Publications by authors named "Monica Coll"

36 Publications

The brain-heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention.

Ann Clin Transl Neurol 2021 Jul 28;8(7):1557-1568. Epub 2021 May 28.

IRCCS Istituto Giannina Gaslini, Genova, Italy.

The influence of the central nervous system and autonomic system on cardiac activity is being intensively studied, as it contributes to the high rate of cardiologic comorbidities observed in people with epilepsy. Indeed, neuroanatomic connections between the brain and the heart provide links that allow cardiac arrhythmias to occur in response to brain activation, have been shown to produce arrhythmia both experimentally and clinically. Moreover, seizures may induce a variety of transient cardiac effects, which include changes in heart rate, heart rate variability, arrhythmias, asystole, and other ECG abnormalities, and can trigger the development of Takotsubo syndrome. People with epilepsy are at a higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Although the cause of SUDEP is still unknown, cardiac abnormalities during and between seizures could play a significant role in its pathogenesis, as highlighted by studies on animal models of SUDEP and registration of SUDEP events. Recently, genetic mutations in genes co-expressed in the heart and brain, which may result in epilepsy and cardiac comorbidity/increased risk for SUDEP, have been described. Recognition and a better understanding of brain-heart interactions, together with new advances in sequencing techniques, may provide new insights into future novel therapies and help in the prevention of cardiac dysfunction and sudden death in epileptic individuals.
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http://dx.doi.org/10.1002/acn3.51382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283165PMC
July 2021

Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies.

Int J Mol Sci 2021 Apr 16;22(8). Epub 2021 Apr 16.

Department of Health Surveillance and Bioethics, Section of Legal Medicine, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete's heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants.
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http://dx.doi.org/10.3390/ijms22084124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074148PMC
April 2021

Malignant Arrhythmogenic Role Associated with : A Comprehensive Interpretation Focused on a Personalized Approach.

J Pers Med 2021 Feb 15;11(2). Epub 2021 Feb 15.

Cardiovascular Genetics Center, University of Girona-IDIBGI, 17001 Girona, Spain.

The gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.
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http://dx.doi.org/10.3390/jpm11020130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918949PMC
February 2021

Rare Variants Associated with Arrhythmogenic Cardiomyopathy: Reclassification Five Years Later.

J Pers Med 2021 Feb 26;11(3). Epub 2021 Feb 26.

Cardiovascular Genetics Center, University of Girona-IdIBGi, Girona 17190, Spain.

Genetic interpretation of rare variants associated with arrhythmogenic cardiomyopathy (ACM) is essential due to their diagnostic implications. New data may relabel previous variant classifications, but how often reanalysis is necessary remains undefined. Five years ago, 39 rare ACM-related variants were identified in patients with features of cardiomyopathy. These variants were classified following the American College of Medical Genetics and Genomics' guidelines. In the present study, we reevaluated these rare variants including novel available data. All cases carried one rare variant classified as being of ambiguous significance (82.05%) or likely pathogenic (17.95%) in 2016. In our comprehensive reanalysis, the classification of 30.77% of these variants changed, mainly due to updated global frequencies. As in 2016, nowadays most variants were classified as having an uncertain role (64.1%), but the proportion of variants with an uncertain role was significantly decreased (17.95%). The percentage of rare variants classified as potentially deleterious increased from 17.95% to 23.07%. Moreover, 83.33% of reclassified variants gained certainty. We propose that periodic genetic reanalysis of all rare variants associated with arrhythmogenic cardiomyopathy should be undertaken at least once every five years. Defining the roles of rare variants may help clinicians obtain a definite diagnosis.
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http://dx.doi.org/10.3390/jpm11030162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996798PMC
February 2021

Genetic variants of uncertain significance: How to match scientific rigour and standard of proof in sudden cardiac death?

Leg Med (Tokyo) 2020 Apr 23;45:101712. Epub 2020 Apr 23.

