Genetics of Cardiac Arrhythmias

Clinical Description and Manifestations of Long QT Syndrome

Congenital LQTS comprises a distinct group of cardiac channelopathies characterized by delayed repolarization of the myocardium resulting in heart rate-corrected QT prolongation (QTc >480 msec as the 50th percentile among individuals with genetically confirmed LQTS; Fig. 63.1A ) and an increased risk of syncope, seizures, and SCD in the setting of a structurally normal heart. The incidence of LQTS may exceed 1 in 2500 persons. However, individuals with LQTS may not manifest QT prolongation on a resting 12-lead surface electrocardiogram (ECG). This repolarization abnormality almost always is without consequence; however, it is rarely triggered by exertion, swimming, emotion, auditory stimuli such as an alarm clock, or the postpartum period, which can cause the heart to become electrically unstable and develop a life-threatening and sometimes lethal arrhythmia, torsade de pointes (TdP) (see Chapter 70 ). Though the cardiac rhythm often returns to normal spontaneously, resulting in only transient syncope, 5% of untreated and unassuming LQTS individuals succumb to a fatal arrhythmia as their sentinel event. However, it is estimated that nearly half of individuals experiencing SCD, stemming from this very treatable arrhythmogenic disorder, may have exhibited prior warning signs (i.e., exertional syncope, family history of premature sudden death) that went unrecognized. LQTS may explain approximately 20% of autopsy-negative SUD in the young and 10% of SIDS.

Genetic Basis for Long QT Syndrome

LQTS is a genetically heterogeneous disorder of cardiac repolarization inherited predominantly in an autosomal dominant pattern (formerly referred to as Romano-Ward syndrome). It is rarely inherited in a recessive pattern as illustrated by Jervell and Lange-Nielsen Syndrome (JLNS), characterized by extreme QTc prolongation, high risk of SCD, and sensorineural hearing loss. Spontaneous/sporadic germline mutations can account for nearly 5% to 10% of LQTS. To date, hundreds of mutations have now been identified in LQTS-susceptibility genes responsible for a nonsyndromic “classical” LQTS phenotype. In addition, three extremely rare, multisystem disorders (ATS formerly referred to as LQT7; ABS formerly referred to as LQT4; and TS formerly referred to as LQT8) associated with marked QTc prolongation and an array of extra-cardiac manifestations have also been described and are detailed in the later sections of this chapter.

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 ( eTable 63.1 )— KCNQ1- encoded I _Ks (K _v 7.1) potassium channel (LQT1, approximately 35%, loss-of-function); KCNH2 -encoded I _Kr (K _v 11.1) potassium channel (LQT2, approximately 30%, loss-of-function); and SCN5A- encoded I _Na (Na _v 1.5) sodium channel (LQT3, approximately 10%, gain-of-function)—which are responsible for the inscription of the cardiac action potential ( Fig. 63.2 ). Approximately 5% to 10% of patients have multiple mutations and such patients present at a younger age and with greater expressivity.

