B P7 C63 Genetics of Cardiac Arrhythmias

Question 1

Congenital LQTS comprises a distinct group of cardiac channelopathies characterized by delayed repolarization of the myocardium resulting in heart rate-corrected QT prolongation (QTc >___ msec)

Answer 1

> 480 msec

Question 2

Though the cardiac rhythm often returns to normal spontaneously, resulting in only transient syncope, ___% of untreated and unassuming LQTS individuals succumb to a fatal arrhythmia as their sentinel event

Answer 2

5%

Question 3

LQTS may explain approximately __% of autopsy-negative SUD in the young and __% of SIDS

Answer 3

SUD: 20%
SIDS: 10%

Question 4

Approximately 75% of patients with a clinically robust diagnosis of LQTS host either loss-of-function or gain-of-function pathogenic/likely pathogenic variants in one of these three major/canonical LQTS genes —_____ (LQT1, approximately 35%, loss-of-function); _____ (LQT2, approximately 30%, loss-of-function); and _____(LQT3, approximately 10%, gain-of-function)—which are responsible for the inscription of the cardiac action potential

Answer 4

LQT1: KCNQ1-encoded IKs (Kv7.1) K channel LOF
LQT2: KCNH2-encoded IKr (Kv11.1) K channel LOF
LQT3: SCN5A-encoded INa (Nav1.5) Na channel GOF

Question 5

Give the genes affected of the major LQTS genotypes

LQTS 1
LQTS 2
LQTS 3

Answer 5

LQTS 1 - loss of function KCNQ1
LQTS 2 - loss of function KCNH2
LQTS 3 - gain of function SCN5A

Question 6

Give the ECG patterns and cardiac event triggers

LQTS 1
LQTS 2
LQTS 3

Answer 6

LQTS 1 - broad based T wave
Swimming, Emotional duress, eXercise induced (SEX)

LQTS 2 - low amplitude notched or biphasic T wave
Postpartum, HypoKalemia, sudden Noises (PKN)

LQTS 3 - long isoelectric segment followed by narrow based T wave (delayed T wave)
Sleep/rest

Question 7

Among the 221 symptomatic LQT1 patients, their first cardiac event was most often associated with _____.

Answer 7

Exercise (55%)
Sleep/rest (21%)
Arousal (14%)
Non- specific (10%) triggers

Question 8

The 204 symptomatic LQT2 patients most often had their first event associated with either _____.

Answer 8

Arousal triggers (44%)
Nonexercise/nonarousal triggers (43%)
Exercise-induced triggered first event (13%)

Question 9

However, exceptions to these relatively gene-specific T wave patterns exist, and due caution must be exercised with making a pre-genetic test prediction of the particular LQTS subtype involved, as the most common clinical mimicker of the LQT3-looking ECG is seen among patients with _____.

Answer 9

LQTS1

Question 10

________________ are extremely protective in LQT1 patients and moderately protective in patients with LQT2 and LQT3

Answer 10

Beta blockers

Question 11

For both LQT1 and LQT2 patients, beta-blockade was associated with a pronounced ____% (LQT2 patients) to ____% (LQT1 patients) reduction in the risk for exercise-triggered cardiac events, but had no statistically significant effect on the apparent risk for arousal- or sleep/rest-triggered events.

Answer 11

LQT1: 78%
LQT2: 71%

Question 12

_______________ rare autosomal recessive form of LQTS characterized by transient/consistent QT prolongation with extensive precordial (V1 –V4 ) T wave inversions, severe and often refractory exercise-induced ventricular arrhythmias during childhood

Gene?

Answer 12

Triadin Knockout Syndrome

Gene - TRDN-encoded triadin

TKOS is primarily a disorder of calcium handling

Reduces the expression of key proteins such as RyR2, c questrin2, and junctin reducing the co-localization of the LTCC/RyR2 and RyR2/Calsequestrin2 in the CRU. 21 The resulting remodeling of the CRU leads to reduced sarcoplasmic reticulum calcium release and impaired LTCC CDI that ultimately leads to calcium overload in the sarcoplasmic reticulum

Triggering delayed afterdepolarization- and/or early afterdepolarization-mediated ventricular arrhythmias.

