RCE - High Yield - Cardiac Genetics Flashcards
VIP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
What are the skin and eye findings in patients with ACTA2 mutations?fcholester
Skin - Livedo reticularis
Eye - Iris flocculi
VIP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
Prophylactic Surgical Repair of the Aorta; when is it done in the following scenarios?
- Loeys-Dietz syndrome
- Marfan syndrome (FBN1)
- ACTA2 mutations
- Pregnancy
Loeys-Dietz syndrome or TGFBR1 or TGFBR2 = 4 cm
ACTA2 mutations = When the aortic root or ascending aorta reaches a maximum diameter of 4.5 cm.
Marfan syndrome (FBN1) = The aortic root can be monitored to 5 cm unless there is a family history of dissection at smaller diameters (<5.0 cm), rapid enlargement (i.e. >0.5 cm per year), or significant aortic regurgitation.
Pregnancy = For women anticipating pregnancy, the threshold is anything that exceeds 4 cm: 4.1-4.5 cm.
___________________
Other notes:
When the specific cause of HTAD has not been identified, surgical repair is based on:
- The aortic diameter at the time of an aortic dissection in affected relatives.
Surgery is typically recommended when the diameter of the aorta is approximately twice normal - which depends on age, sex, and BSA.
VIP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
Multisystem smooth muscle dysfunction syndrome (ACTA2):
- Inheritance?
- Clinical features?
INHERITANCE:
Autosomal dominant
CLINICAL FEATURES:
CNS:
- Early onset Moyamoya-like cerebrovascular disease with:
- Dilatation of the proximal internal carotid artery
- Stenosis/occlusion of the terminal internal carotid artery
- Abnormally straight course of the intracranial arteries
- Small vessels occlusion that cause bilateral periventricular white-matter hyperintensities observed on brain MRI
- Ischemic stroke
EYES:
- Congenital mydriasis (Dilatation of the pupil)
- Small vessel retinal infarcts, tortuosity, and aneurysms
CARDIOVASCULAR:
- Early onset thoracic aortic aneurysm - typically fusiform and initially involve the aortic root, extending into the ascending aorta and aortic arch
- Aortic coarctation
- Large patent ductus arteriosus (PDA)
- Pulmonary artery hypertension
- Early onset coronary artery disease
GASTROINTESTINAL:
- Hypoperistalsis of the gut and malrotation
GENITOURINARY:
- Hypotonic bladder
(associated with dilated ureters, calyces and or renal pelves, hydronephrosis, vesicoureteral reflux and recurrent urinary tract infections)
- Prune belly sequence
EXTREMITIES:
- Brachial artery occlusion with limb ischemia
VIP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
Photo slides
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VIP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
Genotype phenotype correlation in patients with ACTA2 mutations?
Pathogenic variants that alter the Arg.179 residue cause:
- Multisystemic smooth muscle dysfunction syndrome
- Cerebrovascular disease (early onset Moyamoya-like cerebrovascular disease)
The pathogenic variant p.Arg149Cys is associated with iris flocculi.
The pathogenic variants p.Arg118Gln and p.Arg149Cys are associated with early onset coronary artery disease.
IMP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
When evaluating for a thoracic aortic aneurysm, the aortic diameter is measured using which imaging modalities?
Transthoracic Echocardiography: is used to detect aortic root dilation
CT or MRI: can be used to detect dilation above the aortic root if echocardiography cannot properly evaluate these locations.
IMP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
What are the causes of Heritable Thoracic Aortic Disease (HTAD)?
Marfan syndrome (FBN1)
Vascular Ehlers-Danlos syndrome (COL3A1)
Loeys-Dietz syndrome (TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD3)
Multisystem smooth muscle dysfunction syndrome and nonsyndromic HTAD heritable thoracic aortic disease (ACTA2)
FOXE3
LOX (also associated with bicuspid aortic valve, abdominal aortic aneurysm, hepatic artery aneurysm)
MYH11 (also associated with patent ductus arteriosus)
IMP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
What is the advised surveillance for thoracic aortic disease in the:
- Proband
- First-degree relatives
PROBAND and FIRST DEGREE RELATIVES WHO TEST POSITIVE:
After diagnosis of aortic dilatation, aortic imaging should be repeated in six months to assess the rate of aortic growth:
- If it remains stable - yearly imaging.
