Objectives This study aimed to identify the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood and adolescence. Background Although sudden cardiac ...death in the young is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important as it enables the identification of individuals at risk, because except for arrhythmia, IVF does not manifest with identifiable clinical abnormalities. Methods Exome sequencing was carried out on 2 family members who were both successfully resuscitated from a cardiac arrest. Results We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac arrest with documented VF at ages 10 and 16 years, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried by 1 of the siblings who died suddenly, from whom DNA was available. The mutation was present in the mother and in another sibling, both asymptomatic but displaying a marginally prolonged QT interval during exercise. Conclusions We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that F90 mediates the direct interaction of CaM with target peptides. Our approach highlights the utility of exome sequencing in uncovering the genetic defect even in families with a small number of affected individuals.
A surgical procedure for cardiac sympathetic denervation successfully controlled recurrent polymorphic ventricular tachycardia in three patients with a heritable form of catecholaminergic polymorphic ...ventricular tachycardia.
A surgical procedure for cardiac sympathetic denervation successfully controlled recurrent polymorphic ventricular tachycardia in three patients with a heritable form of catecholaminergic polymorphic ventricular tachycardia.
Catecholaminergic polymorphic ventricular tachycardia, first recognized in the 1970s,
1
,
2
is a genetic disorder caused by mutations in genes involved in the calcium homeostasis of cardiac cells. After initial observations linked catecholaminergic polymorphic ventricular tachycardia to chromosome 1,
3
two disease-causing genes were identified: the ryanodine receptor 2 gene (
RYR2
)
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,
5
and the cardiac calsequestrin 2 gene (
CASQ2
).
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,
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Catecholaminergic polymorphic ventricular tachycardia is characterized by life-threatening ventricular arrhythmias, usually polymorphic ventricular tachycardia or ventricular fibrillation, especially under conditions of increased sympathetic activity, including physical exercise and emotional stress.
8
,
9
It is often manifested at a young . . .
Objectives This study evaluated the efficacy and safety of flecainide in addition to conventional drug therapy in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). ...Background CPVT is an inherited arrhythmia syndrome caused by gene mutations that destabilize cardiac ryanodine receptor Ca2+ release channels. Sudden cardiac death is incompletely prevented by conventional drug therapy with β-blockers with or without Ca2+ channel blockers. The antiarrhythmic agent flecainide directly targets the molecular defect in CPVT by inhibiting premature Ca2+ release and triggered beats in vitro. Methods We collected data from every consecutive genotype-positive CPVT patient started on flecainide at 8 international centers before December 2009. The primary outcome measure was the reduction of ventricular arrhythmias during exercise testing. Results Thirty-three patients received flecainide because of exercise-induced ventricular arrhythmias despite conventional (for different reasons, not always optimal) therapy (median age 25 years; range 7 to 68 years; 73% female). Exercise tests comparing flecainide in addition to conventional therapy with conventional therapy alone were available for 29 patients. Twenty-two patients (76%) had either partial (n = 8) or complete (n = 14) suppression of exercise-induced ventricular arrhythmias with flecainide (p < 0.001). No patient experienced worsening of exercise-induced ventricular arrhythmias. The median daily flecainide dose in responders was 150 mg (range 100 to 300 mg). During a median follow-up of 20 months (range 12 to 40 months), 1 patient experienced implantable cardioverter-defibrillator shocks for polymorphic ventricular arrhythmias, which were associated with a low serum flecainide level. In 1 patient, flecainide successfully suppressed exercise-induced ventricular arrhythmias for 29 years. Conclusions Flecainide reduced exercise-induced ventricular arrhythmias in patients with CPVT not controlled by conventional drug therapy.
Abstract
Aims
Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode ...identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome.
Methods and results
A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years interquartile range (IQR) 0.1–5.5 years and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively.
Conclusion
Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.
Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance ...and expressivity of the disease are highly variable, and new tools for risk stratification are needed.
We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype.
We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with <or=90% (M(active)) or >90% (M(inactive)) peak I(Na) reduction were analyzed separately.
The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group.
In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.
Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole‐exome sequencing (WES) was carried out on patients from three different families that presented with ...life‐threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans‐2,3‐enoyl‐CoA reductase‐like protein. Both patients had cardiac arrest, stress‐induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL. Analysis of intracellular calcium (Ca2+i) dynamics in human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) generated from this individual (TECRLHom‐hiPSCs), his heterozygous but clinically asymptomatic father (TECRLHet‐hiPSCs), and a healthy individual (CTRL‐hiPSCs) from the same Sudanese family, revealed smaller Ca2+i transient amplitudes as well as elevated diastolic Ca2+i in TECRLHom‐hiPSC‐CMs compared with CTRL‐hiPSC‐CMs. The Ca2+i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine‐induced Ca2+i transients. In addition, the decay phase of the Ca2+i transient was slower in TECRLHom‐hiPSC‐CMs due to decreased SERCA and NCX activities. Furthermore, TECRLHom‐hiPSC‐CMs showed prolonged action potentials (APs) compared with CTRL‐hiPSC‐CMs. TECRL knockdown in control human embryonic stem cell‐derived CMs (hESC‐CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLHom‐hiPSC‐CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT. Patient‐specific hiPSC‐CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.
Synopsis
Mutations in the novel TECRL gene were identified in patients with malignant exercise‐induced arrhythmias. Increased triggered electrical activity upon stimulation in patient‐specific hiPSC‐CMs was rescued by the antiarrhythmic drug flecainide.
Trans‐2,3‐enoyl‐CoA reductase‐like (TECRL) is preferentially expressed in the heart.
Mutations in TECRL cause lethal arrhythmias in humans.
Cardiac defects in TECRL patients are characterized by overlapping features of long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).
Cardiomyocytes differentiated from patient‐specific human induced pluripotent stem cells (hiPSCs) recapitulate the electrical abnormalities observed in TECRL patients.
Mutations in the novel TECRL gene were identified in patients with malignant exercise‐induced arrhythmias. Increased triggered electrical activity upon stimulation in patient‐specific hiPSC‐CMs was rescued by the antiarrhythmic drug flecainide.
Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS).
The purpose of this study was to determine the clinical, genetic, and ...functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias.
The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations.
A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation.
Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.
This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc).
...Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts.
Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 +/- 15 years, mean QTc 428 +/- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45).
Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons.
Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that approximately 65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.
Mutations in the plakophilin-2 gene (PKP2) have been found in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC). Hence, genetic screening can potentially be a valuable ...tool in the diagnostic workup of patients with ARVC.
To establish the prevalence and character of PKP2 mutations and to study potential differences in the associated phenotype, we evaluated 96 index patients, including 56 who fulfilled the published task force criteria. In addition, 114 family members from 34 of these 56 ARVC index patients were phenotyped. In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2 mutations were identified. Four different mutations were found more than once; haplotype analyses revealed identical haplotypes in the different mutation carriers, suggesting founder mutations. No specific genotype-phenotype correlations could be identified, except that negative T waves in V(2) and V(3) occurred more often in PKP2 mutation carriers (P<0.05). Of the 34 index patients whose family members were phenotyped, 23 familial cases were identified. PKP2 mutations were identified in 16 of these 23 ARVC index patients (70%) with familial ARVC. On the other hand, no PKP2 mutations at all were found in 11 probands without additional affected family members (P<0.001).
PKP2 mutations can be identified in nearly half of the Dutch patients fulfilling the ARVC criteria. In familial ARVC, even the vast majority (70%) is caused by PKP2 mutations. However, nonfamilial ARVC is not related to PKP2. The high yield of mutational analysis in familial ARVC is unique in inherited cardiomyopathies.
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