Cardiac causes of sudden unexpected death in children and their relationship to seizures and syncope: Genetic testing for cardiac electropathies

From SUDEP Wiki
Revision as of 16:34, 23 June 2017 by Ycarmen1 (talk | contribs) (Created page with "'''Author:''' '''''Michael J. Ackerman''''' The sentinel descriptions of congenital long QT syndrome (LQTS) under the eponyms of Jervell and Lange-Nielsen syndrome and Romano...")
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Jump to navigation Jump to search

Author: Michael J. Ackerman

The sentinel descriptions of congenital long QT syndrome (LQTS) under the eponyms of Jervell and Lange-Nielsen syndrome and Romano-Ward syndrome were provided in 1957 and the early 1960s. In 1995, the discipline of cardiac channelopathies was birthed formally with the landmark discoveries of cardiac channel mutations as the pathogenic basis for LQTS. Over the past decade, the discipline has expanded considerably being comprised of at least a dozen distinct heritable arrhythmia syndromes, several disease-susceptibility genes, and hundreds of implicated mutations. Previously confined to the purview of research testing, diagnostic genetic testing for several channelopathies is now available for routine clinical use.


Each day in the United States nearly 1000 individuals die suddenly due to fatal ventricular arrhythmias. Although most of these sudden cardiac deaths occur in middle-aged and elderly individuals with coronary artery disease, a tragic minority involves apparently healthy infants, children, adolescents, and young adults. Many of these youthful deaths are well explained following an autopsy with hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, coronary artery anomalies, and myocarditis implicated as the culprit. However, the cause and manner of death is not established in a significant number of cases prompting speculation for the presence of a silent electrical killer referred to as a “cardiac channelopathy.”

Cardiac channelopathies is a relatively new study discipline to the field of cardiac electrophysiology and comprises congenital long QT syndrome (LQTS), Andersen—Tawil syndrome (ATS), Timothy syndrome (TS), drug-induced Torsade de pointes (TdP), short QT syndrome (SQTS), Brugada syndrome (BrS), congenital sick sinus syndrome, progressive cardiac conduction disease (PCCD), catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1), familial atrial fibrillation, approximately 5 to 10% of sudden infant death syndrome (SIDS), and a significant percentage of sudden unexplained death involving children, adolescents, and young adults called sudden unexplained death syndrome. LQTS is the prototype of these cardiac channelopathies and is understood today as a genetically heterogeneous disease pursuant primarily to defective ion channels whose natural history ranges widely from sudden death in infancy to asymptomatic longevity. This genetic and phenotypic heterogeneity are similarly relevant themes for the other channelopathies as well. Until recently, mutations involving the genes that encode key cardiac channel proteins formed the cornerstone of the channelopathies. However, with the recent demonstration of mutant proteins other than ion channels underlying, for example, type 4 LQTS (LQT4) and type 2 CPVT (CPVT2), this field may be more accurately reflected by the term “cardiac electropathies.”

In the case of LQTS, individuals host an electrical glitch that may or may not be self-evident on a resting 12-lead electrocardiogram (ECG) as a prolonged QT interval. This abnormality in repolarization is almost always without consequence on a beat-to-beat basis. Rarely, when the conduction system is caught off guard by particular triggers such as exertion, auditory stimuli such as phone ringing, or the postpartum period, the heart can “spin out of control” into the trademark dysrhythmia of LQTS, TdP. TdP causes an individual to either faint and wake up, faint and begin seizing, or faint and die with the outcome hinging entirely on whether or not the heart’s rhythm spontaneously returns to normal or is restored by the life-saving action of bystanders equipped with an automatic external defibrillator. This clinical triad of syncope, seizures, and sudden death constitutes the universal clinical presentation for these cardiac electropathies. It is quite common for an individual and their family with LQTS for example to have been diagnosed with a generalized seizure disorder and treated with antiseizure medications.

