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Pan Arrhythmia and Cardiomyopathy Panel

The Pan Arrhythmia and Cardiomyopathy Panel is a comprehensive NGS panel that can be used to confirm a clinical diagnosis of arrhythmia and/or cardiomyopathy 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 other cardiac tests, 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 prior 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.

Cardiomyopathy is a disease of the heart muscle that can cause the heart to become weak, rigid, enlarged, or thickened. Cardiomyopathy can lead to irregular heart beats, progressive heart failure, or sudden cardiac death. There are many forms of cardiomyopathy, some of which are acquired and some of which are inherited. The most common hereditary cardiomyopathies include hypertrophic cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, arrhythmogenic right ventricular cardiomyopathy, and restrictive cardiomyopathy. The disorders may show significant clinical overlap, and demonstrate allelic and locus heterogeneity.

Prevalence

The prevalence of the various forms of arrhythmias and cardiomyopathies 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)
  • Hypertrophic cardiomyopathy- 1/200 to 1/500 (Semsarian et al, 2015)
  • Dilated cardiomyopathy- 1/2,700 (Codd et al, 1989)
  • Left ventricular noncompaction- 1/500 to 1/2,000 (Ronderos et al, 2016)
  • Arrhythmogenic right ventricular cardiomyopathy – 1/1000 to 1/1,250 (Peters, 2006)
  • Restrictive cardiomyopathy – Unknown (rare)

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
  • Hypertrophic cardiomyopathy
  • Dilated cardiomyopathy
  • Left ventricular noncompaction
  • Restrictive cardiomyopathy
  • Danon disease
  • Fabry disease
  • Myofibrillar myopathy
  • Timothy syndrome
  • Transthyretin amyloidosis
  • Wolff-Parkinson-White syndrome
  • Barth syndrome
  • Duchenne and Becker muscular dystrophy
  • Emery-Dreifuss muscular dystrophy
  • Other disorders

Inheritance and Penetrance

Hereditary arrhythmias and cardiomyopathies 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
  • Pompe disease
  • Primary carnitine deficiency
  • Glycogen storage disease type IIIa/b
  • FKTN and FKRP muscular dystrophy-dystroglycanophathies
  • Emery-Dreifuss muscular dystrophy

X-linked:

  • Emery-Dreifuss muscular dystrophy
  • Barth syndrome
  • Danon disease
  • Duchenne muscular dystrophy
  • Fabry disease

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)
  • Hypertrophic cardiomyopathy- 60% (Gersh et al, 2011)
  • Dilated cardiomyopathy- 40% (Hershberger et al, 2013)
  • Left ventricular noncompaction- 20-40% (Klaassen et al, 2008; Hoedemaekers et al, 2010)
  • Arrhythmogenic right ventricular cardiomyopathy- 50% (Quarta et al, 2011)
  • Restrictive cardiomyopathy- ~35% (Teekakirikul et al, 2013)

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 cardiomyopathy
  • Unexplained arrhythmia
  • Risk assessment for asymptomatic family of members of proband with molecular diagnosis of cardiomyopathy or arrhythmia

Included Genes (70)

ABCC9 CALM2 DSG2 GPD1L LDB3 RBM20 TGFB3
ACTC1 CALM3 DSP HCN4 LMNA RYR2 TMEM43
ACTN2 CASQ2 EMD JUP MYBPC3 SCN10A TNNC1
AGL CAV3 EYA4 KCNE1 MYH7 SCN4B TNNI3
ANK2 CRYAB FHL1 KCNE2 MYL2 SCN5A TNNT2
BAG3 CSRP3 FKRP KCNE3 MYL3 SGCD TPM1
CACNA1C DES FKTN KCNH2 PKP2 SLC22A5 TRDN
CACNA2D1 DMD FLNC KCNJ2 PLN SNTA1 TTN
CACNB2 DOLK GAA KCNQ1 PRKAG2 TAZ TTR
CALM1 DSC2 GLA LAMP2 RAF1 TCAP VCL

Additions to the Pan Arrhythmia and Cardiomyopathy 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 Panel (38)

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

AKAP9 GATAD1 MYLK2 RANGRF
ANKRD1 ILK MYOM1 SCN1B
CALR3 JPH2 MYOZ2 SCN2B
CHRM2 KCND3 MYPN SCN3B
CTF1 KCNE5 NEBL SLMAP
CTNNA3 KCNJ5 NEXN TMPO
DTNA KCNJ8 NKX2-5 TRPM4
FHL2 LAMA4 NPPA TXNRD2
GATA4 LRRC10 PDLIM3
GATA6 MYH6 PLEKHM2

RASopathies Add-On Panel (17)

Genes associated with the RASopathy spectrum of disorders, which frequently include cardiomyopathy as a symptom, may be added onto the Pan Arrhythmia and Cardiomyopathy panel (RAF1, a RASopathy gene, is already included in the comprehensive panel).


Mutations in genes related to the Ras/MapK cell signaling pathway cause a group of related disorders known as the RASopathies. These disorders include Noonan syndrome, Cardiofaciocutaneous (CFC) syndrome, Costello syndrome, neurofibromatosis, LEOPARD syndrome, and Legius syndrome, among others. The Ras/MapK pathway is involved in cell growth, differentiation, proliferation, and death. The Ras/MAPK spectrum of disorders shows both genetic and allelic heterogeneity, meaning that different mutations in the same gene can cause different phenotypes, and mutations in different genes can cause the same phenotype. Although the specific phenotype varies by disease, many, but not all, of these disorders include hypertrophic cardiomyopathy as a feature.

A2ML1 MAP2K2 RRAS
BRAF NF1 SHOC2
CBL NRAS SOS1
HRAS PTPN11 SOS2
KRAS RASA1 SPRED1
MAP2K1 RIT1

Syndromic Pediatric Add-On Panel (8)

Genes associated with pediatric onset, syndromic, autosomal recessive disorders with cardiomyopathy as feature can also be added to the Pan Arrhythmia and Cardiomyopathy Panel.

ACADVL ELAC2
ALMS1 MTO1
CPT2 SDHA
DNAJC19 TMEM70

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. Codd MB, Sugrue DD, Gersh BJ, Melton LJ 3rd. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975-1984. Circulation. 1989;80:564–72.
  4. 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.
  5. Gersh BJ, Maron BJ, Bonow RO, 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;124(24):2761-96.
  6. 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.
  7. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10:531–47.
  8. Hoedemaekers YM, Caliskan K, Michels M, et al. The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet. 2010;3(3):232-9.
  9. Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation. 2008;117(22):2893-901.
  10. 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.
  11. 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)
  12. Peters S. Advances in the diagnostic management of arrhythmogenic right ventricular dysplasia-cardiomyopathy. Int J Cardiol. 2006;113(1):4-11.
  13. 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.
  14. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19):1866-74.
  15. 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.
  16. Ronderos R, Avegliano G, Borelli E, Kuschnir P, Castro F, Sanchez G, Perea G, Corneli M, Zanier MM, Andres S, Aranda A, Conde D, Trivi M, Estimation of Prevalence of the Left Ventricular Non Compaction Among Adults, The American Journal of Cardiology (2016), doi: 10.1016/ j.amjcard.2016.06.033.
  17. Schwartz PJ, Spazzolini C, Crotti L. All LQT3 patients need an ICD: true or false?. Heart Rhythm. 2009;6(1):113-20.
  18. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249-54.
  19. Teekakirikul P, Kelly MA, Rehm HL, Lakdawala NK, Funke BH. Inherited cardiomyopathies: molecular genetics and clinical genetic testing in the postgenomic era. J Mol Diagn. 2013;15(2):158-70.