Diagnostics

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Pan Arrhythmia Panel

The Pan Arrhythmia Panel is a comprehensive NGS panel that can be used to confirm a clinical diagnosis of arrhythmia or identify at-risk individuals. Arrhythmias are abnormal heart rhythms, and can be caused by problems with the heart’s electrical system or structural problems within the heart. Arrhythmias may be asymptomatic, and only detectable on ECG, or may cause symptoms such as syncope, shortness of breath, and heart palpitations. In some cases, arrhythmias can lead to cardiac arrest and sudden cardiac death, even in the absence of other symptoms. The most common hereditary arrhythmias are long QT syndrome, short QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. The disorders may show clinical overlap, and demonstrate allelic and locus heterogeneity. This panel also includes cardiomyopathies with prominent arrhythmias (arrhythmogenic cardiomyopathy).

Prevalence

The prevalence of the various forms of arrhythmias are:

  • Long QT syndrome- 1/2,000 (Schwartz et al, 2009)
  • Short QT syndrome- Unknown
  • Catecholaminergic polymorphic ventricular tachycardia- 1/10,000 (Napolitano et al, 2014)
  • Brugada syndrome- 1/2,000 (Gallagher et al, 2008)
  • Arrhythmogenic right ventricular cardiomyopathy – 1/1,000 to 1/1,250 (Peters, 2006)

Included Disorders

This panel includes genes associated with:

  • Long QT syndrome
  • Short QT syndrome
  • Catecholaminergic polymorphic ventricular tachycardia
  • Brugada syndrome
  • Arrhythmogenic cardiomyopathy
  • Andersen-Tawil syndrome
  • Timothy syndrome
  • Jervell Lange-Nielsen syndrome
  • Inheritance and Penetrance

Inheritance and Penetrance

Hereditary arrhythmias are typically inherited in an autosomal dominant manner, although some of the conditions on the panel are inherited in an autosomal recessive or X-linked manner.

Autosomal Recessive:

  • Jervell Lange-Nielsen syndrome
  • TRDN and CASQ2-related CPVT
  • Naxos disease
  • Carvajal syndrome
  • Emery-Dreifuss muscular dystrophy

X-linked:

  • Emery-Dreifuss muscular dystrophy

Hereditary arrhythmias typically demonstrate reduced and age-related penetrance, and often show significant intra- and inter- family variability.

Clinical Sensitivity

The clinical sensitivity of this test is dependent on the patient’s phenotype. In general, the clinical sensitivity for each condition is listed below:

  • Long QT syndrome – 80% (Ackerman et al, 2011)
  • Short QT syndrome – Unknown
  • Catecholaminergic polymorphic ventricular tachycardia – 70% (Ackerman et al, 2011)
  • Brugada syndrome- 15-30% (Kapplinger et al, 2010)
  • Arrhythmogenic cardiomyopathy – 50% (Quarta et al, 2011)

Methodology and Analytical Sensitivity

Next-generation sequencing technology is used to test clinically relevant portions of each gene, including coding exons, adjacent flanking bases, and selected introns/noncoding variants. Pathogenic and likely pathogenic variants are confirmed by orthogonal methods. Copy number variants, including intragenic deletions and duplications are detected to a resolution of a single exon. To request analysis of a specific single exon copy number variant, please contact our Client Services team prior to ordering. Analytical sensitivity and specificity of the assay is 99.5%.

Indications for Testing

  • Confirmation of a clinical diagnosis
  • Unexplained cardiac arrest
  • Unexplained arrhythmia
  • Risk assessment for asymptomatic family of members of proband with molecular diagnosis of cardiomyopathy

Included Genes (42)

 

ABCC9 DES KCNH2 SCN4B
ACTN2 DSC2 KCNJ2 SCN5A
ANK2 DSG2 KCNQ1 SNTA1
CACNA1C DSP LDB3 TGFB3
CACNA2D1 EMD LMNA TMEM43
CACNB2 GPD1L PKP2 TNNI3
CALM1 HCN4 PLN TNNT2
CALM2 JUP PRKAG2 TRDN
CALM3 KCNE1 RBM20 TTN
CASQ2 KCNE2 RYR2
CAV3 KCNE3 SCN10A

Additions to the Pan Arrhythmia Panel:

Emerging evidence genes can also be added on to the comprehensive panel. These genes do not have a clear association with heritable arrhythmias, but emerging evidence suggests that they may play a role in disease.

Emerging Evidence Genes (14)

Emerging evidence genes can also be added onto the comprehensive panel. These genes do not have a clear association with arrhythmias, but emerging evidence suggests that they may play a role in disease pathogenesis.

AKAP9 PDLIM3
ANKRD1 RANGRF
CTNNA3 SCN1B
KCND3 SCN2B
KCNE5 SCN3B
KCNJ5 SLMAP
KCNJ8 TRPM4

 

References

  1. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011;13(8):1077-109.
  2. Antzelevitch C, Brugada P, Brugada J, et al. Brugada syndrome: a decade of progress. Circ Res. 2002;91(12):1114-8.
  3. Gallagher MM, Forleo GB, Behr ER, et al. Prevalence and significance of Brugada-type ECG in 12,012 apparently healthy European subjects. Int J Cardiol. 2008;130(1):44-8.
  4. Goldenberg I, Horr S, Moss AJ, et al. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. J Am Coll Cardiol. 2011;57(1):51-9.
  5. Napolitano C, Priori SG, Bloise R. Catecholaminergic Polymorphic Ventricular Tachycardia. 2004 Oct 14 [Updated 2016 Oct 13]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  6. Napolitano C, Bloise R, Memmi M, Priori SG. Clinical utility gene card for: Catecholaminergic polymorphic ventricular tachycardia (CPVT). Eur J Hum Genet. 2014;22(1)
  7. Peters S. Advances in the diagnostic management of arrhythmogenic right ventricular dysplasia-cardiomyopathy. Int J Cardiol. 2006;113(1):4-11.
  8. Priori SG, Napolitano C, Gasparini M, et al. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: A prospective evaluation of 52 families. Circulation. 2000;102(20):2509-15.
  9. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866-74.
  10. Quarta G, Muir A, Pantazis A, et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011;123(23):2701-9.
  11. Schwartz PJ, Spazzolini C, Crotti L. All LQT3 patients need an ICD: true or false?. Heart Rhythm. 2009;6(1):113-20.