Publications by authors named "Tamara T Koopmann"

36 Publications

Adapting the ACMG/AMP variant classification framework: A perspective from the ClinGen Hemoglobinopathy Variant Curation Expert Panel.

Hum Mutat 2021 Sep 12. Epub 2021 Sep 12.

Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

Accurate and consistent interpretation of sequence variants is integral to the delivery of safe and reliable diagnostic genetic services. To standardize the interpretation process, in 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published a joint guideline based on a set of shared standards for the classification of variants in Mendelian diseases. The generality of these standards and their subjective interpretation between laboratories has prompted efforts to reduce discordance of variant classifications, with a focus on the expert specification of the ACMG/AMP guidelines for individual genes or diseases. Herein, we describe our experience as a ClinGen Variant Curation Expert Panel to adapt the ACMG/AMP criteria for the classification of variants in three globin genes (HBB, HBA2, and HBA1) related to recessively inherited hemoglobinopathies, including five evidence categories, as use cases demonstrating the process of specification and the underlying rationale.
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http://dx.doi.org/10.1002/humu.24280DOI Listing
September 2021

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

Genet Med 2021 Dec 16;23(12):2415-2425. Epub 2021 Aug 16.

Stanford Medicine Clinical Genomics Program, Stanford, CA, USA.

Purpose: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants.

Methods: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized.

Results: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity.

Conclusion: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.
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http://dx.doi.org/10.1038/s41436-021-01296-6DOI Listing
December 2021

The Evolving Role of Next-Generation Sequencing in Screening and Diagnosis of Hemoglobinopathies.

Front Physiol 2021 27;12:686689. Epub 2021 Jul 27.

Department of Clinical Genetics/LDGA, Leiden University Medical Center, Leiden, Netherlands.

During the last few years, next-generation sequencing (NGS) has undergone a rapid transition from a research setting to a clinical application, becoming the method of choice in many clinical genetics laboratories for the detection of disease-causing variants in a variety of genetic diseases involving multiple genes. The hemoglobinopathies are the most frequently found Mendelian inherited monogenic disease worldwide and are composed of a complex group of disorders frequently involving the inheritance of more than one abnormal gene. This review aims to present the role of NGS in both screening and pre- and post-natal diagnostics of the hemoglobinopathies, and the added value of NGS is discussed based on the results described in the literature. Overall, NGS has an added value in large-scale high throughput carrier screening and in the complex cases for which common molecular techniques have some inadequacies. It is proven that the majority of thalassemia cases and Hb variants can be diagnosed using routine analysis involving a combined approach of hematology, hemoglobin separation, and classical DNA methods; however, we conclude that NGS can be a useful addition to the existing methods in the diagnosis of these disorders.
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http://dx.doi.org/10.3389/fphys.2021.686689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353275PMC
July 2021

Usefulness of NGS for Diagnosis of Dominant Beta-Thalassemia and Unstable Hemoglobinopathies in Five Clinical Cases.

Front Physiol 2021 5;12:628236. Epub 2021 Feb 5.

Translational Research in Child and Adolescent Cancer - Rare Anemia Disorders Research Laboratory, Vall d'Hebron Research Institute, ERN-EuroBloodNet Member, Barcelona, Spain.

Unstable hemoglobinopathies (UHs) are rare anemia disorders (RADs) characterized by abnormal hemoglobin (Hb) variants with decreased stability. UHs are therefore easily precipitating, causing hemolysis and, in some cases, leading to dominant beta-thalassemia (dBTHAL). The clinical picture of UHs is highly heterogeneous, inheritance pattern is dominant, instead of recessive as in more prevalent major Hb syndromes, and may occur . Most cases of UHs are not detected by conventional testing, therefore diagnosis requires a high index of suspicion of the treating physician. Here, we highlight the importance of next generation sequencing (NGS) methodologies for the diagnosis of patients with dBTHAL and other less severe UH variants. We present five unrelated clinical cases referred with chronic hemolytic anemia, three of them with severe blood transfusion dependent anemia. Targeted NGS analysis was performed in three cases while whole exome sequencing (WES) analysis was performed in two cases. Five different UH variants were identified correlating with patients' clinical manifestations. Four variants were related to the beta-globin gene (Hb Bristol-Alesha, Hb Debrousse, Hb Zunyi, and the novel Hb Mokum) meanwhile one case was caused by a mutation in the alpha-globin gene leading to Hb Evans. Inclusion of alpha and beta-globin genes in routine NGS approaches for RADs has to be considered to improve diagnosis' efficiency of RAD due to UHs. Reducing misdiagnoses and underdiagnoses of UH variants, especially of the severe forms leading to dBTHAL would also facilitate the early start of intensive or curative treatments for these patients.
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http://dx.doi.org/10.3389/fphys.2021.628236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893112PMC
February 2021

