Search

Background: Inherited cardiac conduction disease is a rare bradyarrhythmia associated with mutations in various genes that affect action potential propagation. It is often characterized by isolated conduction disturbance of the His-Purkinje system, but it is rarely described as a syndromic form., Objectives: The authors sought to identify the genetic defect in families with a novel bradyarrhythmia syndrome associated with bone malformation., Methods: The authors genetically screened 15 European cases with genotype-negative de novo atrioventricular (AV) block and their parents by trio whole-exome sequencing, plus 31 Japanese cases with genotype-negative familial AV block or sick sinus syndrome by targeted exon sequencing of 457 susceptibility genes. Functional consequences of the mutation were evaluated using an in vitro cell expression system and in vivo knockout mice., Results: The authors identified a connexin-45 (Cx45) mutation (p.R75H) in 2 unrelated families (a de novo French case and a 3-generation Japanese family) who presented with progressive AV block, which resulted in atrial standstill without ventricular conduction abnormalities. Affected individuals shared a common extracardiac phenotype: a brachyfacial pattern, finger deformity, and dental dysplasia. Mutant Cx45 expressed in Neuro-2a cells showed normal hemichannel assembly and plaque formation. However, Lucifer yellow dye transfer and gap junction conductance between cell pairs were severely impaired, which suggested that mutant Cx45 impedes gap junction communication in a dominant-negative manner. Tamoxifen-induced, cardiac-specific Cx45 knockout mice showed sinus node dysfunction and atrial arrhythmia, recapitulating the intra-atrial disturbance., Conclusions: Altogether, the authors showed that Cx45 mutant p.R75H is responsible for a novel disease entity of progressive atrial conduction system defects associated with craniofacial and dentodigital malformation., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause., Objectives: This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause., Methods: Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia-LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis., Results: The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia., Conclusions: Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease., Background: Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias., Methods: Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified., Results: Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine., Conclusions: A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate, in a set of 93 mutation-negative long QT syndrome (LQTS) probands, the frequency of copy number variants (CNVs) in LQTS genes., Background: LQTS is an inherited cardiac arrhythmia characterized by a prolonged heart rate-corrected QT (QTc) interval associated with sudden cardiac death. Recent studies suggested the involvement of duplications or deletions in the occurrence of LQTS. However, their frequency remains unknown in LQTS patients., Methods: Point mutations in KCNQ1, KCNH2, and SCN5A genes were excluded by denaturing high-performance liquid chromatography or direct sequencing. We applied Multiplex Ligation-dependent Probe Amplification (MLPA) to detect CNVs in exons of these 3 genes. Abnormal exon copy numbers were confirmed by quantitative multiplex PCR of short fluorescent fragment (QMPSF). Array-based comparative genomic hybridization (array CGH) analysis was performed using Agilent Human Genome 244K Microarrays to further map the genomic rearrangements., Results: We identified 3 different deletions in 3 unrelated families: 1 in KCNQ1 and 2 involving KCNH2. We showed in the largest family that the deletion involving KCNH2 is fully penetrant and segregates with the long QT phenotype in 7 affected members., Conclusions: Our study demonstrates that CNVs in KCNQ1 and KCNH2 explain around 3% of LQTS in patients with no point mutation in these genes. This percentage is likely higher than the frequency of point mutations in ANKB, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, and SNTA1 together. Thus, we propose that CNV screening in KCNQ1 and KCNH2 may be performed routinely in LQTS patients., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)