Question 13

___________ extremely rare (<30 patients described worldwide) multisystem, highly lethal arrhythmia disorder, associated with both cardiac and extracardiac abnormalities.

The typical cardiac manifestation include fetal bradycardia, extreme prolongation of the QT interval (QTc >500 msec) often with macroscopic T wave alternans and 2:1 atrioventricular block at birth

Gene?

Answer 13

Timothy Syndrome
Gene - CACNA1C-encoded cardiac LTCC (Cav1.2)

Cardaic only Timothy Syndrome - if no extracardiac phenothype

Extracardiac abnormalities often consist of simple syndactyly (webbing of the toes and fingers), dysmorphic facial features, abnormal dentition, immune deficiency, severe hypoglycemia, and developmental delay (including autism)

Question 14

Typical cardiac manifestations of Timothy Syndrome

Answer 14

• Fetal bradycardia
• 2:1 atrioventricular block at birth
• Extreme prolongation of the QT interval (QTc >500 msec) often with macroscopic T wave alternans

Question 15

Extracardiac manifestations of Timothy syndrome

Answer 15

Syndactyly (webbing of the toes and fingers)
Hypoglycemia
Abnormal dentition
Immune deficiency
Dysmorphic facial features
Developmental delay (including autism)

Question 16

Genetic basis for Timothy Syndrome

Answer 16

De novo missense mutation, p.G406R-CACNA1C, in the alternatively spliced exon 8A of the CACNA1C-encoded cardiac LTCC (Cav1.2)

It is important for excitation-contraction coupling in the heart and mediates an inward depolarizing current in cardiomyocytes

Question 17

All three pedigrees hosting _____ presented with this unique and atypical phenotypic sequela consistent with cardiac- only Timothy syndrome (COTS).

Answer 17

p.R518C-CACNA1C/p.R518H-CACNA1C

In 2015, Boczek et al. used exome sequencing to identify a novel CAC- NA1C mutation p.R518C-CACNA1C that was most likely responsible for the observed phenotype in a large pedigree with concomitant LQTS,hypertro- phic cardiomyopathy (HCM),congenital heart defects,and sudden cardiac death

Question 18

___________ syndrome associated with a short QT-interval (usually ≤320 msec) on a 12-lead ECG, paroxysmal atrial fibrillation (AF), syncope, and an increased risk for SCD

Genes?

Answer 18

Short QT syndrome

Genes:
Gain-of-function mutations
KCNH2 (SQT1)
KCNQ1 (SQT2)
KCNJ2 (SQT3)

Loss-of-function mutations
CACNA1C (SQT4)
CACNB2b (SQT5)
CACNA2D1 (SQT6)

Symptoms including syncope or cardiac arrest most often occurred during periods of rest or sleep

The typical ECG pattern consists of a QTinterval of ≤320 msec (QTc ≤340 msec) and tall, peaked T waves in the precordial leads with either a short ST segment present or no ST-segment at all.

The T waves tend to be symmetrical in SQT1 but asymmetrical in SQT2-4.

In SQT2, inverted T waves can be observed.

In SQT5, a BrS-like ST elevation in the right precordial lead could be observed as well.

Question 19

Short QT syndrome (SQTS), first described in 2000 by Gussak et al., is associated with a short QT-interval (usually </=____ msec) on a 12-lead ECG, paroxysmal atrial fibrillation (AF), syncope, and an increased risk for SCD

Answer 19

320 mesc

Question 20

They found that 62% of the patients with Short QT syndrome were symptomatic, with _____ being the most common symptom and frequently the first manifestation of the disorder.