Identification of known and unknown genes associated with mitral valve prolapse using an exome slice methodology.

J Med Genet 2020 12 10;57(12):843-850. Epub 2020 Apr 10.

Cardiology, Leiden University Medical Center, Leiden, Zuid-Holland, The Netherlands

Purpose: Although a familial distribution has been documented, the genetic aetiology of mitral valve prolapse (MVP) is largely unknown, with only four genes identified so far: , , and . The aim of this study was to evaluate the genetic yield in known causative genes and to identify possible novel genes associated with MVP using a heart gene panel based on exome sequencing.

Methods: Patients with MVP were referred for genetic counselling when a positive family history for MVP was reported and/or Barlow's disease was diagnosed. In total, 101 probands were included to identify potentially pathogenic variants in a set of 522 genes associated with cardiac development and/or diseases.

Results: 97 (96%) probands were classified as Barlow's disease and 4 (4%) as fibroelastic deficiency. Only one patient (1%) had a likely pathogenic variant in the known causative genes (). However, an interesting finding was that 10 probands (11%) had a variant that was classified as likely pathogenic in six different, mostly cardiomyopathy genes: (1×), (1×), (1×), (1×), (1×) and (5×).

Conclusion: Exome slice sequencing analysis performed in MVP probands reveals a low genetic yield in known causative genes but may expand the cardiac phenotype of other genes. This study suggests for the first time that also genes related to cardiomyopathy may be associated with MVP. This highlights the importance to screen these patients and their family for the presence of arrhythmias and of 'disproportionate' LV remodelling as compared with the severity of mitral regurgitation, unravelling a possible coexistent cardiomyopathy.
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http://dx.doi.org/10.1136/jmedgenet-2019-106715DOI Listing
December 2020

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

J Clin Invest 2019 07 2;129(8):3171-3184. Epub 2019 Jul 2.

Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.
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http://dx.doi.org/10.1172/JCI125538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668697PMC
July 2019

From diagnostic yield to clinical impact: a pilot study on the implementation of prenatal exome sequencing in routine care.

Genet Med 2019 10 28;21(10):2303-2310. Epub 2019 Mar 28.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.

Purpose: Exome sequencing (ES) is an efficient tool to diagnose genetic disorders postnatally. Recent studies show that it may have a considerable diagnostic yield in fetuses with structural anomalies on ultrasound. We report on the clinical impact of the implementation of prenatal ES (pES) for ongoing pregnancies in routine care.

Methods: We retrospectively analyzed the impact of pES on pregnancy outcome and pre- or perinatal management in the first 22 patients counseled for pES because of one or more structural anomalies on fetal ultrasound.

Results: In two cases, a diagnosis was made by chromosomal microarray analysis after ES counseling. The remaining 20 cases were divided in three groups: (1) pES to aid parental decision making (n = 12), (2) pES in the context of late pregnancy termination requests (n = 5), and (3) pES to guide pre- or perinatal management (n = 3). pES had a clinical impact in 75% (9/12), 40% (2/5), and 100% (3/3) respectively, showing an overall clinical impact of pES of 70% (14/20).

Conclusion: We show that clinical implementation of pES is feasible and affects parental decision making or pre- and perinatal management supporting further implementation of ES in the prenatal setting.
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http://dx.doi.org/10.1038/s41436-019-0499-9DOI Listing
October 2019

An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis.

Eur Heart J 2018 11;39(44):3932-3944

The Labatt Family Heart Centre (Department of Pediatrics) and Translational Medicine, The Hospital for Sick Children & Research Institute and the University of Toronto, Room 1725D, 555 University Avenue, Toronto, Ontario, Canada.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC.