ETABLE 63.1

Summary of Putative Heritable Arrhythmia Syndrome Susceptibility Genes

Gene		Locus	Protein
Congenital Long QT Syndrome
Major LQTS Genes
	KCNQ1 (LQT1) ∗	11p15.5	I Ks potassium channel alpha subunit (KVLQT1, K v 7.1)
	KCNH2 (LQT2) ∗	7q35–36	I Kr potassium channel alpha subunit (HERG, K v 11.1)
	SCN5A (LQT3) ∗	3p21–p24	Cardiac sodium channel alpha subunit (Na v 1.5)
Minor LQTS Genes (listed alphabetically)
	AKAP9 #	7q21–q22	Yotiao
	CACNA1C †	12p13.3	Voltage-gated L-type calcium channel (Ca v 1.2)
	CALM1 ∗	14q32.11	Calmodulin 1
	CALM2 ∗	2p21	Calmodulin 2
	CALM3 ∗	19q13.2–q13.3	Calmodulin 3
	CAV3 #	3p25	Caveolin-3
	KCNE1 #	21q22.1	Potassium channel beta subunit (MinK)
	KCNE2 #	21q22.1	Potassium channel beta subunit (MiRP1)
	KCNJ5 #	11q24.3	K ir 3.4 subunit of I KACH channel
	SCN4B #	11q23.3	Sodium channel beta 4 subunit
	SNTA1 #	20q11.2	Syntrophin-alpha 1
Triadin Knockout Syndrome
	TRDN ∗	6q22.31	Cardiac Triadin
Andersen-Tawil Syndrome
	KCNJ2 (ATS1) ∗	17q23	I K1 potassium channel (K ir 2.1)
Timothy Syndrome
	CACNA1C ∗	12p13.3	Voltage-gated L-type calcium channel (Ca v 1.2)
Cardiac-Only Timothy Syndrome
	CACNA1C	12p13.3	Voltage-gated L-type calcium channel (Ca v 1.2)
Short QT Syndrome
	KCNH2 (SQT1)	7q35–36	I Kr potassium channel alpha subunit (HERG, K v 11.1)
	KCNQ1 (SQT2)	11p15.5	I Ks potassium channel alpha subunit (KVLQT1, K v 7.1)
	KCNJ2 (SQT3)	17q23	I K1 potassium channel (K ir 2.1)
	CACNA1C (SQT4)	12p13.3	Voltage-gated L-type calcium channel (Ca v 1.2)
	CACNB2 (SQT5)	10p12	Voltage-gated L-type calcium channel beta 2 subunit
	CACN2D1 (SQT6) SLC22A5 (SQT7) SLC4A3 (SQT8)	7q21–q22 5q31.1 2q35	Voltage-gated L-type calcium channel 2 delta 1 subunit Organic cation transporter 2 (↓ carnitine transport; ↑ I K1 ) Anion exchanger 3 (↑ intracellular pH; ↓ Cl − conductance)
Catecholaminergic Polymorphic Ventricular Tachycardia
	RYR2 (CPVT1)	1q42.1–q43	Ryanodine Receptor 2
	CASQ2 (CPVT2)	1p13.3	Calsequestrin 2
	KCNJ2 (CPVT3)	17q23	I K1 potassium channel (Kir2.1)
	CALM1	14q32.11	Calmodulin 1
	CALM2	2p21	Calmodulin 2
	CALM3	19q13.2–q13.3	Calmodulin 3
	TRDN	6q22.31	Cardiac Triadin
Brugada Syndrome
	SCN5A (BrS1) ∗	3p21–p24	Cardiac sodium channel alpha subunit (Na v 1.5)
	Minor BrS Genes (listed alphabetically)
	ABCC9 #	12p12.1	ATP Binding Cassette, Subfamily C Member 9
	ANK2 # CACNA1C #	2p13.3	Voltage-gated L-type calcium channel (Ca v 1.2)
	CACNA2D1 #	7q21–q22	Voltage-gated L-type calcium channel 2 delta 1 subunit
	CACNB2 #	10p12	Voltage-gated L-type calcium channel beta 2 subunit
	DLG1	3q29	Synapse-associated protein 97
	FGF12 #	3q28	Fibroblast Growth Factor 12
	GPD1L #	3p22.3	Glycerol-3-phosphate dehydrogenase 1-like
	HCN4 #	15q24.1	Hyperpolarization-activated cyclic nucleotide-gated channel 4
	HEY2	6q	Hes Related Family BHLH Transcription Factor With YRPW Motif 2