Answer 20

Cardiac arrest (31%)

Question 21

SQTS is most often inherited in an autosomal dominant manner; however, some de novo sporadic cases have been described. To date, mutations in six genes have been implicated in the pathogenesis of SQTS, including gain-of-function mutations in the potassium channel encoding genes _____ and loss-of-function mutations in _____ encoding for LTCC alpha, beta, and delta subunits, respectively

Answer 21

GOF:
KCNH2 (SQT1)
KCNQ1 (SQT2)
KCNJ2 (SQT3)

LOF:
CACNA1C (SQT4)
CACNB2b (SQT5)
CACNA2D1 (SQT6)

Question 22

The typical ECG in SQTs pattern consists of a QT- interval of <___ msec (QTc <___ msec) and _____.

Answer 22

QT: <320 msec
QTc: <340 msec

Tall, peaked T waves (precordial leads)
+
Short ST segment or no ST-segment at all

Question 23

The T waves tend to be symmetrical in _____ but asymmetrical in SQT2-4

Answer 23

Symmetrical: SQT1
Asymmetrical: SQT2-4

Question 24

In SQT___, a BrS-like ST elevation in the right precordial lead could be observed as well.

Answer 24

SQT5

Question 25

Risk factors for drug induced TdP?

Answer 25

**Modifiable** * Electrolyte abnormalities such as **hypokalemia** * **Co-administration** of multiple QT-prolonging drugs * **Drug accumulation** due to renal/hepatic impairment or inhibition of cytochrome P450 metabolism **Non-modifiable** Female sex Underlying genetic disposition Diabetes Structural heart disease **Class III anti-arrhythmic agents** range between **1% and 8%** depending on the drug and dose.

Question 26

The estimated incidence of DI-LQTS/DI-TdP is drug- dependent, while **class III anti-arrhythmic agents** range between _____% depending on the drug and dose

Answer 26

1-8%

Question 27

Andersen-Tawil Syndrome triad of ______ Gene?

Answer 27

Periodic paralysis Ventricular ectopy/arrhythmia (frequent) Variable developmental abnormalities PVV Gene - Mutations in **KCNJ2** * The burden and nature of the electrocardiographic abnormalities (mostly ventricular bigeminy, polymorphic VT, and in rare circumstances bi-directional VT) observed in ATS is reminiscent of the electrocardiographic hallmarks of CPVT and can lead to misdiagnosis. However, the presence of these findings at rest as well as the variable **presence of micrognathia, low-set ears, widely spaced eyes, and clinodactyly** helps differentiate ATS from CPVT ECG * Prominent U-waves (blue arrows) * QT-U interval prolongation (black bracket) * Frequent ventricular ectopy (orange arrows) in a p.R82W-KCNJ2–positive Andersen-Tawil syndrome patient. After exclusion of the U-wave in the top panel, the patient’s QT interval (443 msec) is within normal limits.

Question 28

Mutations in _____ account for approximately two-thirds of ATS, while the molecular basis of the residual third of ATS cases remains genetically and mechanistically elusive.

Answer 28

KCNJ2

Question 29

In humans, **loss-of-function** variants in **ANK2** were shown to cause a dominantly inherited cardiac arrhythmia with an increased risk for _____ in the setting of _____

Answer 29

SCD Overt QTc prolongation

Question 30

Similar to ATS, this initial discrepancy appears to have been caused partly by the erroneous inclusion of prominent U-waves/sinusoidal T-U abnormalities in QTc calculations. As a result, the QT-U interval may appear markedly prolonged in ABS, but true QTc values typically reside in the normal- to-borderline range as commonly reported.As a result, this disorder has been renamed _____ or the ABS.

Answer 30

SSS with bradycardia

Question 31

_____________ hereditable arrhythmia syndrome characterized clinically by **spontaneous or class I antiarrhythmic-provoked coved type ST-segment elevation (≥2 mm) followed by a negative T wave in ≥1 mm right precordial leads (V 1 or V2 , often referred to as a type 1 Brugada ECG pattern)** on ECG and an increased risk of SCD during **rest, sleep, or febrile episodes** Gene?