Methods And Results: We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified anti-DSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified.

Conclusion: Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehy567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247665PMC
November 2018

Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.

J Am Heart Assoc 2016 09 13;5(9). Epub 2016 Sep 13.

Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias.

Methods And Results: We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild-type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity.

Conclusions: Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.
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http://dx.doi.org/10.1161/JAHA.116.003644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079027PMC
September 2016

Modeling junctional dysrhythmias: Disassembling the JET engine.

Heart Rhythm 2016 12 9;13(12):2356-2357. Epub 2016 Aug 9.

Physiology & Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2016.08.020DOI Listing
December 2016

Sudden Cardiac Arrest and Rare Genetic Variants in the Community.

Circ Cardiovasc Genet 2016 Apr 22;9(2):147-53. Epub 2016 Jan 22.

From the Department of Clinical & Experimental Cardiology, Heart Center, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands (A.M., M.T.B., E.M.L., D.A.v.H., J.B., T.T.K., A.B., L.B., A.A.M.W., C.R.B., H.L.T.); Institut für Humangenetik, Helmholtz Zentrum München, Munich, Germany; Institut für Humangenetik, Technische Universität München, Munich, Germany (P.L.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (M.P.v.d.B.); and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.).

Background: Sudden cardiac arrest (SCA) ranks among the most common causes of death worldwide. Because SCA is most often lethal, yet mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCA could save many lives. In unselected SCA victims from the community, common genetic variants (which are not disease-causing per se, but may increase susceptibility to ventricular fibrillation) are found to be associated with increased SCA risk. However, whether rare genetic variants contribute to SCA risk in the community is largely unexplored.

Methods And Results: We here investigated the involvement of rare genetic variants in SCA risk at the population level by studying the prevalence of 6 founder genetic variants present in the Dutch population (PLN-p.Arg14del, MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X, MYBPC3-p.Pro955fsX95, PKP2-p.Arg79X, and the Chr7q36 idiopathic ventricular fibrillation risk haplotype) in a cohort of 1440 unselected Dutch SCA victims included in the Amsterdam Resuscitation Study (ARREST). The six studied founder mutations were found to be more prevalent (1.1%) in the ARREST SCA cohort compared with an ethnically and geographically matched set of controls (0.4%, n=1379; P<0.05) or a set of Dutch individuals drawn from the Genome of the Netherlands (GoNL) study (0%, n=500; P<0.02).

Conclusions: This finding provides proof-of-concept for the notion that rare genetic variants contribute to some extent to SCA risk in the community.
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http://dx.doi.org/10.1161/CIRCGENETICS.115.001263DOI Listing
April 2016

Analysis for Genetic Modifiers of Disease Severity in Patients With Long-QT Syndrome Type 2.

Circ Cardiovasc Genet 2015 Jun 3;8(3):447-456. Epub 2015 Mar 3.

Department of Clinical and Experimental Cardiology (I.C.R.M.K., P.G.P., J.B., T.T.K., A.A.M.W., C.R.B.), Department of Clinical Epidemiology, Biostatistics and Bioinformatics (I.C.R.M.K., M.W.T.T.), and Department of Clinical Genetics (N.H.), Academic Medical Center, Amsterdam, the Netherlands; ICIN (Netherlands Heart Institute) (J.B., A.A.M.W., C.R.B.), Utrecht, the Netherlands; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France (J.B., J.-J.S.); Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France (J.B., J.-J.S.); Université de Nantes, Nantes, France (J.B., J.-J.S.); Department of Medicine I, University Hospital Munich, Campus Grosshadern and Innenstadt, Ludwig-Maximilians University, Munich, Germany (M.F.S., B.M.B., S.K.); German Center for Cardiovascular Research (DZHK), Munich Heart Alliance, Munich, Germany (S.K.T.M.); Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany (S.Z., A.H., B.S., E.S.-B.); Interdisciplinary Centre for Clinical Research (IZKF) of the University of Münster, Münster, Germany (S.Z., A.H., B.S., E.S.-B.); Institute of Bioinformatics and Systems Biology (A.P.), and Institute of Human Genetics (A.P., P.L., T.M.), Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany (A.P., P.L., T.M.); Department of Medicine (R.J.M., N.H.B.), Department of Molecular and Cellular Pharmacology (R.J.M., N.H.B.), and Hussmann Institute of Human Genomics (R.J.M., N.H.B.), University of Miami Miller School of Medicine, FL; Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN (D.M.R.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.); and Centre Hospitalier Universitaire (CHU) Nantes, L'Institut du Thorax, Service de Cardiologie, Nantes, France (J.-J.S.).