	KCND3 #	1p13.2	Voltage-gated potassium channel (I to ) subunit K v 4.3
	KCNE3 #	11q13.4	Potassium channel beta subunit 3 (MiRP2)
	KCNE5 #	Xq22.3	Potassium channel beta subunit 5
	KCNH2 #	7q35–36	I Kr potassium channel alpha subunit (HERG, K v 11.1)
	KCNJ8 #	12p12.1	Inward rectifier K(+) channel K ir 6.1
	PKP2 #	12p11	Plakophilin-2
	RANGRF # RRAD	17p13.1 16q22.1	RAN guanine nucleotide release factor 1 RAD GTPase (↓ I Na ; ↓ focal adhesions)
	SCN1B #	19q13	Sodium channel beta 1
	SCN2B #	11q23	Sodium channel beta 2
	SCN3B #	11q24.1	Sodium channel beta 3
	SCN10A #	3p22.2	Sodium Voltage-Gated Channel Alpha Subunit 10 (Na v 1.8)
	SEMA3A	7p12.1	Semaphorin 3A
	SLMAP #	3p14.3	Sarcolemma associated protein
	TRPM4 #	19q13.33	Transient receptor potential cation channel, subfamily M, member 4
Early Repolarization Syndrome
	CACNA1C	2p13.3	Voltage-gated L-type calcium channel (Ca v 1.2)
	CACNA2D1	7q21–q22	Voltage-gated L-type calcium channel 2 delta 1 subunit
	CACNB2	10p12	Voltage-gated L-type calcium channel beta 2 subunit
	KCNJ8 SCN5A	12p12.1 3p21–p24	Inward rectifier K(+) channel Kir6.1 Cardiac sodium channel alpha subunit (Na v 1.5)
Idiopathic Ventricular Fibrillation
	CALM1	14q32.11	Calmodulin 1
	DPP6	7q36	Dipeptidyl-peptidase-6
	IRX3	38p13	Iroquois homeobox gene family transcription factor
	RYR2	1q42.1–q43	Ryanodine Receptor 2
Isolated Progressive Cardiac Conduction Disease
	GJA5	1q21	Connexin 40
	SCN1B SCN5A	19q13 3p21–p24	Sodium channel beta 1 Cardiac sodium channel alpha subunit (Na v 1.5)
	TRPM4	19q13.33	transient receptor potential cation channel, subfamily M, member 4
Sick Sinus Syndrome
	ANK2	4q25–q27	Ankyrin B
	HCN4	15q24–q25	Hyperpolarization-activated cyclic nucleotide-gated channel 4
	MYH6	14q11.2	Myosin, Heavy Chain 6, Cardiac Muscle, Alpha
	SCN5A	3p21–p24	Cardiac sodium channel alpha subunit (Na v 1.5)
Ankyrin-B Syndrome
	ANK2	4q25–q27	Ankyrin B
Familial Atrial Fibrillation
	ABCC9 ANK2	12p12.1 4q25–q27	ATP Binding Cassette, Subfamily C Member 9 Ankyrin B
	GATA4	8p23.1–p22	GATA-binding protein 4
	GATA5	20q13.33	GATA-binding protein 5
	GJA5	1q21	Connexin 40
	KCNA5	12p13	I Kur potassium channel (Kv1.5)
	KCNE2	21q22.1	Potassium channel beta subunit (MiRP1)
	KCNH2	7q35–36	I Kr potassium channel alpha subunit (HERG, Kv11.1)
	KCNJ2	17q23	I K1 potassium channel (Kir2.1)
	KCNQ1	11p15.5	I Ks potassium channel alpha subunit (KVLQT1, Kv7.1)
	LMNA	1q22	Lamin A
	MYL4	17q21.32	Myosin Light Chain 4
	NKX2-5	5q35.1	NK homeobox 5
	NPPA	1p36	Atrial natriuretic peptide precursor A
	NUP155	5p13	Nucleoporin 155KD
	PRKAG2	7q36.1	AMP-activated protein kinase 2
	RYR2	1q42.1–q43	Ryanodine Receptor 2
	SCN1B	19q13	Sodium channel beta 1
	SCN2B	11q23	Sodium channel beta 2
	SCN3B	11q24.1	Sodium channel beta 3
	SCN4B	11q23.3	Sodium channel beta 4
	SCN5A	3p21–p24	Cardiac sodium channel alpha subunit (NaV1.5)

