Publications by authors named "Elena Zaklyazminskaya"

22 Publications

  • Page 1 of 1

Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of : A Potential Source of Misinterpretation.

Front Genet 2021 6;12:722291. Epub 2021 Sep 6.

Russian National Research Center of Surgery Named After B.V. Petrovsky, Moscow, Russia.

Primary cardiac channelopathies are a group of diseases wherein the role of DNA testing in aiding diagnosis and treatment-based decision-making is gaining increasing attention. However, in some cases, evaluating the pathogenicity of new variants is still challenging. We report an accurate multistage assessment of a rare genetic variant in the gene using next-generation sequencing (NGS) techniques and Sanger sequencing. Female sportsman (14 years old) underwent genetic counseling and DNA testing due to QT interval prolongation registered during ECG Holter monitoring. Genetic testing of the proband was performed in two independent laboratories. Primary DNA testing was performed by WES using the Ion Proton System. Target panel sequencing of 11 genes was performed using PGM Ion Torrent. Search for variants in non-canonical and canonical exons 6 was performed by Sanger sequencing. The cascade familial screening and control re-sequencing were provided for proband with identified genetic variant p.S216L (g.38655290G>A, NM_198056.2:c.647C>T, and rs41276525) in the canonical exon 6 of the gene after receiving data from another laboratory. Control Sanger and NGS sequencing revealed the absence p.S216L in the canonical exon 6 and confirmed the presence of p.S216L (g.38655522G>A, c.647C>T, and rs201002736) in the non-canonical exon 6 of the gene. The identified variant was re-interpreted. The non-canonical transcripts of the exon 6 of the gene is poorly represented in cardiac tissue (gnomAD). The detected variant was found in proband's healthy mother. The correct interpretation of genetic data requires close cooperation between clinicians and researchers. It can help to avoid financial costs and stress for proband's and families.
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http://dx.doi.org/10.3389/fgene.2021.722291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450431PMC
September 2021

Scintigraphy false-positive results for cardiac amyloidosis in a patient with Danon disease.

Clin Case Rep 2021 Aug 16;9(8):e04652. Epub 2021 Aug 16.

Sechenov University Moscow Russia.

Common diagnostic approach in patients with suspected cardiac amyloidosis includes cardiac magnetic resonance imaging and scintigraphy. We report the first clinical case of false-positive results of scintigraphy in a patient with Danon disease.
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http://dx.doi.org/10.1002/ccr3.4652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365861PMC
August 2021

Editorial: Inherited Arrhythmias of the Cardiac Sodium Channel Na1.5.

Front Physiol 2021 4;12:716553. Epub 2021 Aug 4.

Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.

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http://dx.doi.org/10.3389/fphys.2021.716553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372145PMC
August 2021

Allelic Dropout Is a Common Phenomenon That Reduces the Diagnostic Yield of PCR-Based Sequencing of Targeted Gene Panels.

Front Genet 2021 1;12:620337. Epub 2021 Feb 1.

Medical Genetics Laboratory, Petrovsky National Research Center of Surgery, Moscow, Russia.

Primary cardiomyopathies (CMPs) are monogenic but multi-allelic disorders with dozens of genes involved in pathogenesis. The implementation of next-generation sequencing (NGS) approaches has resulted in more time- and cost-efficient DNA diagnostics of cardiomyopathies. However, the diagnostic yield of genetic testing for each subtype of CMP fails to exceed 60%. The aim of this study was to demonstrate that allelic dropout (ADO) is a common phenomenon that reduces the diagnostic yield in primary cardiomyopathy genetic testing based on targeted gene panels assayed on the Ion Torrent platform. We performed mutational screening with three custom targeted gene panels based on sets of oligoprimers designed automatically using AmpliSeq Designer® containing 1049 primer pairs for 37 genes with a total length of 153 kb. DNA samples from 232 patients were screened with at least one of these targeted gene panels. We detected six ADO events in both IonTorrent PGM (three cases) and capillary Sanger sequencing (three cases) data, identifying ADO-causing variants in all cases. All ADO events occurred due to common or rare single nucleotide variants (SNVs) in the oligoprimer binding sites and were detected because of the presence of "marker" SNVs in the target DNA fragment. We ultimately identified that PCR-based NGS involves a risk of ADO that necessitates the use of Sanger sequencing to validate NGS results. We assume that oligoprimer design without ADO data affects the amplification efficiency of up to 0.77% of amplicons.
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http://dx.doi.org/10.3389/fgene.2021.620337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901947PMC
February 2021

Mixed Hypertrophic and Dilated Phenotype of Cardiomyopathy in a Patient With Homozygous In-Frame Deletion in the Gene Treated as Myocarditis for a Long Time.