Answer 31

Brugada Syndrome Gene - loss of function in SCN5A encoded Channel BrS is defined by electroanatomic and structural abnormalities involving the right ventricular outflow tract (RVOT) epicardium. As a result, BrS is best classified as a **focal epicardial arrhythmogenic cardiomyopathy** ECG - A spontaneous type 1 Brugada syndrome pattern (coved/downsloping ST elevation ≥2 mm [blue arrows] with T wave inversions ≥1 mm [orange arrows] in the right precordial leads) in a genotype-negative patient with Brugada syndrome and easily inducible ventricular fibrillation from the right ventricular outflow tract on electrophysiology study

Question 32

Brugada syndrome (BrS) is a heritable arrhythmia syndrome characterized clinically by _____.

Answer 32

(1) Spontaneous or class I antiarrhythmic-provoked **coved type ST-segment elevation** (>/=2 mm) (2) **Negative T wave** in >/=1 mm right precordial leads on ECG (3) Increased risk of SCD during **rest, sleep, or febrile episodes**

Question 33

Although BrS was initially thought to disproportionately affect males with structurally normal hearts, recent imaging, post-mortem necropsy, and concomitant electroanatomic mapping/targeted endomyocardial biopsy studies have provided evidence that BrS is defined by electroanatomic and structural abnormalities involving the _____.

Answer 33

RVOT epicardium

Question 34

As a result, BrS is best classified as a _____ rather than a true cardiac channelopathy.

Answer 34

Focal epicardial arrhythmogenic cardiomyopathy

Question 35

At present, loss-of-function pathogenic/likely pathogenic variants in the _____-encoded Na 1.5 cardiac sodium channel underlie approximately 20% to 30% of BrS cases and constitute Brugada syndrome type 1 (BrS1)

Answer 35

LOF SCN5A

Question 36

_____________ is a heritable arrhythmia syndrome that affects an estimated 1 in 10,000 individuals, and manifests clinically with exercise-induced syncope or sudden death in individuals with otherwise structurally normal hearts Gene? Trigger? Electrocardiographic hallmark

Answer 36

Catecholaminergic Polymorphic Ventricular Tachycardia Gene - autosomal dominant, mutations in the **RYR2-encoded cardiac ryanodine receptor/calcium release channel** Trigger - swimming, exercise * Adrenergically induced ventricular ectopy/arrhythmias including the pathognomonic finding of **bidirectional VT** that serve as the electrocardiographic hallmarks of CPVT Presentation of exercise-induced syncope or cardiac arrest in the setting of a QTc less than 460 msec should always prompt first consideration of CPVT rather than so-called “concealed” or “normal QT interval” LQT1 EcG - exercise-induced ventricular ectopy in a p.N98S-CALM1-positive catecholaminergic polymorphic ventricular tachycardia patient. During the early stages of exercise (top panel), occasional premature ventricular contractions (blue arrow) are observed. With increasing workloads (middle panel), more complex patterns of ventricular ectopy, most notable premature ventricular contractions in a pattern of bigeminy (blue arrows), is observed. At peak exercise (bottom panel), untreated or sub-optimally treated patients’ manifest findings such as bi-directional couplets (orange box) and triplets (gold boxes) and bidirectional ventricular tachycardia (nonsustained in this case; blue box)

Question 37

Similar to LQT1, _____ is a potentially lethal arrhythmia- precipitating trigger in CPVT.

Answer 37

Swimming

Question 38

However, aside from **nonspecific findings such as bradycardia and subtle U-waves**, the resting 12-lead ECG in CPVT is **completely normal**. As a result, the use of **exercise stress testing (EST), or catecholamine provocation testing (CPT)**, is needed to unearth the adrenergically induced ventricular ectopy/arrhythmias, including the pathognomonic finding of _____, that serve as the electrocardiographic hallmarks of CPVT

Answer 38

Bidirectional VT

Question 39

Clinically, a presentation of **exercise-induced syncope or cardiac arrest** in the setting of a **QTc < 460** msec should always prompt first consideration of _____ rather than so-called “concealed” or “normal QT interval” LQT1

