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.
Over the past 2 decades, investigators in the field of cardiac genetics have evolved a complex understanding of the pathophysiological basis of inherited cardiac diseases, which predispose ...individuals to sudden cardiac death. In this Review, we describe the current status of gene discovery and the associations between phenotype and genotype in the cardiac channelopathies and cardiomyopathies. The various indications for genetic testing and its utility in the clinic are assessed in relation to diagnosis, cascade testing, guiding management, and prognosis. Some common problems exist across all phenotypes: the variable penetrance and expressivity of genetic disease, and the difficulty of assessing the functional and clinical effects of novel mutations. These issues will be of particular importance as the next-generation sequencing technologies are used by genetics laboratories to provide results from large panels of genes. The accurate interpretation of these results will be the main challenge for the future.
Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome characterized by a prolonged QT interval on the 12-lead ECG, torsades de pointes and a higher chance of sudden cardiac death. ...LQTS segregates in a Mendelian fashion, which includes Romano-Ward syndrome with an autosomal dominant pattern as well as a rare autosomal recessive pattern (Jervell and Lange-Nielsen syndrome). Since 1957 when Jervell and Lange-Nielsen reported the first familial LQTS with congenital deafness, progress in understanding the genetic and electrophysiological mechanisms of LQTS has tremendously improved diagnostic methods and treatments. In the meantime, it has become evident that LQTS may not always be explained by a single gene mutation, but seems to follow a more complex genetic model intertwined with genetic common polymorphisms that have a mild to moderate effect on disease expression. In this review, we summarize the characteristics of LQTS (mainly LQT1–3) and briefly describe the most recent advances in LQTS clinical diagnostics as well as genetics. (Circ J 2014; 78: 2827–2833)
Because a quantum measurement generally disturbs the state of a quantum system, one might think that it should not be possible for a sender and receiver to communicate reliably when the receiver ...performs a large number of sequential measurements to determine the message of the sender. We show here that this intuition is not true, by demonstrating that a sequential decoding strategy works well even in the most general 'one-shot' regime, where we are given a single instance of a channel and wish to determine the maximal number of bits that can be communicated up to a small failure probability. This result follows by generalizing a non-commutative union bound to apply for a sequence of general measurements. We also demonstrate two ways in which a receiver can recover a state close to the original state after it has been decoded by a sequence of measurements that each succeed with high probability. The second of these methods will be useful in realizing an efficient decoder for fully quantum polar codes, should a method ever be found to realize an efficient decoder for classical-quantum polar codes.
Abstract Entanglement is a striking feature of quantum mechanics, and it has a key property called unextendibility. In this paper, we present a framework for quantifying and investigating the ...unextendibility of general bipartite quantum states. First, we define the unextendible entanglement, a family of entanglement measures based on the concept of a state-dependent set of free states. The intuition behind these measures is that the more entangled a bipartite state is, the less entangled each of its individual systems is with a third party. Second, we demonstrate that the unextendible entanglement is an entanglement monotone under two-extendible quantum operations, including local operations and one-way classical communication as a special case. Normalization and faithfulness are two other desirable properties of unextendible entanglement, which we establish here. We further show that the unextendible entanglement provides efficiently computable benchmarks for the rate of exact entanglement or secret key distillation, as well as the overhead of probabilistic entanglement or secret key distillation.
Abstract
One of the fundamental tasks in quantum metrology is to estimate multiple parameters embedded in a noisy process, i.e. a quantum channel. In this paper, we study fundamental limits to ...quantum channel estimation via the concept of amortization and the right logarithmic derivative (RLD) Fisher information value. Our key technical result is the proof of a chain-rule inequality for the RLD Fisher information value, which implies that amortization, i.e. access to a catalyst state family, does not increase the RLD Fisher information value of quantum channels. This technical result leads to a fundamental and efficiently computable limitation for multiparameter channel estimation in the sequential setting, in terms of the RLD Fisher information value. As a consequence, we conclude that if the RLD Fisher information value is finite, then Heisenberg scaling is unattainable in the multiparameter setting.
