentation in late-stage disease:
• Heart failure
• Arrhythmias or conduction disease
• Thromboembolic disease
• Pregnancy
• Can present peri-partum or in association with pregnancy.

Dilated Cardiomyopathy

Types of DCM:

• Acquired or secondary
• Commonly due to injury, ie. Myocardial infarction
• Other causes include: toxins, congenital heart disease, thyroid disease, hypertension, radiation, chemotherapy
• Syndromic
• Duchenne muscular dystrophy
• Progressive weakness and atrophy of skeletal and cardiac muscle with completely absent dystrophin
• DMD Gene
• Barth syndrome
• X-linked disease resulting in delayed motor development, failure to thrive, heart failure
• TAZ Gene
• Becker muscular dystrophy
• Progressive weakness and atrophy of skeletal and cardiac muscle with some dystrophin
• DMD gene
• Non-syndromic
• Isolated cardiomyopathy

Genes

• Syndromic
• DMD, EMD, DSP, TAZ, MYH7, etc.
• Non-syndromic
• TTN, LMNA, MYH7, FLNC, BAG3, TNNT2, etc.

Dilated Cardiomyopathy

• Screening and surveillance
• Prompt identification of asymptomatic first-degree relatives of DCM patients is recommended to allow for early detection, initiation of treatment and improved outcomes
• Patients with pathogenic variants should have cardiovascular screening at intervals based on age (echocardiogram, ECG)
• Pathogenic variants with ambiguous echocardiograms are likely early DCM
• Pathogenic variants with normal echocardiogram and abnormal EKG are likely early DCM

• Treatment
• Combination of medications like beta-blockers, ACE-inhibitors, and diuretics
• Asymptomatic patients may consider beta-blockers and/or ACE inhibitors to halt progression or prevent disease
• Consideration of implantable defibrillator, pacemaker, left ventricular assist device and heart transplant, as needed.

Hypertrophic Cardiomyopathy

Clinical Features

• Presence of left ventricular hypertrophy with a maximum wall thickness of >/= 15 mm in adults or a z-score of >3 in children
• If pathogenic variant identified, maximum wall thickness of >/= 13mm is diagnostic
• Often presents during adolescence or young adulthood, but can range from infancy to adulthood
• Variable clinical expressivity, even with same variant. Some presentations include:
• Asymptomatic
• Arrhythmias
• With an increased risk of atrial fibrillation
• Ventricular tachycardia or ventricular fibrillation
• Refractory heart failure
• Progression to end stage disease may require heart transplantation
• Sudden cardiac death is possible as a result of ventricular tachycardia or ventricular fibrillation
• Occurs most often in adolescents or young adults (sudden death in 16% of patients)
• Mortality rate is 3x higher than general population.

Hypertrophic Cardiomyopathy

Diagnosis

• Non-invasive cardiac imaging (echocardiogram, cardiac MRI)

Types of HCM:

• Acquired or secondary
• Not associated with genetic variants
• Associated with high blood pressure, infections, heart damage from heart attack
• Syndromic
• Fabry disease
• Metabolic disorder resulting in extreme pain in hands and feet, heat/cold intolerance, GI problems, proteinuria, etc.
• X-linked disorder
• Fredreich ataxia
• Muscle weakness and spasticity, absent lower-linb reflexes, etc.
• Pompe disease
• Proximal muscle weakness and respiratory insufficiency
• Noonan syndrome
• Developmental delay, short stature, heart defect and characteristic facies
• Non-syndromic
• Sarcomere variants are seen in 50-60% of probands with family history and 20-30% without family history

Genes:

• Syndromic
• GAA, FXN, GLA, etc.
• Non-syndromic
• MYBPC3, MYH7, TNNI3, TNNT2, ACTC1, <YL2, MYL3, PLN, TPM1

Hypertrophic Cardiomyopathy

• Screening and surveillance

• Genetic diagnosis of proband will determine if it syndromic or non-syndromic and inform risk for patient and relatives
• Sequencing with deletion/duplication analysis is recommended for HCM molecular diagnostics
• Recommend genetic diagnosis for eligible relatives of proband
• Family history is a very important factor and predictor in HCM cases
• Individuals that test positive for a known pathogenic variant should have clinical cardiovascular screening with physical exam, EKG, and echocardiogram in alignment with current published recommendations.

