Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing.

Background: Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1).

Objectives: Because CPVT and concealed long QT syndrome (LQTS) phenotypically mimic one other, we sought to determine the spectrum and prevalence of RyR2 mutations in a cohort of unrelated patients who were referred specifically for LQTS genetic testing.

Methods: Using denaturing high-performance liquid chromatography and direct DNA sequencing, targeted mutational analysis of 23 RyR2 exons previously implicated in CPVT1 was performed on genomic DNA from 269 unrelated patients (180 females, average age at diagnosis 24 +/- 17 years) who were referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing.

Gene-specific modifying effects of pro-LVH polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy.

Aims: The purpose of this study was to determine whether the deletion/insertion (D/I) polymorphism in the ACE-encoded angiotensin-converting enzyme or the pooled gene effect of five renin-angiotensin-aldosterone system (RAAS) polymorphisms were disease modifiers in a large cohort of unrelated patients with genotyped hypertrophic cardiomyopathy (HCM).

Methods And Results: Five different RAAS polymorphism genotypes were established by PCR amplification of the surrounding polymorphic regions of genomic DNA in a cohort of 389 unrelated patients comprehensively genotyped for HCM-causing mutations in eight sarcomeric/myofilament genes. Patient clinical data were archived in a database blinded both to the primary myofilament defect and the polymorphism genotype.

Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy.

Objectives: This study sought to determine the impact of surgical myectomy on long-term survival in hypertrophic cardiomyopathy (HCM).

Background: Left ventricular (LV) outflow tract obstruction in HCM increases the likelihood of heart failure and cardiovascular death. Although surgical myectomy is the primary treatment for amelioration of outflow obstruction and advanced drug-refractory heart failure symptoms, its impact on long-term survival remains unresolved.

Functional consequences of hypertrophic and dilated cardiomyopathy-causing mutations in alpha-tropomyosin.

To study the functional consequences of various cardiomyopathic mutations in human cardiac alpha-tropomyosin (Tm), a method of depletion/reconstitution of native Tm and troponin (Tn) complex (Tm-Tn) in cardiac myofibril preparations has been developed. The endogenous Tm-Tn complex was selectively removed from myofibrils and replaced with recombinant wild-type or mutant proteins. Successful depletion and reconstitution steps were verified by SDS-gel electrophoresis and by the loss and regain of Ca2+-dependent regulation of ATPase activity.

Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants.

Background: Eight common (>0.5%) polymorphisms of SCN5A have been described in the US population. Every human also continuously generates two wild-type (WT) splice variants, one with a glutamine residue at position 1077 (Q1077) and one lacking this glutamine (Q1077del).

Yield of genetic testing in hypertrophic cardiomyopathy.

Objective: To determine the clinical parameters of hypertrophic cardiomyopathy (HCM) that correlated significantly with the presence of an identifiable sarcomeric mutation.

Patients And Methods: Previous comprehensive mutational analyses of all protein-coding exons of 8 sarcomeric genes revealed pathogenic mutations in 147 (38%) of 389 unrelated patients seen at the HCM outpatient clinic at the Mayo Clinic in Rochester, Minn, between April 1997 and December 2001. Clinical data, extracted from patient records and blinded to patient genotype, were maintained in a custom database.

Molecular and functional characterization of a human frataxin mutation found in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is associated with marked genetic and phenotypic heterogeneity. Pathogenic mutations in the 10 hypertrophic cardiomyopathy-associated sarcomeric genes cause autosomal dominant disease as a rule, although recessive disease has been reported. Cardiac hypertrophy is also a hallmark of Friedreich ataxia, an autosomal recessive disease caused by deficiency of the mitochondrial protein frataxin.

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

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.

Sudden infant death syndrome: how significant are the cardiac channelopathies?

Having an apparently healthy, thriving infant fail to reach his/her first birthday is profoundly tragic. This tragedy is compounded when the infant's death is unexpected and unexplained, signed out as sudden infant death syndrome (SIDS). Despite impressive success and welcome reductions in these tragic deaths due in large measure to "Back-to-Sleep" campaigns, the fundamental pathogenic mechanisms precipitating such deaths remain dimly exposed.

Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype.

Background: The ECG features of Andersen-Tawil syndrome (ATS) patients with KCNJ2 mutations (ATS1) have not been systematically assessed. This study aimed to define ECG features of KCNJ2 mutation carriers, to determine whether characteristic T-U-wave patterns exist, and to establish whether T-U patterns predict the ATS1 genotype.

Methods And Results: In phase I, evaluation of T-U morphology in ECGs of 39 KCNJ2 mutation carriers identified characteristic T-U patterns: prolonged terminal T downslope, wide T-U junction, and biphasic and enlarged U waves.

Pathogenesis of unexplained drowning: new insights from a molecular autopsy.