Background: Considerable interest exists in the identification of genetic modifiers of disease severity in the long-QT syndrome (LQTS) as their identification may contribute to refinement of risk stratification.

Methods And Results: We searched for single-nucleotide polymorphisms (SNPs) that modulate the corrected QT (QTc)-interval and the occurrence of cardiac events in 639 patients harboring different mutations in KCNH2. We analyzed 1201 SNPs in and around 18 candidate genes, and in another approach investigated 22 independent SNPs previously identified as modulators of QTc-interval in genome-wide association studies in the general population. In an analysis for quantitative effects on the QTc-interval, 3 independent SNPs at NOS1AP (rs10494366, P=9.5×10(-8); rs12143842, P=4.8×10(-7); and rs2880058, P=8.6×10(-7)) were strongly associated with the QTc-interval with marked effects (>12 ms/allele). Analysis of patients versus general population controls uncovered enrichment of QTc-prolonging alleles in patients for 2 SNPs, located respectively at NOS1AP (rs12029454; odds ratio, 1.85; 95% confidence interval, 1.32-2.59; P=3×10(-4)) and KCNQ1 (rs12576239; odds ratio, 1.84; 95% confidence interval, 1.31-2.60; P=5×10(-4)). An analysis of the cumulative effect of the 6 NOS1AP SNPs by means of a multilocus genetic risk score (GRS(NOS1AP)) uncovered a strong linear relationship between GRS(NOS1AP) and the QTc-interval (P=4.2×10(-7)). Furthermore, patients with a GRS(NOS1AP) in the lowest quartile had a lower relative risk of cardiac events compared with patients in the other quartiles combined (P=0.039).

Conclusions: We uncovered unexpectedly large effects of NOS1AP SNPs on the QTc-interval and a trend for effects on risk of cardiac events. For the first time, we linked common genetic variation at KCNQ1 with risk of long-QT syndrome.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770255PMC
June 2015

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Nat Genet 2014 Aug 22;46(8):826-36. Epub 2014 Jun 22.

Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated institute of the University of Lübeck, Lübeck, Germany).

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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http://dx.doi.org/10.1038/ng.3014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124521PMC
August 2014

Genome-wide identification of expression quantitative trait loci (eQTLs) in human heart.

PLoS One 2014 20;9(5):e97380. Epub 2014 May 20.

Department of Experimental Cardiology, Heart Failure Research Centre, Academic Medical Center, Amsterdam, The Netherlands.

In recent years genome-wide association studies (GWAS) have uncovered numerous chromosomal loci associated with various electrocardiographic traits and cardiac arrhythmia predisposition. A considerable fraction of these loci lie within inter-genic regions. The underlying trait-associated variants likely reside in regulatory regions and exert their effect by modulating gene expression. Hence, the key to unraveling the molecular mechanisms underlying these cardiac traits is to interrogate variants for association with differential transcript abundance by expression quantitative trait locus (eQTL) analysis. In this study we conducted an eQTL analysis of human heart. For a total of 129 left ventricular samples that were collected from non-diseased human donor hearts, genome-wide transcript abundance and genotyping was determined using microarrays. Each of the 18,402 transcripts and 897,683 SNP genotypes that remained after pre-processing and stringent quality control were tested for eQTL effects. We identified 771 eQTLs, regulating 429 unique transcripts. Overlaying these eQTLs with cardiac GWAS loci identified novel candidates for studies aimed at elucidating the functional and transcriptional impact of these loci. Thus, this work provides for the first time a comprehensive eQTL map of human heart: a powerful and unique resource that enables systems genetics approaches for the study of cardiac traits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097380PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028258PMC
February 2015

A common genetic variant within SCN10A modulates cardiac SCN5A expression.

J Clin Invest 2014 Apr 18;124(4):1844-52. Epub 2014 Mar 18.

Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.
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http://dx.doi.org/10.1172/JCI73140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973109PMC
April 2014

Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia.

J Am Coll Cardiol 2014 Feb 27;63(6):549-59. Epub 2013 Nov 27.

Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address:

Objectives: The aim of this study was to investigate the modulatory effect of the coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia.

Background: A heritable component in the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the CAR, a cell adhesion molecule predominantly located at the intercalated disks of the cardiomyocyte.

Methods: The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed using CAR haploinsufficient (CAR⁺/⁻) mice.

Results: In human left ventricular samples, the risk allele at the chr21q21 genome-wide association study locus was associated with lower CXADR messenger ribonucleic acid levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced ventricular fibrillation. Hearts from CAR⁺/⁻ mice displayed slowing of ventricular conduction in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia after ligation of the left anterior descending artery. Expression and distribution of connexin 43 were unaffected, but CAR⁺/⁻ hearts displayed increased arrhythmia susceptibility on pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR⁺/⁻ myocytes showed reduced sodium current magnitude specifically at the intercalated disk. Moreover, CAR coprecipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5.

Conclusions: CAR is a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease.
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http://dx.doi.org/10.1016/j.jacc.2013.10.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3926969PMC
February 2014

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.

Nat Genet 2013 Jul 26;45(7):822-4. Epub 2013 May 26.

Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻⁷) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻⁵; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹⁰). Genotype accounted for ~9% of the population-attributable risk of ASD.
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http://dx.doi.org/10.1038/ng.2637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793630PMC
July 2013

Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation.

Circ Res 2013 May 26;112(10):1310-22. Epub 2013 Mar 26.

Department of Medicine, Montreal Heart Institute and Université de Montréal, Montreal, QC, Canada.

Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current (I(to)) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I(to) and that its overexpression might specifically alter PF I(to) properties and repolarization.

Objective: To assess the potential role of DPP6 in PF I(to).

Methods And Results: Clinical data in 5 idiopathic ventricular fibrillation patients suggested arrhythmia origin in the PF-conducting system. PF and ventricular muscle I(to) had similar density, but PF I(to) differed from ventricular muscle in having tetraethylammonium sensitivity and slower recovery. DPP6 overexpression significantly increased, whereas DPP6 knockdown reduced, I(to) density and tetraethylammonium sensitivity in canine PF but not in ventricular muscle cells. The K(+)-channel interacting β-subunit K(+)-channel interacting protein type-2, essential for normal expression of I(to) in ventricular muscle, was weakly expressed in human PFs, whereas DPP6 and frequenin (neuronal calcium sensor-1) were enriched. Heterologous expression of Kv4.3 in Chinese hamster ovary cells produced small I(to); I(to) amplitude was greatly enhanced by coexpression with K(+)-channel interacting protein type-2 or DPP6. Coexpression of DPP6 with Kv4.3 and K(+)-channel interacting protein type-2 failed to alter I(to) compared with Kv4.3/K(+)-channel interacting protein type-2 alone, but DPP6 expression with Kv4.3 and neuronal calcium sensor-1 (to mimic PF I(to) composition) greatly enhanced I(to) compared with Kv4.3/neuronal calcium sensor-1 and recapitulated characteristic PF kinetic/pharmacological properties. A mathematical model of cardiac PF action potentials showed that I(to) enhancement can greatly accelerate PF repolarization.

Conclusions: These results point to a previously unknown central role of DPP6 in PF I(to), with DPP6 gain of function selectively enhancing PF current, and suggest that a DPP6-mediated PF early-repolarization syndrome might be a novel molecular paradigm for some forms of idiopathic ventricular fibrillation.
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http://dx.doi.org/10.1161/CIRCRESAHA.112.300227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465785PMC
May 2013

The chemical compound PTC124 does not affect cellular electrophysiology of cardiac ventricular myocytes.

Cardiovasc Drugs Ther 2012 Feb;26(1):41-5

Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.

Purpose: Nonsense mutations that create premature termination codons (PTC) leading to disease by a mechanism of haploinsufficiency are relatively common in the SCN5A gene encoding the major sodium channel in heart. PTCs in SCN5A are associated with isolated conduction disease and Brugada syndrome (BrS). Pharmacological therapy does not exist for these disorders, but would be highly beneficial. Recently, an orally bio-available drug capable of suppressing premature termination, PTC124, has been identified that selectively induces ribosomal read-through of premature but not normal termination codons. In this study, we tested the acute and long-term effects of PTC124 on action potential characteristics of rabbit ventricular cardiomyocytes.

