Elsevier

Heart Rhythm

Volume 12, Issue 5, May 2015, Pages 1062-1070
Heart Rhythm

Contemporary Review
Next-generation sequencing for the diagnosis of cardiac arrhythmia syndromes

https://doi.org/10.1016/j.hrthm.2015.01.011Get rights and content

Inherited arrhythmia syndromes are collectively associated with substantial morbidity, yet our understanding of the genetic architecture of these conditions remains limited. Recent technological advances in DNA sequencing have led to the commercialization of genetic testing now widely available in clinical practice. In particular, next-generation sequencing allows the large-scale and rapid assessment of entire genomes. Although next-generation sequencing represents a major technological advance, it has introduced numerous challenges with respect to the interpretation of genetic variation and has opened a veritable floodgate of biological data of unknown clinical significance to practitioners. In this review, we discuss current genetic testing indications for inherited arrhythmia syndromes, broadly outline characteristics of next-generation sequencing techniques, and highlight challenges associated with such testing. We further summarize future directions that will be necessary to address to enable the widespread adoption of next-generation sequencing in the routine management of patients with inherited 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

References (46)

  • J.D. Kapplinger et al.

    Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise

    J Am Coll Cardiol

    (2011)
  • J.D. Kapplinger et al.

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

    Heart Rhythm

    (2010)
  • J.D. Kapplinger et al.

    Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test

    Heart Rhythm

    (2009)
  • H.K. Tabor et al.

    Project NES, Bamshad MJ. Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results

    Am J Hum Genet

    (2014)
  • R.C. Green et al.

    ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing

    Genet Med

    (2013)
  • B.J. Gersh et al.

    2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines

    Circulation

    (2011)
  • N. Hofman et al.

    Yield of molecular and clinical testing for arrhythmia syndromes: report of 15 years’ experience

    Circulation

    (2013)
  • A.A. Wilde et al.

    Genetic testing for inherited cardiac disease

    Nat Rev Cardiol

    (2013)
  • S.G. Priori et al.

    Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia

    Circulation

    (2002)
  • A.C. Sturm et al.

    Genetic testing in cardiovascular medicine: current landscape and future horizons

    Curr Opin Cardiol

    (2013)
  • E.A. Nannenberg et al.

    Mortality of inherited arrhythmia syndromes: insight into their natural history

    Circ Cardiovasc Genet

    (2012)
  • A.A. Wilde et al.

    Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel

    Circ Res

    (2011)
  • A.J. Moss et al.

    Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel

    Circulation

    (2002)
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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).

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