Institute of Public Health, Section of Legal Medicine, Catholic University, Rome, Italy. Electronic address:

In many SCD cases, in particular in pediatric age, autopsy can be completely negative and then a post-mortem genetic testing (molecular autopsy) is indicated. In NGS era finding new/rare variants is extremely frequent and, when only variants of unknown significance are found, molecular autopsy fails to find a cause of death. We describe the emblematic case of the sudden death of a 7-year-old girl. We performed a full-body micro-CT analysis, an accurate autopsy, a serum tryptase test and toxicological tests. Since the only macroscopic abnormality we found was a myocardial bridging (length: 1,1 cm, thickness: 0,5 cm) of the left anterior descending coronary artery, a molecular autopsy has been performed. NGS analysis on victim DNA detected rare variants in DPP6, MYH7, SCN2B and NOTCH1 and segregation analysis was then achieved. On the basis of ACMG/AMP (clinical) guidelines, all the found variants were classified as of unknown significance. In other words, both the macroscopic and genetic anomalies we found were of uncertain significance and then the autopsy failed to find the cause of the death. Our case raises three main discussion points: (a) economical, ethical and legal limitations of genetic investigation; (b) risk that genetic testing does not succeed in finding a certain cause of the death; (c) absence of specific guidelines to face the problem of VUS in forensic cases.
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http://dx.doi.org/10.1016/j.legalmed.2020.101712DOI Listing
April 2020

Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes.

EBioMedicine 2020 Apr 5;54:102732. Epub 2020 Apr 5.

Cardiovascular Genetics Center, University of Girona-IDIBGI, C/ Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), 17190 Salt (Girona), Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Cardiology Service, Hospital Josep Trueta, University of Girona, Girona, Spain. Electronic address:

Background: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings.

Methods: In 2010, the rare variants identified through genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations.

Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 post-mortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance.

Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment.

Funding: Obra Social "La Caixa Foundation" (ID 100010434, LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo Investigacion Sanitaria (FIS PI16/01203 and FIS, PI17/01690), Sociedad Española de Cardiología, and "Fundacio Privada Daniel Bravo Andreu".
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http://dx.doi.org/10.1016/j.ebiom.2020.102732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136601PMC
April 2020

Sudden Cardiac Death and Copy Number Variants: What Do We Know after 10 Years of Genetic Analysis?

Forensic Sci Int Genet 2020 07 20;47:102281. Epub 2020 Mar 20.

Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Spain; Centro de Investigación Biomédica en Red, Enfermedades Cardiovasculares (CIBERCV), Spain; Biochemistry and Molecular Genetics Department, Hospital Clinic, University of Barcelona-IDIBAPS, Spain. Electronic address:

Over the last ten years, analysis of copy number variants has increasingly been applied to the study of arrhythmogenic pathologies associated with sudden death, mainly due to significant advances in the field of massive genetic sequencing. Nevertheless, few published reports have focused on the prevalence of copy number variants associated with sudden cardiac death. As a result, the frequency of these genetic alterations in arrhythmogenic diseases as well as their genetic interpretation and clinical translation has not been established. This review summarizes the current available data concerning copy number variants in sudden cardiac death-related diseases.
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http://dx.doi.org/10.1016/j.fsigen.2020.102281DOI Listing
July 2020

Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants.

J Clin Med 2019 Jul 16;8(7). Epub 2019 Jul 16.

Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Girona, Spain.

Short QT syndrome, one of the most lethal entities associated with sudden cardiac death, is a rare genetic disease characterized by short QT intervals detected by electrocardiogram. Several genetic variants are causally linked to the disease, but there has yet to be a comprehensive analysis of variants among patients with short QT syndrome. To fill this gap, we performed an exhaustive study of variants currently catalogued as deleterious in short QT syndrome according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Analysis of the 32 variants described in the literature determined that only nine (28.12%) have a conclusive pathogenic role. All definitively pathogenic variants are located in , , or ; three genes encoding potassium channels. Other variants located in genes encoding calcium or sodium channels are associated with electrical alterations concomitant with shortened QT intervals but do not guarantee a diagnosis of short QT syndrome. We recommend caution regarding previously reported variants classified as pathogenic. An exhaustive re-analysis is necessary to clarify the role of each variant before routinely translating genetic findings to the clinical setting.
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http://dx.doi.org/10.3390/jcm8071035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678338PMC
July 2019

Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies.

Front Genet 2019 15;10:450. Epub 2019 May 15.

Cardiovascular Genetics Center, Biomedical Research Institute of Girona, University of Girona, Girona, Spain.

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner.
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http://dx.doi.org/10.3389/fgene.2019.00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529573PMC
May 2019

Update on the Genetic Basis of Sudden Unexpected Death in Epilepsy.

Int J Mol Sci 2019 Apr 23;20(8). Epub 2019 Apr 23.

Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003 Salt, Spain.