Front Pharmacol 2020 25;11:579450. Epub 2020 Sep 25.

Medical Genetics Laboratory, Petrovsky National Research Centre of Surgery, Moscow, Russia.

Hypertrophic cardiomyopathy (HCM) is the most common inherited disease, with a prevalence of 1:200 worldwide. The cause of HCM usually presents with an autosomal dominant mutation in the genes encoding one of more than 20 sarcomeric proteins, incomplete penetrance, and variable expressivity. HCM classically manifests as an unexplained thickness of the interventricular septum (IVS) and left ventricular (LV) walls, with or without the obstruction of the LV outflow tract (LVOT), and variable cardiac arrhythmias. Here, we present a rare case of mixed cardiomyopathy (cardiac hypertrophy and dilation) and erythrocytosis in a young patient. A 27-year-old man was admitted to the clinic due to biventricular heart failure (HF) NYHA class III. Personal medical records included a diagnosis of dilated cardiomyopathy (DCM) since the age of 4 years and were, at the time, considered an outcome of myocarditis. Severe respiratory infection led to circulatory decompensation and acute femoral thrombosis. The combination of non-obstructive LV hypertrophy (LV walls up to 15 mm), LV dilatation, decreased contractility (LV EF 24%), and LV apical thrombosis were seen. Cardiac MRI showed a complex pattern of late gadolinium enhancement (LGE). Endomyocardial biopsy (EMB) revealed primary cardiomyopathy with intravascular coagulation and an inflammatory response. No viral genome was detected in the plasma or EMB samples. Whole exome sequencing (WES) revealed a homozygous in-frame deletion p.2711_2737del in the gene. The clinically unaffected mother was a heterozygous carrier of this deletion, and the father was unavailable for clinical and genetic testing. Essential erythrocytosis remains unexplained. No significant improvement was achieved by conventional treatment, including prednisolone 40 mg therapy. ICD was implanted due to sustained VT and high risk of SCD. Orthotopic heart transplantation (HTx) was considered optimal. Early manifestation combined hypertrophic and dilated phenotype, and progression may reflect a complex genotype with more than one pathogenic allele and/or a combination of genetic diseases in one patient.
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http://dx.doi.org/10.3389/fphar.2020.579450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546790PMC
September 2020

Clinical Classification of Arrhythmogenic Right Ventricular Cardiomyopathy.

Pulse (Basel) 2020 Aug 11;8(1-2):21-30. Epub 2020 Feb 11.

Laboratory of Medical Genetics, B.V. Petrovsky Russian Research Center of Surgery, Moscow, Russian Federation.

Introduction: Commonly accepted clinical classification of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still not developed.

Objective: To study the clinical forms of ARVC.

Methods: Fifty-four patients (38.7 ± 14.1 years, 42.6% men) with ARVC. Follow-up period: 21 (6-60) months. All patients underwent electrocardiography, 24 h-Holter monitoring, echocardiography, and DNA diagnostic. Magnetic resonance imaging was performed in 49 patients.

Results: According to the features of clinical course of ARVC, 4 clinical forms were identified. (I) Latent arrhythmic form ( = 27) - frequent premature ventricular contractions and/or nonsustained ventricular tachycardia (VT) in the absence of sustained VT and syncope; characterized by absence of fatal arrhythmic events. (II) Manifested arrhythmic form ( = 11) - sustained VT/ventricular fibrillation; the high incidence of appropriate implantation of cardioverter-defibrillator (ICD) interventions (75%) registered. (III) ARVC with progressive chronic heart failure (CHF, = 8) as the main manifestation of the disease; incidence of appropriate ICD interventions was 50%, mortality rate due to CHF was 25%. (IV) Combination of ARVC with left ventricular noncompaction ( = 8); characterized by mutations in desmosomal or sarcomere genes, aggressive ventricular arrhythmias, appropriate ICD interventions in 100% patients. Described 4 clinical forms are stable in time, do not transform into each other, and they are genetically determined.