Answer 39

CPVT

Question 40

In CPVT, exercise-induced _____ is a far more likely observation than the more specific but less sensitive finding of bidirectional VT

Answer 40

PVCs in bigeminy

Question 41

CPVT’s potential lethality is illustrated by mortality rates of _____% by 35 years of age and the presence of a positive family history of young (<40 years) SCD for more than a third of CPVT individuals and in as many as 60% of families hosting RyR2 mutations

Answer 41

30-50%

Question 42

Inherited in an autosomal dominant fashion, mutations in the ____-encoded cardiac ryanodine receptor/calcium release channel represent the most common genetic subtype of CPVT (CPVT1), accounting for 60% of clinically “strong” cases of CPVT

Answer 42

RYR2

Question 43

Unlike CPVT1, patients with this new disorder termed **“calcium release channel deficiency syndrome”** or CRC deficiency syndrome display _____.

Answer 43

(1) Relatively **non-specific ECG** findings (i.e., intermittent QTc prolongation with U-waves) (2) **Modest or no ventricular ectopy** during EST/CPT or prolonged ambulatory Holter monitoring

Question 44

Unlike the RyR2 gain-of-function (i.e., hyperactive/ hyperreactive “leaky” channels) observed in CPVT1, CRC deficiency syndrome appears to result in RYR2 _____-of-function that nearly ablates calcium-induced calcium release in response to catecholamine infusion.

Answer 44

RyR2 loss-of-function

Question 45

_________ syndrome is characterized by the **elevation (≥1 mm above baseline) of the QRS-ST junction (the so-called J-point)** manifesting as either **QRS slurring (at the transition of the QRS to the ST-segment) or notching (a positive deflection inscribed on terminal S wave)**, ST-segment elevation with upper concavity and prominent T waves in ≥2 contiguous leads Gene?

Answer 45

Early Repolarization Syndrome Gene - missense mutation in **KCNJ8** J-point elevation (≥1 mm above baseline) on **inferolateral** ECG leads was over represented significantly (31%) and was greater in magnitude among 206 case subjects who experienced cardiac arrest due to IVF Those patients with ER were more often males and have a personal history of syncope or cardiac arrest during sleep

Question 46

The early repolarization (ER) pattern is characterized by:

Answer 46

(1) Elevation (≥ 1 mm above baseline) of the QRS-ST junction (J-point) manifesting as either QRS **slurring** (at the transition of the QRS to the ST-segment) or **notching** (a positive deflection inscribed on terminal S wave) (2) ST-segment elevation with upper concavity (3) Prominent T waves in≥2 contiguous leads

Question 47

Haissaguerre et al. have noted that J-point elevation (≥ 1 mm above baseline) on _____ ECG leads was over represented significantly (31%) and was greater in magnitude among 206 case subjects who experienced cardiac arrest due to IVF compared to 412 (5%,p < 0.001) age, sex, race, and level of physical activity matched controls

Answer 47

Inferolateral leads

Question 47

The prevalence of the ER pattern in the general population has been reported to range from less than _____%, depending on age, sex, race, and the criteria for J-point elevation

Answer 47

1-13%

Question 48

________ is one of the most common cardiac conduction disturbances in the **absence of structural heart disease** and is characterized by **progressive (age-related) impairment of impulse propagation through the His-Purkinje system**, with **right or left bundle branch block and widening of the QRS complex**. This leads to a complete AV block, syncope, and occasionally sudden death

Answer 48

Progressive Cardiac Conduction Defect, aka Lev-Lenègre disease Can lead complete AV block, syncope, and occasionally sudden death.

Question 49

________ syndrome manifests as **inappropriate sinus bradycardia, sinus arrest, atrial standstill, tachycardia-bradycardia syndrome, or chronotropic incompetence** is the leading diagnosis for pacemaker implantation Genes?