Epilepsy is a common neurological disorder associated with increased morbidity and mortality. Sudden unexpected death in epilepsy, also known as SUDEP, is the main cause of death in patients with epilepsy. SUDEP has an incidence of 1.2 per 1000 person-years in adults and 0.2 per 1000 person-years in children. SUDEP accounts for 8-17% of deaths in patients with epilepsy. It is commonly associated with a history of generalized tonic-clonic seizures, and its risk may be increased by other factors such as postictal electroencephalographic suppression, prone sleeping position, altered heart rate variability, conduction abnormalities, gender, or antiepileptic medications. Recently, electrocardiograms, electroencephalograms, and imaging markers have helped clinicians stratify SUDEP risk and identify patients in need of close monitoring. However, the pathophysiology of SUDEP is likely multifactorial and still unknown. Improving the knowledge of SUDEP incidence, risk factors, and biomarkers can help design and implement effective prevention strategies.
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http://dx.doi.org/10.3390/ijms20081979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515014PMC
April 2019

Genetic interpretation and clinical translation of minor genes related to Brugada syndrome.

Hum Mutat 2019 06 29;40(6):749-764. Epub 2019 Mar 29.

Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona, University of Girona, Girona, Spain.

Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.
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http://dx.doi.org/10.1002/humu.23730DOI Listing
June 2019

Electroanatomic and Pathologic Right Ventricular Outflow Tract Abnormalities in Patients With Brugada Syndrome.

J Am Coll Cardiol 2018 12;72(22):2747-2757

Cardiovascular Department, San Donato Hospital, Arezzo, Italy.

Background: The prevalence and significance of structural abnormalities in Brugada syndrome (BrS) are still largely debated.

Objectives: The authors investigated the relationship between genetic background, electroanatomic abnormalities, and pathologic substrate in BrS.

Methods: They performed 3-dimensional electroanatomic unipolar and bipolar mapping in 30 patients with BrS. Twenty patients underwent 3-dimensional electroanatomic unipolar and bipolar mapping-guided right ventricular outflow tract (RVOT) endomyocardial biopsy. Programmed ventricular stimulation and genetic analysis were performed in all patients.

Results: Low-voltage areas (LVAs) were observed at unipolar map in 93% of patients and at bipolar map in 50% of cases. Unipolar LVAs were always larger than bipolar LVAs, were always colocalized, and in all cases included RVOT. Disease-causing mutations were detected in 10 (33%) patients. Programmed ventricular stimulation was positive in 16 cases (53%). In 75% of patients, RVOT histology showed pathologic findings with myocardial inflammation in 80% of them. Among patients with abnormal bipolar map submitted to endomyocardial biopsy, 9 (81%) showed evidence of myocardial inflammation. Conversely, bipolar map was abnormal in 83% of patients with myocardial inflammation. Myocardial inflammation was also more prevalent among inducible patients (83% vs. 25% in noninducible; p = 0.032).

Conclusions: BrS is characterized by electroanatomical and structural abnormalities localized to RVOT with a gradient of the pathologic substrate from epicardium to endocardium possibly driven by myocardial inflammation. These findings reclassify BrS as a combination of structural and electrical defects opening the way to new risk stratification and therapeutic strategies.
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http://dx.doi.org/10.1016/j.jacc.2018.09.037DOI Listing
December 2018

Molecular autopsy in a cohort of infants died suddenly at rest.

Forensic Sci Int Genet 2018 11 31;37:54-63. Epub 2018 Jul 31.

Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; Cardiology Service, Hospital Josep Trueta, Girona, Spain. Electronic address:

Sudden infant death syndrome is the leading cause of death during the first year of life. A large part of cases remains without a conclusive cause of death after complete autopsy. In these situations, cardiac arrhythmia of genetic origin is suspected as the most plausible cause of death. Our aim was to ascertain whether genetic variants associated with sudden cardiac death might be the cause of death in a cohort of infants died suddenly. We analyzed 108 genes associated with sudden cardiac death in 44 post-mortem samples of infants less than 1 year old of age who died at rest. Definite cause of death was not conclusive in any case after a complete autopsy. Genetic analysis identified at least one rare variant in 90.90% of samples. A total of 121 rare genetic variants were identified. Of them, 33.05% were novel and 39.66% were located in genes encoding ion channels or associated proteins. A comprehensive genetic analysis in infants who died suddenly enables the unraveling of potentially causative cardiac variants in 2045% of cases. Molecular autopsy should be included in forensic protocols when no conclusive cause of death is identified. Large part genetic variants remain of uncertain significance, reinforcing the crucial role of genetic interpretation before clinical translation but also in early identification of relatives at risk.
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http://dx.doi.org/10.1016/j.fsigen.2018.07.023DOI Listing
November 2018

Role of genetic and electrolyte abnormalities in prolonged QTc interval and sudden cardiac death in end-stage renal disease patients.