4.3

Lipidemia

Quiz

In the general population, high cholesterol is caused by a single genetic factor in _________ individuals:

A 1 in 1000

B 1 in 500

C 1 in 300

D 1 in 100

Familial Hypercholesterolemia (FH)

Clinical Characteristics

• Elevated low-density lipoprotein cholesterol (LDL-C)
• Greater than 190 mg/dL
• Atherosclerotic plaque deposition in the coronary arteries and proximal aorta at early age
• Premature cardiovascular events
• Xanthomas
• Fatty deposits seen on skin
• Corneal arcus
• Deposits of cholesterol inside cornea
• Genes:
• APOB, LDLR, PCSK9, LDLRAP1
• Prevalence:
• General population: 1 in 300
• French Canadian: 1 in 80
• Iceland: 1 in 836 (but clinically has a frequency of 1/50)

Familial Hypercholesterolemia

• Screening and diagnosis
• Molecular diagnosis
• Heterozygous or biallelic variants in APOB, LDLR, PCSK9 or biallelic variants in LDLRAP1
• Clinical diagnosis
• High plasma levels of LDL-C, family history of hypercholesterolemia, history of premature atherosclerotic cardiovascular disease and tendon xanthomas.

Familial Hypercholesterolemia

Surveillance

• Requires early, aggressive and lifelong therapeutic interventions
• Monitor lipid levels beginning at age 2
• Statin therapy recommended at age 8-10y for heterozygous FH patients or time of diagnosis for homozygous FH patients
• Consider non-invasive imaging modalities in adults
• Higher risk patients
• Screen with various imaging modalities
• Echocardiogram, CT angiogram, cardiac catheterization

Prevention of primary manifestations

• Heart healthy diet
• Reduced saturated fat
• Increased soluble fiber (10-20g per day)
• Increased physical activity with physician guidance
• No smoking

Treatment

• Statins
• Ezetimibe in combination with statins
• Bile acid sequestrants
• Niacin in combination with statins
• Lomitapide
• Mipomersen
• PCSK9 inhibitors
• Lipoprotein apheresis.

Cascade Screening

Testing of at-risk family members for genetic conditions

• Identification of at-risk individuals
• First-degree relatives (FDR) tested
• First degree relatives of positive FDRs tested
• Cascade of genetic screening based on positive results

For example:

• Proband identified to have Familial Hypercholesterolemia
• All children, parents and siblings tested
• Identification of which parent passed on genetic variation
• Testing of affected parent's siblings, then affected sibling's children, etc.

4.4

Arrhythmias

Long QT Syndrome

Clinical picture

• Isolated cardiac phenotype (also known as Romano Ward syndrome)
• QT prolongation and T wave abnormalities on EKG that are associated with tachyarrhythmias, specifically torsade de pointes (ventricular tachycardia)
• Torsade de pointes (TdP) is self-terminating with a syncopal event
• Cardiac events occur suddenly, without warning and can lead to cardiac arrest and sudden death
• Triggers:
• Emotional stress
• Sleep
• Auditory stimuli
• Exercise
• 50% of molecularly diagnosed individuals that are untreated will have symptoms like syncopal events
• Cardiac events occur most commonly in preteen years through the 20s
• 6-8% risk of sudden cardiac death before age 40
• Some forms are non-syndromic, and some are considered syndromic and have other clinical features, like sensorineural hearing loss in Jervell and Lange Nielson syndrome

Frequency: 1 in 2500 across ethnic groups

Long QT Subtypes

• LQTS1
• Triggered by exercise and emotion
• KCNQ1
• LQTS2
• Triggered by auditory stimuli, emotion, exercise and sleep
• KCNH2
• LQTS3
• Triggered by sleep
• SCN5A