Answer 49

Sick Sinus Syndrome Genes: SCN5A HCN4 ANK2 MYH6 Sinus arrest IASB Chronotropic incompetence Atrial standstill TBD "SICAT"

Question 50

Those patients with ER were more often _____ than those without ER pattern.

Answer 50

* Males * Personal history of syncope or cardiac arrest during sleep

Question 51

Following a 30-year follow-up with the end point being cardiac death, **Tikkanen et al.** noted that compared to subjects without a J-point elevation, subjects with ER (J-point 0.1 mV) in the _____ leads had both an **increased risk of cardiac death** (adjusted relative risk [ARR] = 1.28, 95% confidence interval [CI] = 1.04 to 1.59; P = 0.03) and arrhythmias (ARR = 1.43, 95% CI = 1.06 to 1.94, p = 0.03) and this risk was further elevated (cardiac death, ARR = 2.98, 95% CI = 1.85 to 4.92, p < 0.001; arrhythmia, ARR = 2.92; 95% CI = 1.45 to 5.89, p < 0.001) with increasing elevation (0.2 mV) of the J-point.

Answer 51

Inferior leads

Question 52

However, ER pattern localizing to only the _____ leads did not show a statistically significant association with increased risk for arrhythmic cardiac death

Answer 52

Lateral leads

Question 53

The **first gene** to be implicated in **ERS** was described by Haissaguere et al., who reported finding a rare, functionally uncharacterized, _____ mutation in the **KCNJ8**-encoding pore-forming subunit Kir6.1 of the ATP-sensitive potassium channel in a 14-year-old female with IVF.

Answer 53

Missense mutation (p.S422L- KCNJ8)

Question 54

____ is the most common cardiac arrhythmia with a prevalence of about 1% in the general population and 6% in people over the age of 65 years.

Answer 54

AF

Question 55

However, AF can present even at an early age without any identifiable cardiac anomalies and is termed _____ AF, accounting for 2-16% of all AF cases

Answer 55

Lone AF

Question 56

_____ is a major cause of SCD and often is the “final common arrhythmic pathway” for all the aforementioned channelopathies.

Answer 56

VF

Question 57

IVF accounts for as much as __% of sudden deaths, especially in the young. About __% of IVF- labeled individuals will have recurrent episodes of VF. In 20% of such cases, there is a family history of sudden death or IVF, suggesting a hereditary component in some cases

Answer 57

SD: 10% Recurrent iVF: 30% (+) Family history: 20%

Question 58

At present, pathogenic/likely pathogenic variants in _____ have been found to be linked to IVF

Answer 58

- CALM1-3-encoded calmodulin - IRX3-encoded Iroquois homeobox gene family transcription factor - RYR2-encoded RyR2 calcium release channel - promoter haplotype in the DPP6 gene locus on chromosome 7q36

Question 59

This rare condition results in a high burden of narrow complex, polymorphic ventricular ectopy of fascicular/Purkinje origin, increased risk of sudden death, and in some cases, a reversible and likely PVC-mediated dilated cardiomyopathy

Answer 59

Multifocal Ectopic Purkinje-Related Premature Contractions (MEPPC)

Question 60

SND or “sick sinus syndrome” (SSS) manifesting as _____ is the leading diagnosis for pacemaker implantation

Answer 60

Sinus arrest Inappropriate sinus bradycardia Chronotropic incompetence Atrial standstill Tachycardia-bradycardia syndrome

Question 61

Leading diagnosis for pacemaker implantation

Answer 61

SND/SSS

Question 62

_____ commonly occurs in the elderly (1 in 600 cardiac patients >65 years of age) with acquired cardiac conditions including cardiomyopathy,congestive heart failure, ischemic heart disease, or metabolic diseases. However, there are no identifiable cardiac anomalies or conditions underlying _____, which can occur at any age including in utero in a significant number of cases

Answer 62

SSS: acquired SND: idiopathic

Question 63

Mutational analysis of small cohorts and case reports of patients with idiopathic SSS have so far implicated four genes:

Answer 63

SCN5A HCN4 ANK2 MYH6