PLoS One 2018 18;13(7):e0200756. Epub 2018 Jul 18.

Cardiovascular Genetics Center, IDIBGI, Dr. Trueta University Hospital, Parc Hospitalari Martí i Julià, Edifici M2, Salt, Spain.

Background: Patients with end-stage renal disease have very high mortality. In individuals on hemodialysis, cardiovascular deaths account for ~50% of all deaths in this population, mostly due to arrhythmia. To determine the causes of these arrhythmic deaths is essential in order to adopt preventive strategies. The main objective of this study was to investigate whether, the presence of QTc interval alterations, from electrolyte abnormalities or presence of rare genetic variants, could have a relationship with sudden arrhythmogenic deaths in end-stage renal disease patients.

Methods: We recorded the pre- and post-dialysis QTc interval in 111 patients undergoing hemodialysis. In 47 of them, we analyzed 24 SCD-related genes including the most prevalent genes associated with long QT syndrome using a custom resequencing panel.

Results: We found a positive although not significant association between the presence of long QTc and mortality in a subset of end-stage renal disease patients. In addition, in five patients with long QTc only after dialysis (21.7%) we detected rare potentially pathogenic genetic variants. Three out of these five carriers subsequently died suddenly.

Conclusions: Genetic background may be determinant in the risk of sudden cardiac death in these patients. We recommend evaluating the QTc interval before and after hemodialysis, and performing a genetic analysis of individuals with long QTc after hemodialysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200756PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051653PMC
January 2019

Integration of "Omics" Strategies for Biomarkers Discovery and for the Elucidation of Molecular Mechanisms Underlying Brugada Syndrome.

Proteomics Clin Appl 2018 11 20;12(6):e1800065. Epub 2018 Jul 20.

Laboratory of Proteomics, Research Center of Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, 88100, Catanzaro, Italy.

Purpose: The Brugada syndrome (BrS) is a severe inherited cardiac disorder. Given the high genetic and phenotypic heterogeneity of this disease, three different "omics" approaches are integrated in a synergic way to elucidate the molecular mechanisms underlying the pathophysiology of BrS as well as for identifying reliable diagnostic/prognostic markers.

Experimental Design: The profiling of plasma Proteome and MiRNome is perfomed in a cohort of Brugada patients that were preliminary subjected to genomic analysis to assess a peculiar gene mutation profile.

Results: The integrated analysis of "omics" data unveiled a cooperative activity of mutated genes, deregulated miRNAs and proteins in orchestrating transcriptional and post-translational events that are critical determining factors for the development of the Brugada pattern.

Conclusions And Clinical Relevance: This study provides the basis to shed light on the specific molecular fingerprints underlying BrS development and to gain further insights on the pathogenesis of this life-threatening cardiac disease.
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http://dx.doi.org/10.1002/prca.201800065DOI Listing
November 2018

Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice.

Eur J Hum Genet 2018 07 6;26(7):1014-1025. Epub 2018 Mar 6.

Cardiovascular Genetics Center, University of Girona-IdIBGi, Girona, Spain.

Several studies have identified copy number variants (CNVs) as responsible for cardiac diseases associated with sudden cardiac death (SCD), but very few exhaustive analyses in large cohorts of patients have been performed, and they have been generally focused on a specific SCD-related disease. The aim of the present study was to screen for CNVs the most prevalent genes associated with SCD in a large cohort of patients who suffered sudden unexplained death or had an inherited cardiac disease (cardiomyopathy or channelopathy). A total of 1765 European patients were analyzed with a homemade algorithm for the assessment of CNVs using high-throughput sequencing data. Thirty-six CNVs were identified (2%), and most of them appeared to have a pathogenic role. The frequency of CNVs among cases of sudden unexplained death, patients with a cardiomyopathy or a channelopathy was 1.4% (8/587), 2.3% (20/874), and 2.6% (8/304), respectively. Detection rates were particularly high for arrhythmogenic cardiomyopathy (5.1%), long QT syndrome (4.7%), and dilated cardiomyopathy (4.4%). As such large genomic rearrangements underlie a non-neglectable portion of cases, we consider that their analysis should be performed as part of the routine genetic testing of sudden unexpected death cases and patients with SCD-related diseases.
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http://dx.doi.org/10.1038/s41431-018-0119-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018743PMC
July 2018

Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death.