Methods: The effects of PTC124 on action potentials of isolated adult rabbit ventricular cardiomyocytes were studied using the perforated patch-clamp methodology. Acute effects of PTC124 were measured in freshly isolated cardiomyocytes, while long term effects were measured after 48 h in cultured cardiomyocytes.

Results: Resting membrane potential, maximum upstroke velocity, action potential amplitude and action potential duration at 20, 50 and 90% of repolarization were not affected by application of PTC124, neither acute nor after 48 h.

Conclusion: PTC124 has no acute or long-term effects on rabbit ventricular action potentials. These experiments form the basis for future studies evaluating the use of this therapy in preventing potentially lethal arrhythmias in patients with BrS and/or conduction disease.
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http://dx.doi.org/10.1007/s10557-011-6352-2DOI Listing
February 2012

A complex double deletion in LMNA underlies progressive cardiac conduction disease, atrial arrhythmias, and sudden death.

Circ Cardiovasc Genet 2011 Jun 15;4(3):280-7. Epub 2011 Mar 15.

Heart Failure Research Center, Department of Experimental Cardiology, Amsterdam, The Netherlands.

Background: Cardiac conduction disease is a clinically and genetically heterogeneous disorder characterized by defects in electrical impulse generation and conduction and is associated with sudden cardiac death.

Methods And Results: We studied a 4-generation family with autosomal dominant progressive cardiac conduction disease, including atrioventricular conduction block and sinus bradycardia, atrial arrhythmias, and sudden death. Genome-wide linkage analysis mapped the disease locus to chromosome 1p22-q21. Multiplex ligation-dependent probe amplification analysis of the LMNA gene, which encodes the nuclear-envelope protein lamin A/C, revealed a novel gene rearrangement involving a 24-bp inversion flanked by a 3.8-kb deletion upstream and a 7.8-kb deletion downstream. The presence of short inverted sequence homologies at the breakpoint junctions suggested a mutational event involving serial replication slippage in trans during DNA replication.

Conclusions: We identified for the first time a complex LMNA gene rearrangement involving a double deletion in a 4-generation Dutch family with progressive conduction system disease. Our findings underscore the fact that if conventional polymerase chain reaction-based direct sequencing approaches for LMNA analysis are negative in suggestive pedigrees, mutation detection techniques capable of detecting gross genomic lesions involving deletions and insertions should be considered.
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http://dx.doi.org/10.1161/CIRCGENETICS.110.959221DOI Listing
June 2011

Genetics of lone atrial fibrillation.

Europace 2010 Oct 7;12(10):1351-2. Epub 2010 Sep 7.

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http://dx.doi.org/10.1093/europace/euq323DOI Listing
October 2010

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Heart Rhythm 2010 Jan 8;7(1):33-46. Epub 2009 Oct 8.

Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA.

Background: Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.

Objective: This study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.

Methods: Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.

Results: A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N (8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning regions.

Conclusion: This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.
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http://dx.doi.org/10.1016/j.hrthm.2009.09.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822446PMC
January 2010

A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.

Circ Cardiovasc Genet 2009 Jun 21;2(3):270-8. Epub 2009 Apr 21.

Masonic Medical Research Laboratory, Utica, NY, USA.

Background: Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene.

Methods And Results: A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction-based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the beta 3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of Na(V)beta 3 in human ventricular myocardium.

Conclusions: Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNa(v)1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.
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http://dx.doi.org/10.1161/CIRCGENETICS.108.829192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801870PMC
June 2009

Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.

Am J Hum Genet 2009 Apr 12;84(4):468-76. Epub 2009 Mar 12.

Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease. A family history is present in up to 20% of probands with the disorder, suggesting that at least a subset of IVF is hereditary. A genome-wide haplotype-sharing analysis was performed for identification of the responsible gene in three distantly related families in which multiple individuals died suddenly or were successfully resuscitated at young age. We identified a haplotype, on chromosome 7q36, that was conserved in these three families and was also shared by 7 of 42 independent IVF patients. The shared chromosomal segment harbors part of the DPP6 gene, which encodes a putative component of the transient outward current in the heart. We demonstrated a 20-fold increase in DPP6 mRNA levels in the myocardium of carriers as compared to controls. Clinical evaluation of 84 risk-haplotype carriers and 71 noncarriers revealed no ECG or structural parameters indicative of cardiac disease. Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years. We propose DPP6 as a gene for IVF and increased DPP6 expression as the likely pathogenetic mechanism.
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http://dx.doi.org/10.1016/j.ajhg.2009.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667995PMC
April 2009

Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies.

Heart Rhythm 2009 Mar 11;6(3):341-8. Epub 2008 Nov 11.

Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.

Background: Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed.

Objectives: We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype.

Methods: We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with 90% (M(inactive)) peak I(Na) reduction were analyzed separately.

Results: The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group.

Conclusion: In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.
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http://dx.doi.org/10.1016/j.hrthm.2008.11.009DOI Listing
March 2009

Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans.

J Clin Invest 2008 Jun;118(6):2260-8

Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Brugada syndrome is a genetic disease associated with sudden cardiac death that is characterized by ventricular fibrillation and right precordial ST segment elevation on ECG. Loss-of-function mutations in SCN5A, which encodes the predominant cardiac sodium channel alpha subunit NaV1.5, can cause Brugada syndrome and cardiac conduction disease. However, SCN5A mutations are not detected in the majority of patients with these syndromes, suggesting that other genes can cause or modify presentation of these disorders. Here, we investigated SCN1B, which encodes the function-modifying sodium channel beta1 subunit, in 282 probands with Brugada syndrome and in 44 patients with conduction disease, none of whom had SCN5A mutations. We identified 3 mutations segregating with arrhythmia in 3 kindreds. Two of these mutations were located in a newly described alternately processed transcript, beta1B. Both the canonical and alternately processed transcripts were expressed in the human heart and were expressed to a greater degree in Purkinje fibers than in heart muscle, consistent with the clinical presentation of conduction disease. Sodium current was lower when NaV1.5 was coexpressed with mutant beta1 or beta1B subunits than when it was coexpressed with WT subunits. These findings implicate SCN1B as a disease gene for human arrhythmia susceptibility.
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http://dx.doi.org/10.1172/JCI33891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2373423PMC
June 2008

Exclusion of multiple candidate genes and large genomic rearrangements in SCN5A in a Dutch Brugada syndrome cohort.

Heart Rhythm 2007 Jun 2;4(6):752-5. Epub 2007 Mar 2.

Center for Heart Failure Research, Experimental and Molecular Cardiology Group, University of Amsterdam, Amsterdam, The Netherlands.

Background: The Brugada syndrome is an inherited cardiac electrical disorder associated with a high incidence of life-threatening arrhythmias. Screening for mutations in the cardiac Na+ channel-encoding gene SCN5A uncovers a mutation in approximately 20% of Brugada syndrome cases. Genetic heterogeneity and/or undetected SCN5A mutations, such as exon duplications and deletions, could be involved in the remaining 80% mutation-negative patients.

Objectives: Thirty-eight SCN5A mutation-negative Dutch Brugada syndrome probands were studied. The SCN5A gene was investigated for exon duplication and deletion, and a number of candidate genes (Caveolin-3, Irx-3, Irx-4, Irx-5, Irx-6, Plakoglobin, Plakophilin-2, SCN1B, SCN2B, SCN3B, and SCN4B) were tested for the occurrence of point mutations and small insertions/deletions.

Methods: We used a quantitative multiplex approach to determine SCN5A exon copy numbers. Mutation analysis of the candidate genes was performed by direct sequencing of polymerase chain reaction-amplified coding regions.

Results: No large genomic rearrangements in SCN5A were identified. No mutations were found in the candidate genes. Twenty novel polymorphisms were identified in these genes.

Conclusion: Large genomic rearrangements in SCN5A are not a common cause of Brugada syndrome. Similarly, the studied candidate genes are unlikely to be major causal genes of Brugada syndrome. Further studies are required to identify other genes responsible for this syndrome.
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http://dx.doi.org/10.1016/j.hrthm.2007.02.021DOI Listing
June 2007
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