Objective: To perform a molecular autopsy involving the RyR2-encoded cardiac ryanodine receptor/calcium release channel to determine whether mutations responsible for catecholaminergic polymorphic ventricular tachycardia (CPVT) represent a novel pathogenic basis for unexplained drownings.

Methods: A cardiac channel molecular autopsy was performed on 2 individuals who died of unexplained drowning and whose cases were referred to the Sudden Death Genomics Laboratory at the Mayo Clinic in Rochester, Minn. Comprehensive mutational analysis of all 60 protein-encoded exons of the 5 long QT syndrome-causing cardiac channel genes and a targeted analysis of 18 RyR2 exons known to host RyR2-mediated CPVT-causing mutations (CPVT1) was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing.

Genetic testing for risk stratification in hypertrophic cardiomyopathy and long QT syndrome: fact or fiction?

Purpose Of Review: Hypertrophic cardiomyopathy, affecting 1 in 500 persons, is the most common identifiable cause of sudden cardiac death in the young, whereas congenital long QT syndrome, affecting 1 in 5000 persons, is perhaps one of the most common causes of autopsy negative sudden unexplained death. Since May 2004, genetic testing has been available as a clinical diagnostic test for both hypertrophic cardiomyopathy and long QT syndrome. It is now critical to carefully scrutinize the relationships between genotype and phenotype as they pertain to clinical practice.

Intragenic suppression of trafficking-defective KCNH2 channels associated with long QT syndrome.

Mutations in the KCNH2 or human ether-a-go-go-related gene-encoded K(+) channel reduce functional KCNH2 current (I(KCNH2)) to cause long QT syndrome (LQT2) by multiple mechanisms, including defects in intracellular transport (trafficking). Trafficking-deficient, or class 2, LQT2 mutations reduce the Golgi processing and surface membrane expression of KCNH2 channel proteins. Drugs that associate with pore-S6 intracellular drug binding domain of KCNH2 channel proteins to cause high-affinity block of I(KCNH2) also can increase the processing of class 2 LQT2 channel proteins through the secretory pathway.

Epinephrine-induced T-wave notching in congenital long QT syndrome.

Objectives: The purpose of this study was to characterize the effect of epinephrine on T-wave morphology in patients with congenital long QT syndrome (LQTS).

Background: QT prolongation is a paradoxical, LQT1-specific response to low-dose epinephrine infusion. At rest, notched T waves are more common in LQT2.

Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.

Objectives: The purpose of this study was to determine the prevalence and spectrum of nonsynonymous polymorphisms (amino acid variants) in the cardiac sodium channel among healthy subjects.

Background: Pathogenic mutations in the cardiac sodium channel gene, SCN5A, cause approximately 15 to 20% of Brugada syndrome (BrS1), 5 to 10% of long QT syndrome (LQT3), and 2 to 5% of sudden infant death syndrome.

Methods: Using single-stranded conformation polymorphism, denaturing high-performance liquid chromatography, and/or direct DNA sequencing, mutational analysis of the protein-encoding exons of SCN5A was performed on 829 unrelated, anonymous healthy subjects: 319 black, 295 white, 112 Asian, and 103 Hispanic.

Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome.

Objectives: The aim of this study was to elucidate the genetic basis for long QT syndrome (LQTS) in patients with a personal or family history of postpartum cardiac events.

Background: The postpartum period is a time of increased arrhythmogenic susceptibility in women with LQTS.

Methods: Between August 1997 and May 2003, 388 unrelated patients (260 females, average age at diagnosis, 23 years, and average QTc, 482 ms) were referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing.

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Objectives: The purpose of this study was to determine the spectrum and prevalence of cardiac channel mutations among a large cohort of consecutive, unrelated patients referred for long QT syndrome (LQTS) genetic testing.

Background: Congenital LQTS is a primary cardiac channelopathy. More than 300 mutations have been identified in five genes encoding key ion channel subunits.

Sarcomeric genotyping in hypertrophic cardiomyopathy.

Objective: To pool results from studies of patients with hypertrophic cardiomyopathy (HCM) to elucidate important phenotypic differences among genotypes.

Material And Methods: Data published from November 1998 through November 2004 were gathered and compared from unrelated study population genotyping studies from the Mayo Clinic (Rochester, Minn), Harvard Medical School (Boston, Mass), France, Germany, Sweden, Finland, and Spain. Standard statistical analysis techniques were used to pool and compare data across genotypes with respect to frequency of mutations, age at diagnosis, and degree of hypertrophy (left ventricular wall thickness).

Blockade of HERG channels by HIV protease inhibitors.

The HIV protease inhibitor class of antiretroviral drug causes unpredicted adverse effects by changing elements of normal cellular metabolism. A case of QT prolongation in a patient receiving protease inhibitors made us question whether these drugs might be responsible. We identified 24 patients with QT prolongation or torsade de pointes, or both, associated with protease inhibitors, using the Food and Drug Administration's voluntary adverse event reporting system.