Biology (Basel) 2017 Dec 26;7(1). Epub 2017 Dec 26.

Cardiovascular Genetics Center, University of Girona-IDIBGI, 17190 Salt, Spain.

Sudden cardiac death is defined as an unexpected decease of cardiac origin. In individuals under 35 years old, most of these deaths are due to familial arrhythmogenic syndromes of genetic origin, also known as channelopathies. These familial cardiac syndromes commonly follow an autosomal dominant pattern of inheritance. Diagnosis, however, can be difficult, mainly due to incomplete penetrance and variable expressivity, which are hallmarks in these syndromes. The clinical manifestation of these diseases can range from asymptomatic to syncope but sudden death can sometimes be the first symptom of disease. Early identification of at-risk individuals is crucial to prevent a lethal episode. In this review, we will focus on the genetic basis of channelopathies and the effect of genetic and non-genetic modifiers on their phenotypes.
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http://dx.doi.org/10.3390/biology7010003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872029PMC
December 2017

Targeted next-generation sequencing provides novel clues for associated epilepsy and cardiac conduction disorder/SUDEP.

PLoS One 2017 19;12(12):e0189618. Epub 2017 Dec 19.

Cardiovascular Genetics Center, IDIBGI, Dr. Trueta University Hospital, Parc Hospitalari Martí i Julià, Edifici, Salt (Spain).

Sudden unexpected death in epilepsy is an unpredicted condition in patients with a diagnosis of epilepsy, and autopsy does not conclusively identify cause of death. Although the pathophysiological mechanisms that underlie this entity remain unknown, the fact that epilepsy can affect cardiac function is not surprising. The genetic factors involving ion channels co-expressed in the heart and brain and other candidate genes have been previously described. In the present study, 20 epilepsy patients with personal or family history of heart rhythm disturbance/cardiac arrhythmias/sudden death were sequenced using a custom re-sequencing panel. Twenty-six relatives were genetically analysed to ascertain the family segregation in ten individuals. Four subjects revealed variants with positive genotype-phenotype segregation: four missense variants in the CDKL5, CNTNAP2, GRIN2A and ADGRV1 genes and one copy number variant in KCNQ1. The potential pathogenic role of variants in new candidate genes will need further studies in larger cohorts, and the evaluation of the potential pathogenic role in the cardio-cerebral mechanisms requires in vivo/in vitro studies. In addition to family segregation, evaluation of the potential pathogenic roles of these variants in cardio-cerebral mechanisms by in vivo/in vitro studies should also be performed. The potential pathogenic role of variants in new candidate genes will need further studies in larger cohorts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189618PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736193PMC
January 2018

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.

PLoS One 2017 3;12(8):e0181465. Epub 2017 Aug 3.

Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.

Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation.

Methods: Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease.

Results: The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN.

Conclusions: A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181465PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542623PMC
August 2017

Sudden death due to catecholaminergic polymorphic ventricular tachycardia following negative stress-test outcome: genetics and clinical implications.

Forensic Sci Med Pathol 2017 Jun 13;13(2):217-225. Epub 2017 Apr 13.

Institute of Public Health, Legal Medicine Section, Catholic University, School of Medicine, Largo Francesco Vito 1, 00168, Rome, Italy.

This paper discusses the case of a young boy who died suddenly during a football match. The victim's personal and family medical histories were negative for cardiac events. He had undergone a cardiological investigation some months before his death, enabling him to participate in competitive sports. Only post-mortem molecular analysis allowed for a clearer determination of the most plausible cause of death, which was identified as inherited arrhythmogenic heart disease, known as catecholaminergic polymorphic ventricular tachycardia. It was possible to detect a novel, previously undescribed, variant in the RYR2 gene. This case report highlights the importance of a meaningful forensic multidisciplinary investigation in such cases, and also discusses possible medical malpractice claims.
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http://dx.doi.org/10.1007/s12024-017-9862-9DOI Listing
June 2017

Sudden Arrhythmic Death During Exercise: A Post-Mortem Genetic Analysis.