- If the rate of growth > 0.5 cm per year or if the ascending aorta and/or the aortic root exceeds about 4.0 cm in diameter - more frequent imaging should be considered
FIRST-DEGREE RELATIVE - NO GENE IDENTIFIED:
If the proband has:
- An aortic root aneurysm, screen by echocardiography
- An ascending aortic aneurysm, screen by CT or MRI (if echocardiography cannot visualize the aortic root adequately).
IMP - Familial Thoracic Aortic Aneurysms Leading to Acute Aortic Dissections
What is the advised medical treatment?
Medical therapy should be started once the aorta is dilated or in individuals with a known pathogenic variant in an HTAD-related gene and no enlargement of the aorta.
- Medications include:
- Beta adrenergic-blocking agents - e.g. atenolol
- Angiotensin II receptor blocker (ARB) - e.g. Losartan (has shown efficacy in Marfan syndrome) - Hypertension should be aggressively treated and controlled.
- Other cardiovascular risk factors, including smoking and hyperlipidemia, should be addressed.
- Avoidance of isometric exercises and contact sports is recommended.
VIP - Long QT syndromes
What is the trigger for long-QT syndrome in individuals with variants in the following genes?
KCNQ1
KCNH2
SCN5A
NB: Of the 15 genes known to be associated with LQTS, these are the most common, in this order.
KCNQ1 = LQTS1 (AD; potassium channel)
- Exercise (jumping into cold water, swimming, running, competitive sports)
- Emotion (anger, crying, test taking, or other stressful situations, amusement park rides, frightening movies)
KCNH2 = LQTS2 (AD; potassium channel)
- Exercise
- Emotion (anger, crying, test taking, or other stressful situations)
- Auditory stimuli (startling, alarm clock, loud horn, ringing phone)
- Sleep
SCN5A = LQTS3 if GOF (Brugada if LOF) - (AD; sodium channel)
- Sodium channel blocking medications
- High fever
- Sleep
MNEMONIC:
- Q1 = That’s me - I get palpitations with exercise, anxiety
- H2 = That’s Heba - include startled and sleep
- S for sodium; sleep; sweaty
VIP - Long QT syndromes
What medication is the first line management?
What is important to note?
MEDICATION:
- B-blockers (Nadolol - longer acting)
NB:
- All asymptomatic individuals meeting diagnostic criteria for LQTS, including those who have a pathogenic variant on molecular testing and a normal QTc interval - should be started on medication.
VIP - Long QT syndromes
What advice/recommendations should you give to the patient with a diagnosis of LQTS?
GENERAL ADVICE
- Avoid triggers such as:
- Vigorous exercise, competitive sports / activities associated with intense physical activity and/or emotional stress
- Exposure to loud noises such as alarm clocks and phone ringing - Avoid medications that cause further prolongation of the QT interval or provoke torsade de pointes, such as:
- Mood stabilizers (Lithium)
- Antibiotics (Fluoroquinolones)
- Tricyclic antidepressants (Amitriptyline)
- Antipsychotics (Quetiapine) - Consider implantable cardioverter-defibrillators (ICD) for those with:
- Beta-blocker-resistant symptoms
- Inability to take beta blockers
- History of cardiac arrest
- Asymptomatic but suspected to be at very high risk (e.g., those with ≥2 pathogenic variants on molecular testing) - Testing of presymptomatic at-risk family members (especially of individuals age <18 years, as the risk for cardiac events is greatest in childhood):
- To prevent syncope and sudden death. - Consider availability of automatic external defibrillators at home, at school, and in play areas
- Importance of follow up for surveillance and ensuring compliance.
VIP - Long QT syndromes
A pregnant woman, previously shown to be a carrier of a pathogenic KCNH2 variant with normal ECG’s for the past 10 years is on a B-blocker.
The variant has recently been reclassified as a VUS, and so the patient wants to stop the medication.
What is your advice for follow up and management?
INQUIRE:
1. What lead to her investigation for LQTS in the first place? Was she symptomatic? Is there a family history?
- Who else in the family has been tested for this variant? Are they symptomatic?
POSSIBILITIES:
1. If a clinical diagnosis was made in the family, and she was just tested for the familial variant, it is possible that she is still at risk, but the underlying molecular cause has not yet been identified.
