The current role of next-generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions: a viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the European Society of Human Genetics

Mogensen, Jens; Tintelen, J. Peter van; Fokstuen, Siv; Elliott, Perry; Langen, Irene M. van; Meder, Benjamin; Richard, P.; Syrris, Petros; Caforio, Alida L.P.; Adler, Yehuda; Anastasakis, Aris; Gimeno, Juan R.; Klingel, Karin; Linhart, Aleš; Imazio, Massimo; Pinto, Yigal M.; Newbery, Ruth; Schmidtke, J.; Charron, Philippe

doi:10.1093/eurheartj/ehv122

Cited by 74 publications

(53 citation statements)

References 14 publications

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“…2013; Mogensen et al. 2015). All together, these findings suggest a revision of previously DCM‐associated variants and an optimized approach for the clinical application of genetic findings.…”

Section: Discussionmentioning

confidence: 99%

Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy

Nouhravesh

Ahlberg

Ghouse

et al. 2016

Mol Genet Genomic Med

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BackgroundHundreds of genetic variants have been described as disease causing in dilated cardiomyopathy (DCM). Some of these associations are now being questioned. We aimed to identify the prevalence of previously DCM associated variants in the Exome Aggregation Consortium (ExAC), in order to identify potentially false‐positive DCM variants.MethodsVariants listed as DCM disease‐causing variants in the Human Gene Mutation Database were extracted from ExAC. Pathogenicity predictions for these variants were mined from dbNSFP v 2.9 database.ResultsOf the 473 DCM variants listed in HGMD, 148 (31%) were found in ExAC. The expected number of individuals with DCM in ExAC is 25 based on the prevalence in the general population. Yet, 35 variants were found in more than 25 individuals. In 13 genes, we identified all variants previously associated with DCM; four genes contained variants above our estimated cut‐off. Prediction tools found ExAC variants to be significantly more tolerated when compared to variants not found in ExAC (P = 0.004).ConclusionIn ExAC, we identified a higher genotype prevalence of variants considered disease‐causing than expected. More importantly, we found 13 genes in which all variants previously associated with DCM were identified in ExAC, questioning the association of these genes with the monogenic form of DCM.

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Section: Discussionmentioning

confidence: 99%

Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy

Nouhravesh

Ahlberg

Ghouse

et al. 2016

Mol Genet Genomic Med

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“…First-degree relatives of a living DCM proband with suspected but unconfirmed LHD warrant echocardiography and ECG beyond 10–12 years of age, and if CCD is also a feature, 24-hour Holter 26. Genotype-positive relatives are to be offered clinical surveillance, while genotype-negatives can be reassured and discharged from follow-up 27. No cost–benefit assessment has yet appraised whether family screening by a combined genetic test and clinical screening approach is superior to sole clinical screening in LHD 28.…”

Section: Diagnosticsmentioning

confidence: 99%

Lamin and the heart

Captur

Arbustini

Bonne

et al. 2017

Heart

118

116

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Lamins A and C are intermediate filament nuclear envelope proteins encoded by the gene. Mutations in cause autosomal dominant severe heart disease, accounting for 10% of dilated cardiomyopathy (DCM). Characterised by progressive conduction system disease, arrhythmia and systolic impairment, lamin A/C heart disease is more malignant than other common DCMs due to high event rates even when the left ventricular impairment is mild. It has several phenotypic mimics, but overall it is likely to be an under-recognised cause of DCM. In certain clinical scenarios, particularly familial DCM with early conduction disease, the pretest probability of finding an mutation may be quite high.Recognising lamin A/C heart disease is important because implantable cardioverter defibrillators need to be implanted early. Promising oral drug therapies are within reach thanks to research into the mitogen-activated protein kinase (MAPK) and affiliated pathways. Personalised heart failure therapy may soon become feasible for, alongside personalised risk stratification, as variant-related differences in phenotype severity and clinical course are being steadily elucidated.Genotyping and family screening are clinically important both to confirm and to exclude mutations, but it is the three-pronged integration of such genetic information with functional data from in vivo cardiomyocyte mechanics, and pathological data from microscopy of the nuclear envelope, that is properly reshaping our knowledge base, one variant at a time. This review explains the biology of lamin A/C heart disease (genetics, structure and function of lamins), clinical presentation (diagnostic pointers, electrocardiographic and imaging features), aspects of screening and management, including current uncertainties, and future directions.

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“…• Completion of the Human Genome Project 14,15 • Launch of the International HapMap Project 16 • Availability of next-generation sequencing 17 • Reports of the importance of proteomics 18 , metabolomics 19 , transcriptomics, and epigenetics 20 that spurred interest in studying 'omics' to understand human disease 21 • Systems biology and network medicine 23,24 • Cloud computing and new techniques in computational biology were developed, making the handling of large datasets possible ('big data') 22 • Widespread emergence of electronic medical records • Blossoming of biomedical informatics • Development of networks of sites for enrolling participants in clinical studies 26 • Increase in data sharing in the research and clinical communities 27 • The Quantified Self movement 28,29 , which aims to increase the use of implanted medical devices • Growth in the use of smartphones and mobile health (mHealth) devices and apps for acquiring continuous physiological data on a real-time basis 30 biological phenomena. The main elements required to achieve this goal include the big data pool of 'omic' information in healthy and diseased states; advanced computational and analytical techniques for explor ing the complex inter actions within the molecular networks that govern pheno types; and nuanced, quantitative, deep pheno typing in health and disease (FIGS 1,2).…”

Section: Box 1 | Major Medical Advances Enabling Precision Medicinementioning

confidence: 99%

“…First, the completion of the Human Genome Project 14,15 , the launch of the International HapMap Project 16 , the avail ability of nextgeneration sequencing 17 , and reports of the importance of proteomics 18 , metabolomics 19 , tran scriptomics, and epigenetics 20 spurred interest in study ing 'omics' to understand human disease 21 . Second, cloud computing and new techniques in computational biology were developed, making the handling of large datasets possible ('big data') 22 , as we learn to think more in terms of systems biology and network med icine 23,24 .…”

mentioning

confidence: 99%

Precision medicine in cardiology

2016

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The cardiovascular research and clinical communities are ideally positioned to address the epidemic of noncommunicable causes of death, as well as advance our understanding of human health and disease, through the development and implementation of precision medicine. New tools will be needed for describing the cardiovascular health status of individuals and populations, including 'omic' data, exposome and social determinants of health, the microbiome, behaviours and motivations, patient-generated data, and the array of data in electronic medical records. Cardiovascular specialists can build on their experience and use precision medicine to facilitate discovery science and improve the efficiency of clinical research, with the goal of providing more precise information to improve the health of individuals and populations. Overcoming the barriers to implementing precision medicine will require addressing a range of technical and sociopolitical issues. Health care under precision medicine will become a more integrated, dynamic system, in which patients are no longer a passive entity on whom measurements are made, but instead are central stakeholders who contribute data and participate actively in shared decision-making. Many traditionally defined diseases have common mechanisms; therefore, elimination of a siloed approach to medicine will ultimately pave the path to the creation of a universal precision medicine environment.

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The current role of next-generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions: a viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the European Society of Human Genetics

Cited by 74 publications

References 14 publications

Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy

Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy

Lamin and the heart

Precision medicine in cardiology

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