Sports Med 2017 Oct;47(10):2101-2115

Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.

Background: Sudden cardiac death is a natural and unexpected death that occurs within 1 h of the first symptom. Most sudden cardiac deaths occur during exercise, mostly as a result of myocardial infarction. After autopsy, some cases, especially in the young, are diagnosed as cardiomyopathies or remain without a conclusive cause of death. In both situations, genetic alterations may explain the arrhythmia.

Objective: Our aim was to identify a genetic predisposition to sudden cardiac death in a cohort of post-mortem cases of individuals who died during exercise, with a structurally normal heart, and were classified as arrhythmogenic death.

Methods: We analyzed a cohort of 52 post-mortem samples from individuals <50 years old who had a negative autopsy. Next-generation sequencing technology was used to screen genes associated with sudden cardiac death.

Results: Our cohort showed a male prevalence (12:1). Half of the deaths occurred in individuals 41-50 years of age. Running was the most common exercise activity during the fatal event, accounting for 46.15% of cases. Genetic analysis identified 83 rare variants in 37 samples (71.15% of all samples). Of all rare variants, 36.14% were classified as deleterious, being present in 53.84% of all cases.

Conclusions: A comprehensive analysis of sudden cardiac death-related genes in individuals who died suddenly while exercising enabled the identification of potentially causative variants. However, many genetic variants remain of indeterminate significance, thus further work is needed before clinical translation. Nonetheless, comprehensive genetic analysis of individuals who died during exercise enables the detection of potentially causative variants and helps to identify at-risk relatives.
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http://dx.doi.org/10.1007/s40279-017-0705-3DOI Listing
October 2017

Genetic analysis in post-mortem samples with micro-ischemic alterations.

Forensic Sci Int 2017 Feb 3;271:120-125. Epub 2017 Jan 3.

Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Cardiology Service, Hospital Josep Trueta, Girona, Spain. Electronic address:

Sudden cardiac arrest is a leading cause of death worldwide. Most cardiac arrests happen in patients who have previously suffered a myocardial infarct. The risk of sudden death after infarction may increase in people who carry a pathogenic genetic alteration in cardiac ion channels. We hypothesized that micro-ischemia could trigger lethal arrhythmogenesis, thus we sought to identify genetic alterations in cardiac ion channels in patients with micro-ischemic disease. We studied a cohort of 56 post-mortem samples. Autopsy studies identified myocardial infarction as the cause of death in each case. We used both Sanger sequencing and next-generation sequencing to screen candidate genes associated with sudden cardiac death. We identified six rare missense genetic variations in five unrelated patients. Two variants have been previously reported; one is associated with atrial fibrillation (SCN5A_p.H445D), and the other is predicted to be benign (ANK2_p.T2059M). The novel variants were predicted in silico as benign, except for one (RyR2_p.M4019T), which was classified as deleterious. Our post-mortem, micro-infarction cohort displayed a rate of nearly 10% non-common genetic variants. However, the clinical significance of most of the identified variants remains unknown due to lack of family assessment. Further analyses should be performed in large cohorts to clarify the role of ion-channel gene analysis in samples showing microscopic ischemic alterations.
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http://dx.doi.org/10.1016/j.forsciint.2016.12.035DOI Listing
February 2017

A novel variant in RyR2 causes familiar catecholaminergic polymorphic ventricular tachycardia.

Forensic Sci Int 2017 Jan 9;270:173-177. Epub 2016 Dec 9.

Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain; Cardiovascular Genetics Unit, Hospital Josep Trueta, Girona, Spain. Electronic address:

Catecholaminergic polymorphic ventricular tachycardia is a rare familial arrhythmogenic disease. It usually occurs in juvenile patients with a structurally normal heart and causes exercise-emotion triggered syncope and sudden cardiac death. The main gene associated with catecholaminergic polymorphic ventricular tachycardia is RyR2, encoding the cardiac ryanodine receptor protein which is involved in calcium homeostasis. After the identification of a 16 year-old man presenting with exercise-induced sudden cardiac death, clinically diagnosed as catecholaminergic polymorphic ventricular tachycardia, we collected the family information and performed a comprehensive genetic analysis using Next Generation Sequencing technology. The initial electrocardiogram in the emergency department revealed ventricular fibrillation. On electrocardiogram monitoring, sinus tachycardia degenerated into bidirectional ventricular and into ventricular fibrillation. Catecholaminergic polymorphic ventricular tachycardia was clinically diagnosed in 5 of the 14 family members evaluated. There were no additional reports of seizures, pregnancy loss, neonatal death, or sudden cardiac death in family members. Genetic analysis of the index case identified only one rare novel variant p.Ile11Ser (c.32T>G) in the RyR2 gene. Subsequent familial analysis identified segregation of the genetic variant with the disease. All current evidence supports that novel p.Ile11Ser variant in the RyR2 gene is a potential disease-causing variant in catecholaminergic polymorphic ventricular tachycardia. To our knowledge, there has been no previous case report of catecholaminergic polymorphic ventricular tachycardia associated to this missense variant.
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http://dx.doi.org/10.1016/j.forsciint.2016.12.001DOI Listing
January 2017