Genes without any of the above symbols have yet to be assessed by a ClinGen working group and the strength of epidemiologic and functional evidence to support their gene-disease associations is highly variable.

∗ Denotes genes that received “definitive” or “strong” evidence designations from the Clinical Genome Resource (ClinGen).

# Denotes genes that received “disputed” or “limited” evidence designations from ClinGen.

† Denotes genes that received “moderate” evidence designations from ClinGen.

Following the discovery of the canonical LQTS-susceptibility genes in 1995 and 1996, rapid advances in deoxyribonucleic acid (DNA) sequencing technology has facilitated the discovery of new disease-susceptibility genes in scenarios (i.e., singletons and small pedigrees) not feasible with classical linkage analysis. As a result, the last two decades have seen a rapid explosion in the number of new disease-susceptibility genes, which includes the 14 minor LQTS-susceptibility genes that may underlie an additional 5% to 10% of LQTS cases ( eTable 63.1 ).

However, many of the minor LQTS-susceptibility genes (e.g., AKAP9 , ANK2 , CAV3 , KCNE1 , KCNE2 , SCN4B , and SNTA1 ; eTable 63.1 ) were discovered using hypothesis-driven, candidate-based analysis of biologically plausible genes rather than unbiased approaches (linkage analysis, next-generation sequencing-based trio/pedigree analysis, etc.). ^, Furthermore, many putative disease-causative variants used to establish these minor LQTS disease-gene associations (GDAs) were discovered before the true background rate of rare and presumably innocuous amino acid-altering variants was illuminated by large-scale sequencing projects such as the Genome Aggregation Database (gnomAD). Therefore, it comes as little surprise that some putative LQTS-causative nonsynonymous variants are observed at frequencies in public exomes/genomes that far exceed the anticipated contribution of the minor LQTS-susceptibility gene in which it resides (i.e., 1:250,000 or 0.0004% for a ≤1% contributor) or in some cases the estimated prevalence of LQTS as a whole (i.e., 1:2500 or 0.04%). ^,

As a result, the strength of many minor LQTS GDAs is rightfully in question. To this end, the Clinical Genome Resource (ClinGen) Clinical Domain Channelopathy Working Group recently released a semi-quantitative, evidence-based assessment of the GDA strength for the 17 putative LQTS-susceptibility genes. ^, However, the canonical LQTS-susceptibility genes ( KCNQ1 /LQT1, KCNH2 /LQT2, and SCN5A /LQT3) and redundant genes ( CALM1-3 ) responsible for calmodulinopathic LQTS received “definitive” evidence designations, and the majority of the remaining LQTS-susceptibility genes received a “limited” or “disputed” evidence designation (see eTable 63.1 ). ^, As a result, the majority (9/17; 53%) of alleged LQTS-susceptibility genes have now been demoted to so-called gene of uncertain significance (GUS) status.

Unfortunately, owing to the limited number of sentinel variants used to establish initial GDAs, nearly all novel, nonsynonymous variants identified in a minor LQTS-GUS are destined to receive, at best, an ambiguous variant of uncertain significance (VUS) designation in accordance with the current American College of Medical Genetics and Genomics (ACMG) guidelines. ^, Therefore, the continued inclusion of GUS on gene panels likely elevates the signal-to-noise ratio associated with LQTS genetic testing as well as the risk of genetic testing misinterpretation, and subsequent diagnostic miscues. ^,

However, in light of (1) the increasing contribution of common genetic variants (oligogenic/polygenic basis) to the genetic architecture of LQTS, particularly in the approximately 10% to 20% of individuals that remain genotype-negative, ^, (2) clear role of rare and common variants in some GUS, most notably the KCNE1 -encoded MiRP1 β-subunit, ^, in low penetrant and acquired/drug-induced forms of LQTS, and (3) potential that new evidence could elevate the ClinGen designation of a minor LQTS GUS, it is difficult to argue for the blanket removal of all limited- and disputed-evidence genes from commercial LQTS genetic testing panels at this time.

As minor LQTS GUS are likely to remain on LQTS genetic testing panels for the foreseeable future, ordering health care professionals should prioritize clinically actionable (ACMG pathogenic/likely pathogenic) variants identified in ClinGen definitive ( KCNQ1 , KCNH2 , SCN5A , and CALM1-3 ), strong ( TRDN ), and moderate ( CACNA1C ) evidence genes and approach any variant (ACMG pathogenic, likely pathogenic, or VUS) identified in a ClinGen limited/disputed evidence gene with caution, as detailed in Figure 63.3 . Importantly, if any doubt exists in regards to the clinical implications of variants labeled, currently or previously, as pathogenic/likely pathogenic in a GUS or VUS in definitive, strong, or moderate-evidence LQTS-susceptibility genes, strong consideration should be given to referring the patient to a dedicated Cardiovascular Genomics Clinic with the suitable infrastructure and expertise needed to carefully interpret, continually reappraise, and if needed act on these genetic findings (see Fig. 63.3 ).