Conclusions: The described clinical forms of ARVC are determined by a combination of genetic and environmental factors and do not transform into each other. The proposed classification could be used in clinical practice to determine the range of diagnostic and therapeutic measures and to assess the prognosis of the disease in a particular patient.
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http://dx.doi.org/10.1159/000505652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506253PMC
August 2020

Compound heterozygous mutations in and in a patient with severe Andersen-Tawil syndrome.

BMJ Case Rep 2020 Aug 25;13(8). Epub 2020 Aug 25.

Laboratory of Medical Genetics, Petrovsky National Research Centre of Surgery, Moscow, Russian Federation.

Andersen-Tawil syndrome (ATS) is a rare channelopathy, sometimes referred to as long QT syndrome type 7. ATS is an autosomal dominant disease predominantly caused by mutations in the gene. Patients with ATS present with episodes of muscle weakness, arrythmias, including prolonged QT intervals, and various skeletal abnormalities. Unlike other channelopathies, ATS has a relatively mild clinical course and low risk of sudden cardiac death. In this study, we describe a female patient with typical symptoms of ATS with the addition of unusually severe arrhythmias. Extensive DNA testing was performed to find the possible cause of this unique presentation. In addition to a known mutation in , the patient carried a variant in The combination of genetic variants may lead to the severe clinical manifestation of ATS. Additional genetic information allowed accurate genetic counselling to be provided to the patient.
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http://dx.doi.org/10.1136/bcr-2020-235703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449271PMC
August 2020

Calmodulin binds to the N-terminal domain of the cardiac sodium channel Na1.5.

Channels (Austin) 2020 12;14(1):268-286

Institute of Biochemistry and Molecular Medicine, University of Bern , Bern, Switzerland.

The cardiac voltage-gated sodium channel Na1.5 conducts the rapid inward sodium current crucial for cardiomyocyte excitability. Loss-of-function mutations in its gene are linked to cardiac arrhythmias such as Brugada Syndrome (BrS). Several BrS-associated mutations in the Na1.5 N-terminal domain (NTD) exert a dominant-negative effect (DNE) on wild-type channel function, for which mechanisms remain poorly understood. We aim to contribute to the understanding of BrS pathophysiology by characterizing three mutations in the Na1.5 NTD: Y87C-here newly identified-, R104W, and R121W. In addition, we hypothesize that the calcium sensor protein calmodulin is a new NTD binding partner. Recordings of whole-cell sodium currents in TsA-201 cells expressing WT and variant Na1.5 showed that Y87C and R104W but not R121W exert a DNE on WT channels. Biotinylation assays revealed reduction in fully glycosylated Na1.5 at the cell surface and in whole-cell lysates. Localization of Na1.5 WT channel with the ER did not change in the presence of variants, as shown by transfected and stained rat neonatal cardiomyocytes. We demonstrated that calmodulin binds the Na1.5 NTD using modeling, SPOTS, pull-down, and proximity ligation assays. Calmodulin binding to the R121W variant and to a Na1.5 construct missing residues 80-105, a predicted calmodulin-binding site, is impaired. In conclusion, we describe the new natural BrS Na1.5 variant Y87C and present first evidence that calmodulin binds to the Na1.5 NTD, which seems to be a determinant for the DNE.
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http://dx.doi.org/10.1080/19336950.2020.1805999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515574PMC
December 2020

Lack of association between mitochondrial DNA haplogroups J and T and clinical manifestation in Russian patients with Brugada syndrome.

Biomed Rep 2020 Sep 2;13(3):16. Epub 2020 Jul 2.

Petrovsky National Research Centre of Surgery, Moscow 119991, Russia.

