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      Novel SCN5A Frameshift Mutation in Brugada Syndrome Associated With Complex Arrhythmic Phenotype

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          Abstract

          In this case report, we characterize a novel inherited frameshift mutation c.4700_4701del (p.Phe1567Cysfs *221) in a single copy of the SCN5A gene and its association with Brugada syndrome (BrS). The proband experienced a life-threatening ventricular arrhythmia successfully treated with DC-shock and he also suffered from supraventricular tachycardia. Ajmaline test confirmed the BrS diagnosis. No other mutation nor low frequency variants in the other 23 analyzed genes were detected. The same mutation was found in the father and sister, who were both diagnosed with BrS. We hypothesize that this mutation could be responsible for BrS and potentially linked to supraventricular tachycardias. Further studies are needed to confirm this observation and to assess the clinical relevance of this mutation, in terms of risk-stratification.

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          Most cited references15

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          The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

          Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. Here, we show that MOTS-c, a peptide encoded in the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5′-adenosine mono-phosphate-activated protein kinase (AMPK)-dependent manner. In the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress-responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2). Our findings indicate that the mitochondrial and nuclear genomes co-evolved to independently encode for factors to cross-regulate each other, suggesting that mitonuclear communication is genetically integrated. The mitochondrial genome is regulated by factors encoded in the nucleus. Kim et al. now show that, reciprocally, MOTS-c, a mitochondrial-encoded peptide, can dynamically translocate to the nucleus in response to metabolic stress and regulate adaptive nuclear gene expression. Their findings suggest that mitonuclear communication is genetically integrated.
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            Sodium channel mutations and susceptibility to heart failure and atrial fibrillation.

            Dilated cardiomyopathy (DCM), a genetically heterogeneous disorder, causes heart failure and rhythm disturbances. The majority of identified DCM genes encode structural proteins of the contractile apparatus and cytoskeleton. Recently, genetic defects in calcium and potassium regulation have been discovered in patients with DCM, implicating an alternative disease mechanism. The full spectrum of genetic defects in DCM, however, has not been established. To identify a novel gene for DCM at a previously mapped locus, define the spectrum of mutations in this gene within a DCM cohort, and determine the frequency of DCM among relatives inheriting a mutation in this gene. Refined mapping of a DCM locus on chromosome 3p in a multigenerational family and mutation scanning in 156 unrelated probands with DCM, prospectively identified at the Mayo Clinic between 1987 and 2004. Relatives underwent screening echocardiography and electrocardiography and DNA sample procurement. Correlation of identified mutations with cardiac phenotype. Refined locus mapping revealed SCN5A, encoding the cardiac sodium channel, as a candidate gene. Mutation scans identified a missense mutation (D1275N) that cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay. In the DCM cohort, additional missense (T220I, R814W, D1595H) and truncation (2550-2551insTG) SCN5A mutations, segregating with cardiac disease or arising de novo, were discovered in unrelated probands. Among individuals with an SCN5A mutation 27% had early features of DCM (mean age at diagnosis, 20.3 years), 38% had DCM (mean age at diagnosis, 47.9 years), and 43% had atrial fibrillation (mean age at diagnosis, 27.8 years). Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both.
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              J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge.

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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                06 June 2019
                2019
                : 10
                : 547
                Affiliations
                [1] 1Arrhythmology Department, IRCCS Policlinico San Donato , Milan, Italy
                [2] 2Genomic Unit for the Diagnosis of Human Pathologies, Division of Genetics and Cellular Biology, IRCCS San Raffaele Hospital , Milan, Italy
                [3] 3Vita-Salute San Raffaele University , Milan, Italy
                [4] 4Laboratory of Clinical Molecular Biology and Cytogenetics, IRCCS San Raffaele Hospital , Milan, Italy
                Author notes

                Edited by: Prashant Kumar Verma, All India Institute of Medical Sciences Rishikesh, India

                Reviewed by: Nelson L. S. Tang, The Chinese University of Hong Kong, China; Giannis G. Baltogiannis, Vrije Universiteit Brussel, Belgium

                *Correspondence: Carlo Pappone, carlo.pappone@ 123456af-ablation.org

                This article was submitted to Genetic Disorders, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2019.00547
                6565861
                31231430
                6bbaacb1-c966-4582-9638-f3ada40791e4
                Copyright © 2019 Micaglio, Monasky, Ciconte, Vicedomini, Conti, Mecarocci, Giannelli, Giordano, Pollina, Saviano, Pozzi, Di Resta, Benedetti, Ferrari, Santinelli and Pappone.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 July 2018
                : 23 May 2019
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 18, Pages: 7, Words: 0
                Categories
                Genetics
                Case Report

                Genetics
                brugada syndrome,sudden cardiac death,genetic testing,mutation,scn5a,sodium channel,arrhythmia,atrial fibrillation

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