Phenotypic Correlates for the Three Canonical Long QT Syndrome Genotypes

Specific genotype/phenotype associations in LQTS have emerged, suggesting relatively gene-specific triggers, ECG patterns, and response to therapy (see Fig. 63.1A ). Swimming and exertion-induced cardiac events are strongly associated with mutations in KCNQ1 (LQT1), whereas auditory triggers and events occurring during the postpartum period most often occur in patients with LQT2. While exertion- or emotional stress-induced events are most common in LQT1, events occurring during periods of sleep/rest are most common in LQT3. In a study of 721 LQT1 and 634 LQT2 genetically confirmed patients from the U.S. portion of the international LQTS registry, a multivariate analysis was used to assess the independent contribution of clinical and mutation-specific factors in the occurrence of a first triggered event associated with exercise, arousal, or sleep/rest. Among the 221 symptomatic LQT1 patients, their first cardiac event was most often associated with exercise (55%) followed by sleep/rest (21%), arousal (14%), and nonspecific (10%) triggers, whereas the 204 symptomatic LQT2 patients most often had their first event associated with either arousal triggers (44%) or nonexercise/nonarousal triggers (43%), and only 13% of the symptomatic LQT2 patients had an exercise-induced triggered first event. For LQT2 patients, the rate of arousal-triggered events was similar between male and female children, whereas there was a significantly higher rate of arousal-triggered events in women than men (26% vs. 6%, at age 40 years) following the onset of adolescence. Characteristic gene-suggestive ECG patterns have been described previously. LQT1 is associated with a broad-based T wave, LQT2 with a low amplitude notched or biphasic T wave, and LQT3 with a long isoelectric segment followed by a narrow-based T wave (see Fig. 63.1A ).

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 LQT1. This is key because the underlying genetic basis heavily influences the response to standard LQTS pharmacotherapy where beta blockers are extremely protective in LQT1 patients and moderately protective in patients with LQT2 and LQT3. Additionally, targeting the pathologic, LQT3-associated late sodium current with agents such as mexiletine, flecainide, or ranolazine represents a gene-specific therapeutic option for LQT3. Attenuation in repolarization with clinically apparent shortening in the QTc has been demonstrated with such a strategy and recently, a reduction in LQT3-triggered events using this strategy has been demonstrated. While the generalization that beta-blocker efficacy is genotype-type dependent has been well accepted, the effectiveness of beta-blocker therapy may be largely trigger-specific, rather than dependent on genotype. For both LQT1 and LQT2 patients, beta-blockade was associated with a pronounced 71% (LQT2 patients) to 78% (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. However, it should be noted that many symptomatic LQT1 and LQT2 patients experience a subsequent cardiac event associated with a different trigger. For example, an LQT2 patient first presenting with an arousal event or event during sleep may present subsequently with an exercise-triggered event. Therefore, beta-blocker therapy remains first-line therapy even for patients experiencing a non-exercise-associated first event.

In addition, intra-genotype risk stratification has been realized for the two most common subtypes of LQTS based on mutation type, mutation location, and cellular function. Patients with LQT1 secondary to Kv7.1 missense mutations localizing to the transmembrane-spanning domains clinically have a twofold greater risk of a LQT1-triggered cardiac event than LQT1 patients with mutations localizing to the C-terminal region. In addition, missense mutations localizing to the so-called cytoplasmic loops (C-loops) within the transmembrane-spanning domains, an area of the protein involved in adrenergic channel regulation, are associated with the highest rate of both exercise- and arousal-triggered events, but were not associated with an increase rate of sleep/rest associated events. C-loop K _v 7.1 missense mutations were consistently associated with a sixfold increase in risk for exercise-triggered events compared to non-missense mutations, and a nearly threefold increase compared to N- and C-terminal missense mutations.