The autosomal recessive form of LQTS (known as Jervell and Lange-Nielsen syndrome, (JLNS)), which includes the auditory phenotype of sensorineural hearing loss, was first described in 1957. In the early 1960s, Drs. Romano and Ward (known as Romano—Ward syndrome) described the autosomal-dominant form of LQTS having an isolated cardiac phenotype. Thirty years later in 1991, the Keating laboratory discovered the first LQTS-associated genetic locus and the precise genetic identity of this particular locus would elude these investigators for 5 years. Then, on March 10, 1995, the pathogenic basis for LQTS was unveiled with tandem publications in Cell by the Keating laboratory revealing mutations in the HERG-encoded IKr potassium channel (now annotated KCNH2) and the SCN5A-encoded INa sodium channel as the genetic underpinnings for LQTS.

These studies formed the cornerstone for subsequent work on channelopathies and provided an exquisite molecular model to study ventricular arrhythmogenesis. The previously elusive chromosome 11p15.5 LQTS-linked locus was captured in 1996 with the identification of LQT1-causing mutations in the IKs potassium channel alpha subunit encoded by KVLQT1 (now annotated KCNQ1). A year later, Splawski and coworkers demonstrated that mutations involving both alleles of KVLQT1 (“double hits”) yielded JLNS. Hundreds of mutations involving these three genes, KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), have been identified to date and these genotypes represent the three most common LQTS genotypes conveniently and coincidentally in rank order: LQT1 (30 to 35%), LQT2 (25 to 30%), and LQT3 (5 to 10%, Fig. 1). In addition, mutations involving the KCNE1-encoded beta subunit for IKs and the KCNE2-encoded beta subunit for IKr rarely cause LQTS (LQT5 and LQT6, respectively).

Double hits involving either KCNQ1 or KCNE1 or compound heterozygosity in KCNQ1 and KCNE1 provide the substrate for autosomal-recessive JLNS. Finally, the molecular basis underlying the chromosome 4 linked LQTS (conveniently annotated LQT4) was exposed in 2003 with the identification of mutations in the ANKB-encoded ankyrin-B. With the identification of the first nonchannel form of LQTS, consideration to broaden the term to “electropathies” seems appropriate. Recently, approximately 1% of patients having a potpourri of dysrhythmia phenotypes were found to harbor ANKB mutations.

Given the rarity of LQT4-, LQT5-, and LQT6-causing mutations, the vast majority of genotype—phenotype correlations that have emerged during the past decade has focused on the three principal genotypes of LQTS, namely LQT1, LQT2, and LQT3. These genotype—phenotype studies have revealed a plethora of clinically relevant associations including relatively gene-specific electrocardiographic profiles, gene-specific responses to epinephrine QT stress testing, gene-specific arrhythmogenic triggers, gene-specific responsiveness to beta-blocker therapy, gene-directed treatment strategies, and gene-specific risk stratification.

In addition, structure-function insights of these three principal LQTS-causing genes have also markedly expanded the list of potentially heritable arrhythmia syndromes. In contrast to the loss-of-function LQT2-causing KCNH2 mutations, gain-of-function mutations in KCNH2 have now been associated with the repolarization opposite of LQTS, namely short QT syndrome (SQT1). Similarly, gain-of-function mutations in KCNQ1 have been implicated in type 2 SQTS (SQT2) as well as one pedigree of familial atrial fibrillation. On the other hand, loss-of-function SCN5A mutations underlie approximately 15 to 30% of BrS as well as idiopathic ventricular fibrillation, progressive cardiac conduction disease (Lenegre syndrome), congenital sick sinus syndrome, and now rarely dilated cardiomyopathy often accompanied by atrial fibrillation. Approximately 5% of SIDS stems from a cardiac channelopathy such as LQT3.

All of these clinically relevant genotype—phenotype correlations have been enabled by “pseudoclinical” LQTS genetic testing performed over the last decade in select few laboratories under IRB-approved research protocols. During this time, the research subjects participating in these genetic testing research protocols have not benefited to the degree in which the science of LQTS and the other channelopathies has been advanced. During this era of free research testing, results had to be communicated directly to the research subject rather than the physician seeking the test. In addition, if the results were ever disclosed to the participant, it was not uncommon for 6 to 24 months (some cases longer) to elapse. In general, research laboratories did not contact the research subject to convey that no LQTS-associated mutations were detected. These factors largely prevented the incorporation of genetic testing into the clinical evaluation and management of the patient and family with a suspected channelopathy.