IMPORTANT POINTS TO EMPHASIZE:
1. LQTS exhibits both inter- and intrafamilial VARIABILITY as well as REDUCED PENETRANCE of the ECG changes and symptoms; i.e. individuals with a pathogenic variant may have a normal QTc (defined as <440 msec) on baseline ECG and remain asymptomatic.
- Age-related risk in individuals with pathogenic variants: Cardiac events may occur from infancy through middle age but are most common from the preteen years through the 20s; cardiac events are uncommon after age 40 years, but females remain at risk after age 40 years.
- Whether the variant is clinically significant or insignificant, it may be transmitted in a clinically significant fashion to future generations as either autosomal dominant LQTS (i.e., Romano-Ward syndrome) or JLNS, a confusing phenomenon during pedigree evaluation.
- Regarding pregnancy, the postpartum period is associated with increased risk for a cardiac event, especially in individuals with the LQTS type 2 phenotype. Beta blocker treatment was associated with a reduction of events in this nine-month time period after delivery.
VIP - Long QT syndromes
Important points to ask on history.
Personal or family history of:
- A confirmed clinical/molecular diagnosis of LQTS
- Symptoms of tachyarrhythmias (torsades de pointes), like palpitations, dizziness, nausea
- Syncope with or without stress in the absence of warning (ruling out vasovagal and orthostatic forms of syncope), and in the absence of aura, incontinence, and postictal findings (ruling out seizures)
- Aborted cardiac arrest
- Any identifiable triggers precipitating the attacks, like exercise, emotion, stress, or if they occured during sleep
- Unexplained sudden cardiac death at age <30 years (i.e. in a child or young adult) or SIDS, in an immediate family member.
Rule out other factors that can lengthen the QTc interval:
- QT-prolonging drugs
- Electrolyte imbalance (like hypokalemia) secondary to diarrhea, vomiting, metabolic conditions, and unbalanced diets for weight loss (malnutrition or liquid protein diet).
- Neurological conditions (subarachnoid bleed)
- Primary myocardial problems: cardiomyopathy (HCM, DCM), myocarditis, ischemia
Review of systems inquiring about features that may be associated with syndromic LQTS:
- Hearing loss
- Dysmorphic features
VIP - Long QT syndromes
Important findings on physical exam and investigations.
PHYSICAL EXAM:
Features that may be associated with syndromic LQTS:
- Hearing loss
- Dysmorphic features
INVESTIGATIONS - ECG:
1. QTc prolongation (>470 msec in males; >480 msec in females), torsade de pointes
- During exercise:
- Failure of the QTc to shorten normally
- Prolongation of the QTc interval
- Characteristic T-wave abnormalities - QTc interval measurement during change from supine to standing position (prolonged)
CONFIRMS THE DIAGNOSIS:
The presence of a corrected QT interval ≥500 ms in repeated ECGs in the absence of a secondary cause for QT prolongation.
VIP - Long QT syndromes
Jervell and Lange-Nielsen syndrome
- Classic presentation
- Triggers
- Gene
- Inheritance
- Treatment
- Important counseling points
CLASSIC PRESENTATION:
- Deafness: congenital profound bilateral sensorineural hearing loss
- Prolongation of the QTc interval (usually >500 msec) is associated with: tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation
- Syncopal episodes during periods of stress, exercise, or fright
- Sudden death (more than half of untreated children with JLNS die before age 15 years)
- Extra: Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS (> in KCNQ1)
TRIGGERS:
- Intense or sudden emotion (anger, crying, test taking, or other stressful situations, amusement park rides, frightening movies)
- Exercise (jumping into cold water, swimming, running, competitive sports)
GENES:
- KCNQ1 or KCNE1.
INHERITANCE:
- Autosomal recessive: caused by biallelic pathogenic variants in either gene.
- The milder presentation of JLNS associated with KCNE1 pathogenic variants compared to JLNS associated with KCNQ1 pathogenic variants.
TREATMENT:
- Cochlear implantation to treat hearing loss
- Beta-adrenergic blockers for long QT interval (only partially effective.);
- Implantable cardioverter defibrillators (ICDs) for those with a history of cardiac arrest and/or failure to respond to other treatments;
- Ensure availability of automated external defibrillators where appropriate;
- Family members of individuals with JLNS should be trained in cardiopulmonary resuscitation (CPR) as up to 95% of individuals with JLNS have a cardiac event before adulthood;
- Standard treatment for those with iron-deficiency anemia.