Patients with mutations resulting in a greater degree of K _v 7.1 loss-of-function at the cellular in vitro level (dominant negative) have a twofold greater clinical risk compared to mutations that damaged the biology of the K _v 7.1 channel less severely (haploinsufficiency). Adding to the traditional clinical risk factors, molecular location and cellular function are independent risk factors used in the evaluation of patients with LQTS.

Akin to molecular risk stratification in LQT1, patients with LQT2 secondary to K _v 11.1 pore-region mutations have a longer QTc, a more severe clinical manifestation of the disorder, and experience significantly more arrhythmia-related cardiac events occurring at a younger age than those LQT2 patients with non-pore mutations in K _v 11.1. Similarly, in a Japanese cohort of LQT2 patients, those with pore mutations had a longer QTc, though not significant among probands, non-probands with pore mutations experienced their first cardiac event at an earlier age than those with a non-pore mutation. Most recently, additional information has been gleaned suggesting that LQT2 patients with mutations involving the transmembrane pore region had the greatest risk for cardiac events, those with frame-shift/nonsense mutations in any region had an intermediate risk, and those with missense mutations in the C-terminus had the lowest risk for cardiac events. Interestingly, LQT2 patients with mutations in the pore-loop region of the K _v 11.1 channel have a greater than twofold increased risk for arousal-triggered events, and LQT2 patients with non-pore loop TM region mutations have a nearly sevenfold increase in the risk for exercise-triggered cardiac events compared with patients with N-terminal/C-terminal mutations.

Incomplete penetrance and variable expressivity are clinical hallmark features of LQTS, and it has been long thought that co-inheritance of a true disease-causing mutation and either a common or rare channel genetic variant may determine the expressed severity of the disorder. For example, the co-existence of the common K897T-KCNH2 polymorphism and the A1116V-KCNH2 mutation (on opposite alleles) led to a more severe clinical course in a single Italian LQTS family. The A1116V mutation by itself produced a sub-clinical phenotype of mild QT prolongation and an asymptomatic course, while the proband hosting both variants had clinically overt disease consisting of a diagnostic QT prolongation, presyncopal episodes, and cardiac arrest. Besides cardiac ion channels, single nucleotide polymorphisms (SNPs) of non-ion channel genes like NOS1AP (the gene encoding the nitric oxide synthase 1 adapter protein), ADRA2C (alpha-2C adrenergic receptor), and ADRB1 (beta-1 adrenergic receptor) can modify disease severity in LQTS.

There is compelling evidence for a strong disease modifying effect of a 3′ untranslated region (3′UTR) KCNQ1 allele-specific haplotype in LQT1 mutation positive pedigrees; the magnitude of the effect on the QTc and symptomology go well beyond any other currently described genetic modifiers. The KCNQ1 gene encodes a single K _v 7.1 ion channel alpha subunit that assemble to create a pore-forming K _v 7.1 tetrameric channel. Therefore, if a patient had a heterozygous KCNQ1 mutation (i.e., one normal KCNQ1 gene allele and one mutant allele), one would expect that if both the normal and mutant gene alleles were expressed in equal amounts, then 1/16 of the K _v 7.1 channels would be a normal homomeric tetramer and 1/16 of the K _v 7.1 channels would be a mutant homomeric tetramer. The remaining channels would be hybrids containing both normal and mutant alpha-subunits. If expression of the normal KCNQ1 gene allele was somehow suppressed, then there would be relatively more KCNQ1 mutant alpha-subunits translated and ultimately assembled to provide more dysfunctional K _v 7.1 channels, thus leading to a more severe manifestation of the disorder (see eFig. 63.1 ). The opposite would be true if the mutation containing the KCNQ1 allele was suppressed.