Today, however, building on these pioneering observations, both LQTS and BrS genetic testing are now commercially available as a clinical diagnostic test. Akin to breast cancer genetic testing, LQTS genetic testing represents one of the first sequencing-based genetic tests for any cardiac disorder. Genaissance Pharmaceuticals provides comprehensive high-throughput DNA sequencing of the entire open reading frame (60 amino acid encoding exons and 6807 translated nucleotide base pairs) and adjacent spice site regions totaling over 12 kb of genetic material for the five cardiac channel genes implicated in LQTS: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6), via their test called FAMILION™ ([]).

The comprehensive FAMILION™ genetic test for cardiac ion channel mutations costs $5400 for the index case. SNC5A analysis only for BrS ($2700) is also available with the caveat that the yield of genetic testing for BrS is presently 15 to 30% with the majority of BrS remaining genetically undefined. With respect to LQTS, nearly three of four patients with a robust clinical phenotype consistent with LQTS will have a disease-associated mutation(s) elucidated by comprehensive scanning of these five channel genes with the three genotypes (LQT1-3) accounting for >97% of genetically identifiable LQTS to date. However, with both KCNE1 and KCNE2 containing only a single translated exon, genetic testing for LQT5 and LQT6 is included in the comprehensive analysis. FAMILION™ genetic test does not include LQT4 genotyping. Importantly, approximately 10% of patients with an identifiable mutation will also have a second putative pathogenic mutation; thus, it is critical for any genetic testing strategy to be comprehensive in scope rather than the initial “find and stop” genetic testing strategy that was implemented in research laboratories. Following identification of a LQTS-causing mutation, mutation-specific confirmatory testing is available ($900). The patient’s genetic test result, whether positive or negative, is reported to the ordering physician in 4 to 6 weeks. Since its availability in May 2004, the FAMILION™ genetic test has been covered variably by insurance providers ranging from denial to 100% coverage with the majority covering at least 50 to 75% of the cost.

Commercial genetic testing for LQTS is also offered presently by the Center for Human Genetics at Boston University ([]). However, only 18 of the 60 (30%) translated exons within the five cardiac channel genes are analyzed. Recently, we completed comprehensive analysis of the five cardiac channel genes in 541 consecutive, unrelated patients referred for LQTS genetic testing. Of the 211 unique LQTS-associated mutations identified in our study, 74 (35%) would have been missed by this restricted analysis including 28, 35, and 44% of the LQT1-, LQT2-, and LQT3-associated mutations. In addition, this selected analysis includes only exons 26 and 28 of SCN5A; thus, the vast majority of BrS1-associated mutations would not be detected.

Based on the established clinical evidence that genotype has both prognostic and therapeutic relevance in LQTS, Table 2 summarizes the clinical indications for LQTS genetic testing. Essentially, all patients with a suspected clinical diagnosis of LQTS should undergo genetic testing. For those index cases with a positive genetic test, concentric circles of first-degree relatives should be offered testing to distinguish normal relatives from genotype-positive, preclinical carriers. Genetic counseling, preventative health measures including avoidance of medications associated with QT liability, and treatment decisions can be tailored according to the presence or absence of a particular LQTS-associated genotype.