Brugada syndrome (BrS) is an inherited disorder characterized by specific ST segment elevation in the right precordial leads, pseudo right bundle branch block, and a high risk of sudden cardiac death due to ventricular tachycardia. It was initially described as a monogenic disorder with an autosomal dominant mode of inheritance. It is hypothesized that modifying genetic factors, in addition to disease-causing mutations, may significantly contribute to the clinical symptoms and the risk of sudden cardiac death. These modifying factors can include mitochondrial DNA (mtDNA) variants. In particular, combination of mtDNA m.T4216C, m.A11251G, m.C15452A and m.T16126C variants (defining haplogroups T and J), is considered to be a factor that promotes manifestation of BrS manifestation, with no pro-arrhythmic effects. The aim of the present study was to confirm the reported association of BrS with MtDNA variants in a cohort of Russian patients. mtDNA haplogroups were genotyped in 47 Russian BrS probands and the prevalence of common mtDNA haplogroups was compared with the general population in European part of Russia. The distribution and prevalence of all but the J mtDNA haplogroups were comparable in BrS probands and the general Russian population. The mitochondrial J haplogroup was not found in the BrS cohort. In conclusion, it was shown that the mtDNA polymorphism, m.T4216C (haplogroups J and T) does not contribute significantly to the clinical manifestation of BrS in Russian patients.
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http://dx.doi.org/10.3892/br.2020.1324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391294PMC
September 2020

New genetic variant in the SERPINC1 gene: hereditary Antithrombin deficiency case report, familial thrombosis and considerations on genetic counseling.

BMC Med Genet 2020 04 6;21(1):73. Epub 2020 Apr 6.

Medical Genetics Laboratory, Petrovsky National Research Centre of Surgery, Abricosovsky lane, 2, Moscow, 119991, Russian Federation.

Background: Inherited deficiency of the antithrombin (hereditary antithrombin deficiency, AT deficiency, OMIM #613118) is a relatively rare (1:2000-3000) autosomal-dominant disorder with high risk of venous thromboembolism. Mutations in the serpin family C member 1 gene (SERPINC1) can lead to Quantitative (type I) and Qualitative (type II) types of antithrombin deficiency. We describe a new genetic variant in the SERPINC1 gene and our approach to variant interpretation.

Case Presentation: We observed a 29 y.o. female proband with the episode of venous thrombosis at the age of 18 and family history of thrombosis. The antithrombin level in our patient was low, 44-48% (AT deficiency type I). A new genetic variant c.662G > C (p.W221S) in the SERPINC1 gene was detected in proband and affected father but was absent in healthy sister. We used in silico tools to evaluate the possible impact of p.W221S variant on protein structure and function. In mutated SERPINC1 protein a new N-linked glycosylation site is formed, however, it is unclear if the glycosylation at 219-221 site is possible.

Conclusion: The proband was provided with appropriate genetic counseling and referred to a hematologist. Based on all the evidence we classify the p.W221S variant as variant of unknown clinical significance. In this paper we discuss some aspects of genetic counseling, variant interpretation and thromboembolic prophilaxis.
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http://dx.doi.org/10.1186/s12881-020-01001-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137186PMC
April 2020

Low mutation rate in the TTN gene in paediatric patients with dilated cardiomyopathy - a pilot study.

Sci Rep 2019 11 11;9(1):16409. Epub 2019 Nov 11.

Petrovsky National Research Center of Surgery, 2, Abricosovsky side-street, 119991, Moscow, Russia.