Most genes have a 3′UTR that generates an mRNA transcript containing regions of cis-regulatory binding sites for small noncoding microRNAs (miRNAs) that bind to the transcript and ultimately inhibit that gene’s expression. Naturally occurring genetic variation within these 3′UTRs (miR-SNPs) can either abolish existing or creating new miRNA binding sites. SNPs in the KCNQ1 3′UTR create a “suppressive” haplotype by generating new miRNA binding sites that suppress the expression of the KCNQ1 allele in which they reside. Inheritance of the “suppressive” haplotype residing on the normal “healthy” allele produced a more severe LQT1 phenotype, whereas the inheritance of the “suppressive” haplotype residing on the same allele as the KCNQ1 mutation gave a less severe LQT1 phenotype (shorter QTc and fewer symptoms). This intriguing discovery both explains a significant component of reduced penetrance and variable expressivity that is a common feature of arrhythmia syndromes, and also represents a paradigm shift in our thinking about disease-modifying genetic-drivers of mendelian disorders (as one of the most important genetic determinants of disease severity in LQT1 appears to be the 3′UTR KCNQ1 haplotype on the allele inherited from the unaffected “non-LQTS” parent).

In line with the concept that common variants within noncoding regions of the human genome may impact the penetrance and expressivity (a.k.a. clinical variability) of rare LQTS pathogenic/likely pathogenic variants, recent studies have demonstrated that an aggregate polygenic risk score (PRS) comprised of common variants that influence QTc duration at the level of population can explain 2% to 15% of the clinical variability observed among LQTS patients. ^, Although the clinical utility of these PRSs in the management of genotype-positive LQTS patients remains unclear, they do provide intriguing and potentially clinically relevant insights into the genetic architecture of the 10% to 20% of LQTS patients that remain genotype-negative for monogenic LQTS.

Of note, the recent rare disease genome-wide association study (GWAS) by Lahrouchi et al. provided compelling evidence, by way of a 68 SNP/common variant–weighted PRS, that genotype-negative LQTS likely represents a polygenic subtype that arises secondary to the accumulation of multiple QTc-prolonging common genetic variants. Interestingly, in comparison to patients with canonical LQTS (i.e., LQT1-LQT3), these genotype-negative patients had longer aggregate QTc intervals and a similar rate of event-free survival. These observations are in line with those from other genetic heart diseases considered, at least initially, to be predominantly mendelian/monogenic such as familial hypercholesterolemia and BrS.

LQTS, like many cardiovascular disorders, appears to have a more complex genetic architecture than anticipated initially that likely includes monogenic, oligogenic, and polygenic subtypes ( Fig. 63.4 ). As our understanding of the genetic architecture underlying LQTS continues to grow, it appears increasingly likely that commercial gene panel-based LQTS genetic tests in use today require an overhaul to better accommodate assessment of the 10% to 20% of patients that have oligogenic/polygenic subtypes, and the genetic background that influences the penetrance and expressivity of canonical LQTS-causative variants.

Calmodulinopathic Long QT Syndrome

In the early 2010s, three independent, unbiased exome sequencing studies implicated heterozygous sporadic/de novo pathogenic variants in the biologically redundant CALM1 , CALM2 , and CALM3 genes that collectively encode calmodulin (an ubiquitously expressed and essential calcium-handling protein) in infants/young children with extreme QT prolongation (i.e., >600 msec) and adrenergic-triggered life-threatening ventricular arrhythmias. Subsequently, pathogenic variants in CALM1-3 have also been identified in patients with CPVT , IVF , and CPVT/LQTS overlap phenotypes. However, recent data from the multicenter International Calmodulinopathy Registry indicate that LQTS (49%) and CPVT (28%) phenotypes predominate.

From a pathophysiological perspective, it is interesting to note that all LQTS-causative CALM1-3 mutations described to date localize within or proximal to calcium-coordinating residues of the C-terminal lobe (C-lobe) of calmodulin and impart a marked reduction in calcium-binding affinity. ^, Although calmodulin is known to regulate a number of cardiac ion channels, the predominant effect of LQTS pathogenic/likely pathogenic CALM1-3 variants appears to be loss of calcium-dependent inactivation (CDI) of the L-type calcium channel (LTCC) resulting in unrestrained calcium influx (i.e., LTCC/I _CaL gain-of-function). In contrast, CPVT pathogenic/likely pathogenic variants in CALM1-3 localized at the N-terminal (N-lobe) and C-lobe increase RyR2-binding affinity/single channel open probability and spontaneous calcium release from the sarcoplasmic reticulum rather than calcium-binding affinity.