Besides congenital LQTS, many exogenous factors can affect cardiac repolarization (acquired LQTS). For example, over 50 FDA-approved medications are associated with QT prolongation and are potentially “torsadogenic” and several medications such as terfenadine, astemizole, and propulsid have been removed from the market due to their rare association with drug-induced TdP and sudden death. Otherwise quiescent LQTS-causing mutations have been implicated as the pathogenic substrate for a subset of drug-induced sudden cardiac death (SCD). Therefore, it seems reasonable to consider LQTS genetic testing in the individual having a history of drug-induced TdP or drug-induced aborted cardiac arrest. In the absence of a family history suggestive of congenital LQTS, comprehensive five gene mutational analysis in the setting of solely QT interval lengthening during exposure to a “QT drug” may be of limited value. It remains to be determined whether a person’s profile of common cardiac channel polymorphisms mediates either pharmacogenetic susceptibility to arrhythmias in the setting of medications or pathogenetic susceptibility for an arrhythmia in the setting of acquired heart disease such as congestive heart failure, myocardial infarction, or hypertrophic cardiomyopathy.

Postmortem genetic testing of the five LQTS-associated channel genes can be considered in SIDS and SUDS bearing in mind two important considerations. First, although a cogent argument can be proffered in support of this type of molecular autopsy, reimbursement for genetic testing on decedents is likely to be declined. Second, approximately 5% of SIDS is due to LQTS and the prevalence of cardiac channel mutations in SUDS has not been ascertained. In a rigorous evaluation of family members following a case of SUD, approximately one-third were found to have a potentially heritable cardiovascular diagnosis including LQTS. Furthermore, we elicited putative CPVT1-associated mutations involving the RyR2-encoded calcium release channel in 7 of 49 cases of SUDS where the average age of the decedent was 14 years. Currently, mutational analysis of RyR2 is not commercially available. This is also an important consideration with regards to LQTS genetic testing as CPVT mimics the clinical phenotype of LQTS, particularly concealed LQT1. Recently, we demonstrated that among families referred for LQTS genetic testing chiefly because of a personal or family history of a drowning or near-drowning, fully 20% had CPVT1-associated RyR2 mutations rather than mutations in the LQTS-associated genes corresponding with the suspected clinical diagnosis.

With respect to BrS genetic testing, except for perhaps longer H-V intervals in BrS1, there do not appear to be any significant phenotypic distinctions between SCN5A-based BrS (BrS1) and genotype-negative BrS. Thus, the primary purpose of BrS genetic testing would be to establish a gold standard diagnostic marker to be used for the accurate classification of preclinical, SCN5A-positive carriers. Again, it must be kept in mind that 15 to 30% of index cases with BrS will in fact have BrS1. Genetic testing for all the other electropathies including KCNJ2 analysis for ATS, CACNA1C for TS, and RYR2 and CASQ2 for CPVT remains relegated to research-based testing.

From the sentinel descriptions of congenital LQTS by Drs. Jervell, Lange-Nielsen, Romano, and Ward in the late 1950s and early 1960s to the predominantly Keating-led discoveries of the fundamental molecular underpinnings of LQTS and the other channelopathies in the 1990s to the arrival of the first sequencing-based genetic test for any heart rhythm condition in particular and any cardiac disorder for that matter in 2004, the discipline of cardiac channelopathies has experienced tremendous maturation. Genetic testing for LQTS has matured fully from a research-based test to a routine clinically available molecular test available to all.

Research laboratories that have attempted to stand in the gap on behalf of families affected by this malady by trying to provide “pseudoclinical” genetic testing are now able to return or continue their quests for discovery of novel pathogenic mechanisms underlying these heritable arrhythmia syndromes. Indeed, to that end, the Keating laboratory has done it again with the identification in 2004 of the molecular basis (namely an identical sporadic mutation in the CACNA1C-encoded alpha subunit for the L-type calcium channel) of a complex multisystem phenotype coined Timothy syndrome. Although LQT8 has been suggested to annotate this phenotype, Timothy syndrome and TS1 is preferred by this author as there will surely be genetic heterogeneity governing this multisystem disorder not to mention the well deserved recognition for Dr. Keating’s study coordinator, Katherine Timothy, who has devoted the past two decades of her life to make a difference on behalf of these families.

To be sure, the research and researchers devoted to the study of cardiac channelopathies can now claim to not only have advanced the science of their discipline and concurrently their curriculum vitae but to have truly enabled and facilitated the healing of the sick with the full translation of their genomic discoveries that are now being delivered to the mainstream of clinical practice.