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation.

PLoS One 2016 8;11(12):e0167358. Epub 2016 Dec 8.

Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona (Spain).

Background: Sudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases.

Methods And Findings: Our cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively.

Conclusions: Cardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167358PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145162PMC
July 2017

Large Genomic Imbalances in Brugada Syndrome.

PLoS One 2016;11(9):e0163514. Epub 2016 Sep 29.

Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.

Purpose: Brugada syndrome (BrS) is a form of cardiac arrhythmia which may lead to sudden cardiac death. The recommended genetic testing (direct sequencing of SCN5A) uncovers disease-causing SNVs and/or indels in ~20% of cases. Limited information exists about the frequency of copy number variants (CNVs) in SCN5A in BrS patients, and the role of CNVs in BrS-minor genes is a completely unexplored field.

Methods: 220 BrS patients with negative genetic results were studied to detect CNVs in SCN5A. 63 cases were also screened for CNVs in BrS-minor genes. Studies were performed by Multiplex ligation-dependent probe amplification or Next-Generation Sequencing (NGS).

Results: The detection rate for CNVs in SCN5A was 0.45% (1/220). The detected imbalance consisted of a duplication from exon 15 to exon 28, and could potentially explain the BrS phenotype. No CNVs were found in BrS-minor genes.

Conclusion: CNVs in current BrS-related genes are uncommon among BrS patients. However, as these rearrangements may underlie a portion of cases and they undergo unnoticed by traditional sequencing, an appealing alternative to conventional studies in these patients could be targeted NGS, including in a single experiment the study of SNVs, indels and CNVs in all the known BrS-related genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163514PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042553PMC
September 2016

Medico-legal perspectives on sudden cardiac death in young athletes.

Int J Legal Med 2017 Mar 21;131(2):393-409. Epub 2016 Sep 21.

Cardiovascular Genetics Center, Gencardio Institut d'Investigacions Biomèdiques de Girona (IDIBGI), Girona, Spain.

Sudden cardiac death (SCD) in a young athlete represents a dramatic event, and an increasing number of medico-legal cases have addressed this topic. In addition to representing an ethical and medico-legal responsibility, prevention of SCD is directly correlated with accurate eligibility/disqualification decisions, with an inappropriate pronouncement in either direction potentially leading to legal controversy. This review summarizes the common causes of SCD in young athletes, divided into structural (hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, congenital coronary artery anomalies, etc.), electrical (Brugada, congenital LQT, Wolf-Parkinson-White syndrome, etc.), and acquired cardiac abnormalities (myocarditis, etc.). In addition, the roles of hereditary cardiac anomalies in SCD in athletes and the effects of a positive result on them and their families are discussed. The medico-legal relevance of pre-participation screening is analyzed, and recommendations from the American Heart Association and European Society of Cardiology are compared. Finally, the main issues concerning the differentiation between physiologic cardiac adaptation in athletes and pathologic findings and, thereby, definition of the so-called gray zone, which is based on exact knowledge of the mechanism of cardiac remodeling including structural or functional adaptions, will be addressed.
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http://dx.doi.org/10.1007/s00414-016-1452-yDOI Listing
March 2017

Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death.

Int J Mol Sci 2015 Oct 27;16(10):25773-87. Epub 2015 Oct 27.

Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain.

A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death.
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http://dx.doi.org/10.3390/ijms161025773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632826PMC
October 2015

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing.

Int J Legal Med 2016 Mar 30;130(2):331-9. Epub 2015 Sep 30.

Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain.

Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥ 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy.
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http://dx.doi.org/10.1007/s00414-015-1269-0DOI Listing
March 2016
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