Long QT Syndrome

Diagnosis:

• Prolongation of QTc interval in absence of other conditions known to lengthen this interval (ie. QT prolonging drugs)
• Molecular genetic testing with pathogenic or likely pathogenic variant

Treatment:

• Beta blockers as primary treatment
• Used in symptomatic and asymptomatic individuals
• Monitor careful to ensure at efficacious dose
• Implantable cardioverter-defibrillators (ICD)
• Left cardiac sympathetic denervation (LCSD) if beta-blocker resistant symptoms, or history of cardiac arrest
• Potential for sodium channel blockers

Management:

• Avoid drugs that prolong QT interval
• Avoid competitive sports or intense physical activity
• Avoid emotional stress
• Avoid swimming

4.5

Syndromic conditions with cardiac associations

Quiz

Cardiogenetic conditions arealways autosomal dominant?

True

False

Pompe Disease

Gene:

• GAA
• Autosomal recessive metabolic disorder

Diagnosis

• Enzyme activity of acid alpha glucosidase (GAA) evaluated for diagnosis on NBS

Clinical Picture:

• Infantile
• Onset before 12 months with cardiomyopathy
• Hypotonia, feeding difficulties, failure to thrive, respiratory distress and hypertrophic cardiomyopathy
• Death by age 2 without proper enzyme replacement therapy due to progressive left ventricular outflow obstruction and respiratory insufficiency
• Late-onset
• Onset before 12 months without cardiomyopathy or onset after 12 months
• Proximal muscle weakness, respiratory insufficiency

Management:

• Enzyme replacement therapy (aglucosidase alfa) initiated immediately after diagnosis
• Physical therapy to maintain range of motion and assist ambulation
• Nutrition and feeding support
• Respiratory support.

Marfan Syndrome:Connective Tissue Disorder

Gene:

• FBN1
• Autosomal dominant

Clinical Picture:

• Ocular
• Myopia in >50% of patients
• Ectopia lentis in 60% of patients
• Retinal detachment, glaucoma, and early cataracts
• Skeletal
• Bone overgrowth
• Joint laxity
• Disproportionately long extremities
• Pectus excavatum or pectus carinatum
• Scoliosis
• Cardiovascular
• Dilation of aorta predisposing to aortic tear and dissection
• Mitral valve prolapse with or without regurgitation
• Can predispose to left ventricular dysfunction and heart failure
• Tricuspid valve prolapse
• Enlargement of proximal pulmonary artery

Management

• Can be properly managed with similar life expectancy to general population.

Vascular Ehlers-Danlos Syndrome

Gene:

• Autosomal dominant
• Heterozygous variants in COL3A1, COL1A1

Clinical Picture:

• Skin hyperextensibility
• Blood vessel fragility
• Risk of uterine rupture during pregnancy
• Atrophic scarring
• Generalized joint hypermobility
• Hypotonia with delayed motor development
• Fatigue and muscle cramps
• Aortic root dilation, especially in young individuals
• Arterial rupture
• Organ rupture or aneurysm

Management

• Physiotherapy
• Anti-inflammatory drugs
• Personalized wound care plans
• Treat aortic root dilation if it presents.

4.6

EmergingCardio-genetics

Emerging Cardio-genetics

ApoE

• Isoforms of ApoE differ by single amino acid change and impact risk for cardiac and neurodegenerative disease
• ApoE2 and ApoE4 increase risk for heart disease
• ApoE2 increases atherogenic lipoprotein levels by binding poorly to LDL receptors
• ApoE4 increases LDL levels (binds preferentially to triglyceride-rich, very low density lipoproteins leading to downregulation of LDL receptors).

FH Foundation

American Heart Association

Resources

Sudden Arrhythmia Death Syndromes (SADS) Foundation

Hypertrophic Cardiomyopathy Association

Next Sessions

Module 5 Nutrigenomics

Module 6 Genetics Resources

THANKYOU!

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