Contemporary ReviewNext-generation sequencing for the diagnosis of cardiac arrhythmia syndromes
Section snippets
A. Introduction
Inherited arrhythmia syndromes (Table 1) are collectively associated with substantial risks of morbidity and sudden cardiac death. Over the past 3 decades, recognized familial aggregation and traditional genetic mapping efforts have substantiated the genetic basis of these arrhythmia syndromes. Yet for many inherited arrhythmia syndromes, our understanding of the genetic architecture and causal mechanisms remains limited.
Recent technological advances in DNA sequencing have enabled insights into
B. Genetic basis of arrhythmia syndromes
Over the past 3 decades, causal genes have been identified for most recognized inherited arrhythmia syndromes (Table 1). Discovered mutations in ion channel subunits governing cardiac electrical function, in sarcomeric proteins critical for cardiac contractile and structural integrity, and in other genes have informed our understanding of cardiac development and physiology. Yet currently recognized disease susceptibility genes, summarized elsewhere,1, 2, 3, 4, 5, 6, 7, 8 represent merely a
C. Establishing the rationale for performing genetic testing
Broadly, genetic testing is used for diagnostic, predictive, therapeutic, pharmacogenetic, preimplant testing, newborn screening, and forensic applications. In adult cardiovascular medicine, genetic testing for inherited arrhythmia syndromes is most often reserved for diagnostic, predictive, or therapeutic applications.
The clinical utility of genetic testing for inherited arrhythmia syndromes is most relevant for confirmation of a suspected condition, or cascade screening in relatives of
D. Inherited arrhythmia conditions for which genetic testing is indicated
In recent years, consensus guidelines have emerged that provide recommendations for genetic testing for suspected inherited arrhythmia syndromes.1, 2 Whereas these guidelines provide general consensus as to when testing may or may not be medically indicated, it is acknowledged that a variety of disease-specific, patient-level, and external factors must be weighed to determine the appropriateness of genetic testing in any given individual.9, 19 In Table 2, we have summarized current indications
E. Overview of genetic sequencing techniques
The human genome is composed of about 3 billion nucleotide pairs and contains about 20,000 known genes.20, 21, 22 Each gene is composed of both protein coding (exons) and noncoding (eg, introns and promoter region) sequences. Protein-coding regions comprise about 1% of the human genome. Despite widespread and increasing recognition that noncoding portions of the genome have important regulatory properties and may participate in disease pathogenesis,23, 24 clinical genetic testing for inherited
F. Practical genetic testing in the clinic
The advent of high-throughput sequencing has produced a number of commercially available sequencing options that include (1) targeted panels that range from a handful or more genes, (2) broad panels containing dozens of genes for a class of traits such as pan cardiomyopathy or pan arrhythmia, (3) whole exomes, and (4) whole genomes. Additional commercially available options for testing include insertion or deletion tests, as well as targeted single-variant testing (which is typically reserved
Future directions/challenges
Technological innovations have improved the extent to which we can now probe the genome, in both research and clinical settings. However, several obstacles remain with respect to the appropriate use of next-generation sequencing and other technologies in clinical settings. Among these challenges are cost, technological hurdles, determination of variant pathogenicity, and legal and ethical conundrums. The utility of genetic sequencing in the clinic, particularly in the area of complex or
Conclusion
The efficiency of next-generation sequencing promises to elucidate the genetic contributions to many diseases. Next-generation sequencing has facilitated the development of various different sequencing options to choose from when testing patients with inherited arrhythmia syndromes. Yet the implementation of next-generation sequencing into clinical practice carries unique challenges. The data generated from this tool require thoughtful analysis in order to be of practical use. With improvements
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2022, International Journal of CardiologyCitation Excerpt :Because of the incomplete knowledge of the genetic background of inherited CVDs, a negative result does not exclude the diagnosis and the genetic nature of the disease, that may be caused by mutations on a still unrecognized disease-related gene [6,7]. Furthermore, the identification of gene variants of uncertain significance accounts for equivocal testing result that may lead to a disease misdiagnosis in the presence of inconclusive phenotypic features [8]. For all these reasons, it is important to know the yield of molecular genetic testing for different genetic CVDs as well as the potential implications of the test results for clinical management and sports eligibility in the athlete.
Genetic variants of uncertain significance: How to match scientific rigour and standard of proof in sudden cardiac death?
2020, Legal MedicineCitation Excerpt :On the other side, channelopathies (Table 2) are the leading cause of SUD. Syndromes responsible for SUD are generally characterized by autosomal dominant inheritance, locus heterogeneity, incomplete penetrance and variable expressivity [10,14–16]. Currently, more than 100 genes have been associated with syndromes leading to SCD, but in cases at risk genetic analyses often are restricted to a limited number of genes - mainly because of economic reasons [17].
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2016, Heart RhythmCitation Excerpt :Recent development of next-generation sequencing (NGS) has enabled simultaneous sequencing and analysis of a large number of genes, thus providing a fast and cost-effective means of generating genetic data.7 NGS facilitates the genetic testing of multiple inherited cardiac disorder-associated genes, including channelopathy-, cardiomyopathy-, or other heart disease–associated genes.8 Genetic analysis using advanced technology, such as NGS, may therefore have a substantial potential to improve the diagnosis of SUDS and the clinical management of the relatives of affected individuals.
Postmortem genetic analysis of 17 sudden cardiac deaths identified nonsense and frameshift variants in two cases of arrhythmogenic cardiomyopathy
2023, International Journal of Legal MedicineHow Functional Genomics Can Keep Pace With VUS Identification
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This work was supported by grants from the National Institutes of Health (grant nos. 1RO1HL092577, 1RO1HL104156, 1K24HL105780, and HL065962). Dr Lubitz was also supported by a grant from the National Institutes of Health/National Heart, Lung, and Blood Institute (grant no. K23HL114724) and a Doris Duke Charitable Foundation Clinical Scientist Development Award (award no. 2014105). Dr Ellinor was also supported by an Established Investigator Award from the American Heart Association (award no. 13EIA14220013) and by the Fondation Leducq (award no. 14CVD01).