Unfortunately, the calmodulinopathies (such as CALM-LQTS and CALM-CPVT) are frequently refractory to conventional LQTS- and CPVT-directed therapies (beta-blockers). At present, it is not known whether the varying levels of neurodevelopmental delay observed in a minority of patients with a calmodulinopathy (17%) are secondary to anoxic brain injury in the setting of recurrent cardiac arrhythmias or are related to developmental effects of perturbed calcium-handling in the central nervous system. Regardless, a combination of pharmacologic, sympathectomy, and device-related therapies is typically required and even then is often inadequate. As such, the calmodulinopathies represent an important target for gene-therapy and other targeted precision medicine approaches.

Clinical Description and Manifestations of Timothy Syndrome

Timothy syndrome (TS) is an extremely rare (<30 patients described worldwide) multisystem, highly lethal arrhythmia disorder, associated with both cardiac and extracardiac abnormalities. The typical cardiac manifestation of TS includes fetal bradycardia, extreme prolongation of the QT interval (QTc >500 msec) often with macroscopic T wave alternans and 2:1 atrioventricular block at birth (see Fig. 63.1C ). These abnormalities often coincide with congenital heart defects or cardiomyopathies. 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). Currently, most TS patients die before reaching puberty. While the majority of TS has been described as sporadic/de novo occurrences, few cases with somatic mosaicism associated with a less severe phenotype have recently been described. For example, the CACNA1C mutation may be present in the patient’s skeletal muscle, but could only be present in traces or even completely absent in other cell types of the human body (i.e., absent in heart, blood lymphocytes), where the patient may present with simple syndactyly.

Clinical Description and Manifestations of Short QT Syndrome

Short QT syndrome (SQTS), first described in 2000 by Gussak et al., is associated with a short QT-interval (usually ≤320 msec) on a 12-lead ECG ( Fig. 63.1D ), paroxysmal atrial fibrillation (AF), syncope, and an increased risk for SCD. Giustetto et al. analyzed the clinical presentation of 53 patients with SQTS from 29 families (the largest cohort studied to date). They found that 62% of the patients were symptomatic, with cardiac arrest being the most common symptom (31% of patients) and frequently the first manifestation of the disorder. A fourth of the patients had a history of syncope, and nearly 30% had a family history of SCD. Symptoms including syncope or cardiac arrest most often occurred during periods of rest or sleep. Nearly one-third presented with AF. SCD was observed during infancy, suggesting the potential role for SQTS as a rare pathogenic basis for some cases of SIDS.

Genotype-Phenotype Correlates in Short QT Syndrome

While there are insufficient data to clearly define genotype-phenotype correlations in SQTS (probably fewer than 60 cases have been described in the literature to date), gene-specific ECG patterns are beginning to emerge. The typical ECG pattern consists of a QT-interval 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.

Owing to the prematurely small sample size, a recent report revealed that SQTS patients with KCNH2 mutations have a shorter QT and a greater response to hydroquinidine therapy than patients with a non-KCNH2 mediated SQTS. Based on a clinical variable analysis of 65 mutation-positive SQTS patients among 132 SQTS cases previously reported in the literature, Harrell et al. indicated that patients with KCNH2 -mediated SQTS (SQT1) exhibit a later age of onset of manifestation, whereas patients with KCNQ1 -mediated SQTS (SQT2) have a higher prevalence of bradyarrhythmias and AF.

Clinical Description and Manifestations of Drug-Induced Torsade de Pointes

Drug-induced long QT syndrome (DI-LQTS) and torsades de pointes is a multifactorial clinical entity that tends to surface in the setting of multiple 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) and non-modifiable (female sex, underlying genetic disposition, structural heart disease, and diabetes) risk factors (see Chapter 64, Chapter 9 ). The estimated incidence of DI-LQTS/DI-TdP is drug-dependent, while class III anti-arrhythmic agents range between 1% and 8% depending on the drug and dose. DI-TdP and subsequent sudden death are rare events; however, the list of potential “QT-liability” or “torsadegenic” drugs is extensive and includes both anti-arrhythmic drugs (quinidine, sotalol and dofetilide) and many noncardiac medications (antipsychotics, methadone, antimicrobials, antihistamines, and the gastrointestinal stimulant cisapride [see https://www.crediblemeds.org for a comprehensive list]).