Abstract
The interplay between superconductivity and charge-density wave (CDW) in 2
H
-NbSe
2
is not fully understood despite decades of study. Artificially introduced disorder can tip the delicate ...balance between two competing long-range orders, and reveal the underlying interactions that give rise to them. Here we introduce disorder by electron irradiation and measure in-plane resistivity, Hall resistivity, X-ray scattering, and London penetration depth. With increasing disorder, the superconducting transition temperature,
T
c
, varies non-monotonically, whereas the CDW transition temperature,
T
CDW
, monotonically decreases and becomes unresolvable above a critical irradiation dose where
T
c
drops sharply. Our results imply that the CDW order initially competes with superconductivity, but eventually assists it. We argue that at the transition where the long-range CDW order disappears, the cooperation with superconductivity is dramatically suppressed. X-ray scattering and Hall resistivity measurements reveal that the short-range CDW survives above the transition. Superconductivity persists to much higher dose levels, consistent with fully gapped superconductivity and moderate interband pairing.
Objectives This study was designed to assess the clinical course and to identify risk factors for life-threatening events in patients with long-QT syndrome (LQTS) with normal corrected QT (QTc) ...intervals. Background Current data regarding the outcome of patients with concealed LQTS are limited. Methods Clinical and genetic risk factors for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) from birth through age 40 years were examined in 3,386 genotyped subjects from 7 multinational LQTS registries, categorized as LQTS with normal-range QTc (≤440 ms n = 469), LQTS with prolonged QTc interval (>440 ms n = 1,392), and unaffected family members (genotyped negative with ≤440 ms n = 1,525). Results The cumulative probability of ACA or SCD in patients with LQTS with normal-range QTc intervals (4%) was significantly lower than in those with prolonged QTc intervals (15%) (p < 0.001) but higher than in unaffected family members (0.4%) (p < 0.001). Risk factors ACA or SCD in patients with normal-range QTc intervals included mutation characteristics (transmembrane-missense vs. nontransmembrane or nonmissense mutations: hazard ratio: 6.32; p = 0.006) and the LQTS genotypes (LQTS type 1:LQTS type 2, hazard ratio: 9.88; p = 0.03; LQTS type 3:LQTS type 2, hazard ratio: 8.04; p = 0.07), whereas clinical factors, including sex and QTc duration, were associated with a significant increase in the risk for ACA or SCD only in patients with prolonged QTc intervals (female age >13 years, hazard ratio: 1.90; p = 0.002; QTc duration, 8% risk increase per 10-ms increment; p = 0.002). Conclusions Genotype-confirmed patients with concealed LQTS make up about 25% of the at-risk LQTS population. Genetic data, including information regarding mutation characteristics and the LQTS genotype, identify increased risk for ACA or SCD in this overall lower risk LQTS subgroup.
Abstract
Brugada syndrome (BrS) was first described as a primary electrical disorder predisposing to the risk of sudden cardiac death and characterized by right precordial lead ST elevation. Early ...description of right ventricular structural abnormalities and of right ventricular outflow tract (RVOT) conduction delay in BrS patients set the stage for the current controversy over the pathophysiology underlying the syndrome: channelopathy or cardiomyopathy; repolarization or depolarization. This review examines the current understanding of the BrS substrate, its genetic and non-genetic basis, theories of pathophysiology, and the clinical implications thereof. We propose that the final common pathway for BrS could be viewed as a disease of ‘reduced RVOT conduction reserve’.
Graphical abstract
Brugada syndrome (BrS) as a disease of impaired right ventricular outflow tract (RVOT) conduction reserve. Normally, intrinsic RVOT conduction reserve may be affected by a patient’s age and gender. In BrS, cellular and tissue abnormalities cause a reduction in RVOT conduction reserve: genetic abnormalities, whether mediated by a pathogenic SCN5A variant, an increased BrS-PRS, and/or additional genetic insults, may have direct effects on Nav1.5, as well as tissue effects causing RVOT inflammation, fibrosis, and gap junction abnormalities. Decreased Nav1.5 current, together with electrical discontinuity caused by RVOT structural changes, converges to disrupt normal depolarization, with or without secondary repolarization effects, leading to impairment of the conduction reserve of the RVOT. In this framework, the marginal conduction reserve can be exposed by acute modulators such as fever, drugs, and altered vagal tone which further impair conduction and expose the Brugada phenotype.
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