Idiopathic dilated cardiomyopathy (DCM) is a common cardiomyopathy with the prevalence of 1:250, and at least one-third of all the cases are inherited. Mutations in the TTN gene are considered as the most frequent cause of inherited DCM and cover 10-30% of the cases. The studies were mainly focused on the adult or mixed age group of patients with DCM. The mutation rate in the TTN gene, the characteristics of manifestations and their prognostic significance in childhood have not been studied. To determine TTN mutation rate in children with DCM and the relevance of including this gene in the DNA diagnostic protocol for paediatric DCM, complete clinical and instrumental examination of 36 DCM patients (up to 18 years) with the manifestation of the disease was conducted in specialised cardiology centres. Molecular genetic testing included sequencing of coding and adjacent regulatory regions of the major cardiac TTN isoform N2BA using IonTorrent ™ semiconductor sequencing (for 25 isolated cases) and trio whole exome sequencing (trio WES)on the Illumina platform (for 11 family cases). Our pilot group included 36 probands with DCM diagnosis first established on the basis of the generally accepted criteria at the age of 5 days to 18 years(average age: 6.5 years). The sex ratio (M:F) was 23: 8. There were 25 sporadic DCM cases and 11 cases of familial DCM (at least one of the parents and/or siblings were also diagnosed with DCM). The only likely pathogenic truncating variant p.Arg33703*in the TTN gene (TTNtv) was found in a 16-year-oldmale proband out of 36 (3%). Apparently, TTN-dependent forms of DCMs manifest later at a young (but older than 18 years) or more mature age, and TTN gene cannot be considered as the first-line genetic testing for DCM in the paediatric group, despite several studies have reported a generally high mutation rate in this gene with DCM. Further research is needed to compare the representation of mutations in the TTN gene in different age groups of DCM patients.
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http://dx.doi.org/10.1038/s41598-019-52911-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848193PMC
November 2019

Common pathogenic mechanism in patients with dropped head syndrome caused by different mutations in the MYH7 gene.

Gene 2019 May 19;697:159-164. Epub 2019 Feb 19.

Medical Genetics Laboratory, Petrovsky Russian Research Center of Surgery, Moscow 119991, Russia; Pirogov Russian National Research Medical University, Moscow 117997, Russia.

Mutations in the MYH7 gene are the source of an allelic series of diseases, including various cardiomyopathies and skeletal myopathies that usually manifest in adulthood. We observed a 1.5 y.o. male patient with congenital weaknesses of the axial muscles, "dropped head" syndrome, and dilated cardiomyopathy. The clinical evaluation included medical history, an echocardiogram, electromyography, and a histopathological study. The genetic evaluation included whole exome sequencing. Muscle biopsy samples from the proband were used for mRNA extraction. We revealed a novel genetic variant c.5655 + 5G > C in the MYH7 gene. The analysis of the cDNA showed an in-frame skipping of exon 38 (p.1854_1885del). This variant and two previously published mutations (c.5655G > A and c.5655 + 1G > A), also presumably leading to exon 38 skipping, were studied by expression analysis in the HEK293T cell line transfected with 4 plasmids containing the MYH7 minigene (wt, c.5655G > C, c.5655 + 1G > A and c.5655 + 5G > A). A quantitative difference in expression was shown for cell lines with each of the three mutant plasmids. All mutation carriers had a similar phenotype and included congenital axial myopathy and variable cardiac involvement. Prominent dropped head syndrome was mentioned in all patients. Early-onset axial myopathy with a dropped head syndrome is a distinct clinical entity within MYH7-related disorders. We suggest that mutations in the MYH7 gene affecting the C-terminal domain of beta-myosin heavy chain should also be considered as a possible cause in cases of early-onset myopathy with "dropped head" syndrome.
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http://dx.doi.org/10.1016/j.gene.2019.02.011DOI Listing
May 2019

Simultaneous Non-Invasive Epicardial and Endocardial Mapping in Patients With Brugada Syndrome: New Insights Into Arrhythmia Mechanisms.

J Am Heart Assoc 2016 11 14;5(11). Epub 2016 Nov 14.

Department of Medicine, University Medical Center Mannheim, Mannheim, Germany.

Background: The underlying mechanisms of Brugada syndrome (BrS) are not completely understood. Recent studies provided evidence that the electrophysiological substrate, leading to electrocardiogram abnormalities and/or ventricular arrhythmias, is located in the right ventricular outflow tract (RVOT). The purpose of this study was to examine abnormalities of epicardial and endocardial local unipolar electrograms by simultaneous noninvasive mapping in patients with BrS.

Methods And Results: Local epicardial and endocardial unipolar electrograms were analyzed using a novel noninvasive epi- and endocardial electrophysiology system (NEEES) in 12 patients with BrS and 6 with right bundle branch block for comparison. Fifteen normal subjects composed the control group. Observed depolarization abnormalities included fragmented electrograms in the anatomical area of RVOT endocardially and epicardially, significantly prolonged activation time in the RVOT endocardium (65±20 vs 38±13 ms in controls; P=0.008), prolongation of the activation-recovery interval in the RVOT epicardium (281±34 vs 247±26 ms in controls; P=0.002). Repolarization abnormalities included a larger area of ST-segment elevation >2 mV and T-wave inversions. Negative voltage gradient (-2.5 to -6.0 mV) between epicardium and endocardium of the RVOT was observed in 8 of 12 BrS patients, not present in patients with right bundle branch block or in controls.