IMPORTANT COUNSELING POINTS:
- Parents and other heterozygous carriers will not have SNHL, but may or may not have the long QT syndrome (LQTS) phenotype associated with fainting and death heritable in an autosomal dominant manner. This form of LQTS is called Romano-Ward syndrome (RWS).
- At conception, each sib of an affected individual has a: 25% chance of being affected with JLNS
50% chance of being a carrier of a JLNS-causing pathogenic variant and potentially at risk for LQTS,
25% chance of being unaffected and not a carrier.
VIP - Long QT syndromes
Romano–Ward syndrome
- Classic presentation
- Gene
- Inheritance
- Triggers
CLASSIC PRESENTATION:
- The term “Romano-Ward syndrome” (RWS) refers to forms of long QT syndrome with a purely cardiac electrophysiologic disorder, inherited in an autosomal dominant manner (LQTS types 1-3, type 5, type 6, and types 9-15).
- Characterized by:
QT prolongation
T-wave abnormalities
Ventricular tachycardia torsade de pointes (TdP)
GENES:
- Many: KCNQ1, KCNH2, and SCN5A are the most common
- Only KCNQ1 and KCNE1 have been implicated in both RWS and JLNS.
INHERITANCE:
- Autosomal dominant
TRIGGERS:
- Noted previously
IMP - Long QT syndromes
Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia - give examples
Andersen-Tawil syndrome (LQTS type 7 - KCNJ2 - AD) is associated with prolonged QT interval, muscle weakness, and facial dysmorphism.
Timothy syndrome (LQTS type 8 - CACNA1C - AD) is characterized by prolonged QT interval and hand/foot, facial, and neurodevelopmental features.
Jervell and Lange-Nielson syndrome (JLNS), an LQTS disorder associated with biallelic pathogenic KCNQ1 or KCNE1 variants, is associated with profound sensorineural hearing loss.
VIP - Long QT syndromes
OSCE scenario: VUS in one gene and pathogenic variant in another gene.
LQTS associated with biallelic pathogenic variants or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) is generally associated with a more severe phenotype with longer QTc interval.
IMP - Long QT syndromes
Genotype-phenotype correlation = KCNH2
- Genotype
- Phenotype
- Average QTc
- ST-T-Wave Morphology
- Incidence of Cardiac Events
- Cardiac Event Trigger
- Sudden Death Risk
- Genotype: LOF - potassium channel gene
- Phenotype: LQTS type 2
- Average QTc: 480 msec
- ST-T-Wave Morphology: Bifid T-waves
- Incidence of Cardiac Events: 46%
- Cardiac Event Trigger: Exercise, Emotion (anger, crying, test taking, or other stressful situations), Auditory stimuli (startling, alarm clock, loud horn, ringing phone), Sleep
- Sudden Death Risk: 6%-8%
IMP - Long QT syndromes
Genotype-phenotype correlation = KCNQ1
- Genotype
- Phenotype
- Average QTc
- ST-T-Wave Morphology
- Incidence of Cardiac Events
- Cardiac Event Trigger
- Sudden Death Risk
- Genotype: LOF - potassium channel gene
- Phenotype: LQTS type 1
- Average QTc: 480 msec
- ST-T-Wave Morphology: Broad-base T-wave
- Incidence of Cardiac Events: 63%
- Cardiac Event Trigger: Exercise (jumping into cold water, swimming, running, competitive sports), Emotion (anger, crying, test taking, or other stressful situations, amusement park rides, frightening movies)
- Sudden Death Risk: 6%-8%
IMP - Long QT syndromes
Genotype-phenotype correlation = SCN5A
- Genotype
- Phenotype
- Average QTc
- ST-T-Wave Morphology
- Incidence of Cardiac Events
- Cardiac Event Trigger
- Sudden Death Risk
- Genotype: GOF - sodium channel gene
- Phenotype: LQTS type 3
- Average QTc: ~490 msec
- ST-T-Wave Morphology: Long ST, small T
- Incidence of Cardiac Events: 18%
- Cardiac Event Trigger: Sodium channel blocking medications, High fever, Sleep
- Sudden Death Risk: 6%-8%