Conclusions: Abnormalities of epicardial and endocardial electrograms associated with depolarization and repolarization properties were found using NEEES exclusively in the RVOT of BrS patients. These findings support both, depolarization and repolarization abnormalities, being operative at the same time in patients with BrS.
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http://dx.doi.org/10.1161/JAHA.116.004095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210320PMC
November 2016

The role of mutations in the SCN5A gene in cardiomyopathies.

Biochim Biophys Acta 2016 Jul 23;1863(7 Pt B):1799-805. Epub 2016 Feb 23.

Petrovsky Russian Research Centre of Surgery, Abricosovsky pereulok, 119991 Moscow, Russia. Electronic address:

The SCN5A gene encodes the alpha-subunit of the Nav1.5 ion channel protein, which is responsible for the sodium inward current (INa). Since 1995 several hundred mutations in this gene have been found to be causative for inherited arrhythmias including Long QT syndrome, Brugada syndrome, cardiac conduction disease, sudden infant death syndrome, etc. As expected these syndromes are primarily electrical heart diseases leading to life-threatening arrhythmias with an "apparently normal heart". In 2003 a new form of dilated cardiomyopathy was identified associated with mutations in the SCN5A gene. Recently mutations have been also found in patients with arrhythmogenic right ventricular cardiomyopathy and atrial standstill. The purpose of this review is to outline and analyze the following four topics: 1) SCN5A genetic variants linked to different cardiomyopathies; 2) clinical manifestations of the known mutations; 3) possible molecular mechanisms of myocardial remodeling; and 4) the potential implications of gene-specific treatment for those disorders. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
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http://dx.doi.org/10.1016/j.bbamcr.2016.02.014DOI Listing
July 2016

The use of noninvasive ECG imaging for examination of a patient with Brugada syndrome.

HeartRhythm Case Rep 2015 Jul 6;1(4):260-263. Epub 2015 May 6.

1 Department of Medicine, University Medical Center Mannheim, Mannheim, Germany.

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http://dx.doi.org/10.1016/j.hrcr.2015.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419418PMC
July 2015

Complex genetic background in a large family with Brugada syndrome.

Physiol Rep 2015 Jan 27;3(1). Epub 2015 Jan 27.

I. M. Sechenov First Moscow State Medical University, Moscow, Russia Petrovsky Russian Research Center of Surgery, RAMS, Moscow, Russia.

The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST-segment elevation in V1-V3 leads and negative T wave on standard ECG. BrS patients are at risk of sudden cardiac death (SCD) due to ventricular tachyarrhythmia. At least 17 genes have been proposed to be linked to BrS, although recent findings suggested a polygenic background. Mutations in SCN5A, the gene coding for the cardiac sodium channel Nav1.5, have been found in 15-30% of index cases. Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) in SCN5A. By performing whole-cell patch-clamp experiments using HEK293 cells expressing wild-type (WT) or p.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant-induced alterations lead to a loss of function of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation. Additional next generation sequencing analyses revealed the p.R25W mutation in KCNH2 gene in SCN5A-negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN5A genetic variant.
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http://dx.doi.org/10.14814/phy2.12256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387754PMC
January 2015

Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias.

J Cardiovasc Electrophysiol 2013 Sep 20;24(9):1037-46. Epub 2013 May 20.

Department of Clinical Research, University of Bern, Switzerland.

Hundreds of genetic variants in SCN5A, the gene coding for the pore-forming subunit of the cardiac sodium channel, Na(v) 1.5, have been described in patients with cardiac channelopathies as well as in individuals from control cohorts. The aim of this study was to characterize the biophysical properties of 2 naturally occurring Na(v) 1.5 variants, p.R689H and p.R689C, found in patients with cardiac arrhythmias and in control individuals. In addition, this study was motivated by the finding of the variant p.R689H in a family with sudden cardiac death (SCD) in children. When expressed in HEK293 cells, most of the sodium current (I(Na)) biophysical properties of both variants were indistinguishable from the wild-type (WT) channels. In both cases, however, an ∼2-fold increase of the tetrodotoxin-sensitive late I(Na) was observed. Action potential simulations and reconstruction of pseudo-ECGs demonstrated that such a subtle increase in the late I(Na) may prolong the QT interval in a nonlinear fashion. In conclusion, despite the fact that the causality link between p.R689H and the phenotype of the studied family cannot be demonstrated, this study supports the notion that subtle alterations of Na(v) 1.5 variants may increase the risk for cardiac arrhythmias.
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http://dx.doi.org/10.1111/jce.12173DOI Listing
September 2013

Cardiac channelopathies: genetic and molecular mechanisms.

Gene 2013 Mar 22;517(1):1-11. Epub 2012 Dec 22.

Department of Clinical Research, University of Bern, Switzerland.

Channelopathies are diseases caused by dysfunctional ion channels, due to either genetic or acquired pathological factors. Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since seminal observations made in 1995, thousands of mutations have been found in many of the different genes that code for cardiac ion channel subunits and proteins that regulate the cardiac ion channels. The main phenotypes observed in patients carrying these mutations are congenital long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS) and variable types of conduction defects (CD). The goal of this review is to present an update of the main genetic and molecular mechanisms, as well as the associated phenotypes of cardiac channelopathies as of 2012.
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http://dx.doi.org/10.1016/j.gene.2012.12.061DOI Listing
March 2013

Prevalence of Significant Genetic Variants in Congenital Long QT Syndrome is Largely Underestimated.

Front Pharmacol 2012 27;3:72. Epub 2012 Apr 27.

Laboratory of Medical Genetics, Petrovsky Russian Research Center of Surgery Moscow, Russia.

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http://dx.doi.org/10.3389/fphar.2012.00072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338122PMC
October 2012

Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics.

Can J Cardiol 2012 Mar-Apr;28(2):196-200. Epub 2012 Jan 28.

Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.

Background: Brugada syndrome (BrS) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias. Previously, the genes SCN1B, SCN3B, MOG1, and KCND3 have been associated with BrS. Recent data from exome screening efforts permit better discrimination between low-frequency genetic variants and true monogenetic disease-causing variants. We aimed to screen the genes SCN1B through SCN4B, MOG1, CAV3, and KCND3 for variations in a population of SCN5A negative Danish and Iranian BrS patients, as well as research prior associations using newly released exome data.

Methods: Screening of all exons and splice sites was performed using Sanger sequencing. Bioinformatic searches were performed in the Single-nucleotide polymorphism database (build 132) and in the National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project (ESP) for both previously published variant-BrS associations and newly uncovered variations within the noted genes.

Results: A total of 42 BrS patients were screened, and 2 different nonsynonymous mutations in SCN1Bb (H162P and R214Q) were found in 2 different Danish patients. The variants were not found in 216 Danish controls, but R214Q was present in ESP data (5 of 841 alleles). No other mutations were found. Previously BrS-associated mutations in KNCD3 and SCN3B were also present in ESP data. This was not the case for MOG1, but a nonsense polymorphism was present in 0.5% of alleles.

Conclusions: Our study supports the association of SCN1Bb with BrS. However, recently released exome data make some of the prior associations of BrS with genes SCN3B, MOG1, and KCND3 less likely.
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http://dx.doi.org/10.1016/j.cjca.2011.11.011DOI Listing
July 2012

The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratification.

Circulation 2007 Nov 5;116(21):2366-75. Epub 2007 Nov 5.

Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy.

Background: The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)-causing mutation (KCNQ1-A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families.

Methods And Results: Seventy-eight patients, all with a single KCNQ1-A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484+/-42 versus 485+/-45 ms (P=NS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485+/-43 versus 465+/-38 ms) (all P<0.001). Arrhythmic risk remained higher (P<0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite beta-blocker therapy.

Conclusions: The hot spot KCNQ1-A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.107.726950DOI Listing
November 2007
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