Cardiomyopathy and Arrhythmia Panel, Sequencing and Deletion/Duplication

Content Review: March 2022 Last Update:

Use to confirm the hereditary form of cardiomyopathy or arrhythmia.

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Inherited cardiomyopathy and arrhythmia disorders are genetically and phenotypically heterogeneous. Phenotypes include arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular noncompaction (LVNC), long QT syndrome (LQTS), and short QT syndrome (SQTS). Molecular testing is used to determine if a genetic etiology can be identified, which can facilitate patient management and screening of at-risk relatives.

Disease Overview

See Common Disorders table below.

Genetics

See Genes Tested table for genes included in the panel.

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing, or NGS) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for the detection of large deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

Variable, dependent on phenotype/condition

  • ARVC: 50% 
  • BrS: 15-30% 
  • CPVT: 60% 
  • DCM: 25-40% for familial DCM, 10-25% for isolated DCM 
  • HCM: 50-60% for familial HCM, 20-30% for isolated HCM 
  • LQTS: 60-75% 

Analytic Sensitivity

Variant Class

Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region

Analytic Specificity (NPA)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]

>99.9

Exon-levelc duplications

83.3 (56.4-96.4) [3 exons or larger]

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; PPA, positive percent agreement; NPA, negative percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a heritable form of cardiomyopathy or arrhythmia.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Variants in the mitochondrial genome
    • Regulatory region and deep intronic variants
    • Deletions/duplications in PTPN11
    • Breakpoints of large deletions/duplications
    • SNVs and small deletions/insertions will not be called in the following exons due to technical limitations of the assay:
      • BRAF (NM_004333) exon(s) 5,18
      • BRAF (NM_001354609) exon(s) 5,18,19
      • BRAF (NM_001374244) exon(s) 5,10,19
      • BRAF (NM_001374258) exon(s) 5,10,19,20
      • BRAF (NM_001378467) exon(s) 5,18,19
      • BRAF (NM_001378468) exon(s) 5,18
      • BRAF (NM_001378469) exon(s) 5,18
      • BRAF (NM_001378470) exon(s) 4,17,18
      • BRAF (NM_001378471) exon(s) 5,17,18
      • BRAF (NM_001378472) exon(s) 5,18,19
      • BRAF (NM_001378473) exon(s) 5,18
      • BRAF (NM_001378474) exon(s) 5,18
      • BRAF (NM_001378475) exon(s) 4,17,18
      • CALM1 (NM_001363670) exon(s) 1
      • CSRP3 (NM_001369404) partial exon(s) 5(Chr11:19204180-19204196)
      • DES (NM_001382712) exon(s) 9
      • FKTN (NM_001351497) exon(s) 6
      • FKTN (NM_001351498) partial exon(s) 9(Chr9:108382363-108382373)
      • FLNC (NM_001458) exon(s) 47,48
      • FLNC (NM_001127487) exon(s) 46,47
      • MYH6 (NM_002471) exon(s) 26
      • MYH7 (NM_000257) exon(s) 27
      • PRKAG2 (NM_016203) exon(s) 13
      • PRKAG2 (NM_001040633) exon(s) 13
      • PRKAG2 (NM_001304527) exon(s) 11
      • PRKAG2 (NM_001304531) exon(s) 10
      • PRKAG2 (NM_001363698) exon(s) 11
      • PRKAG2 (NM_024429) exon(s) 9
      • RAF1 (NM_001354689) exon(s) 8
      • RAF1 (NM_001354694) exon(s) 7
      • SOS1 (NM_001382394) exon(s) 1
      • TECRL (NM_001363796) exon(s) 12
      • TPM1 (NM_001365777) partial exon(s) 9(Chr15:63358119-63358186)
      • TPM1 (NM_001365780) partial exon(s) 8(Chr15:63358119-63358186)
      • TTN (NM_001267550) exon(s) 172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197
      • TTN (NM_001256850) exon(s) 154,155,156
      • TTN (NM_133378) exon(s) 153,154,155
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Large duplications less than 3 exons in size
    • Noncoding transcripts
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

Common Disorders

Disorder Clinical Characteristics Prevalence Inheritance Comments
ARVC

Progressive fibrofatty replacement of the myocardium predisposing to ventricular tachycardia and sudden death

1/1,000

AD

Commonly implicated genes include PKP2, DSP, DSG2
BrS

Cardiac conduction abnormalities that can result in sudden death

Unknown

AD, 1% de novo

Variants in SCN5A account for 15-30% of BrS
CPVT

Episodic syncope or ventricular arrhythmias occurring during exercise or acute emotion without presence of structural cardiac abnormalities

1/10,000

AD or AR

Variants in RYR2 account for 50-55% of all CPVT
DCM

Left ventricular enlargement and systolic dysfunction

1/250-1/2,500

Typically AD; AR/XL/Mitochondrial less common

~20-50% of cases are familial

Variants in TTN account for 15-20% of nonsyndromic DCM
HCM

Left ventricular hypertrophy with absence of other cardiovascular causes

1/500

AD

Variants in MYH7 and MYBPC3 account for the majority of familial HCM 
LVNC

Hypertrophic and hypokinetic left ventricle with distinctive morphology

Unknown

Typically AD

MYH7 and MYBPC3 are commonly implicated genes
LQTS

Cardiac electrophysiologic disease with prolonged QT- and T-wave abnormalities on ECG associated with ventricular tachycardia (torsade de pointes)

1/2,500

AD

Incomplete penetrance
SQTS

Cardiac arrhythmia with short QT interval on ECG

Unknown

AD

Associated genes: KCNH2,
KCNJ2, KCNQ1

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked

Genes Tested

Gene

MIM Number

Disorder

Inheritance

ABCC9

601439

Cantu syndrome

DCM 10

Familial atrial fibrillation 12

AD

ACTC1

102540

HCM 11

Atrial septal defect 5

DCM 1R

AD

ACTN2

102573

DCM 1AA with or without LVNC

HCM 23 with or without LVNC

AD

AGL

610860

Glycogen storage disease IIIa or IIIb

AR

ALMS1

606844

Alstrom Syndrome

AR
ALPK3 18052 HCM 27 AR

BAG3

603883

Myofibrillar myopathy 6

DCM 1HH

AD
BRAF 164757

Cardiofaciocutaneous syndrome 1

Noonan syndrome 7

 AD

CACNA1C

114205

Timothy syndrome

LGTS 8

AD

CALM1

114180

LQTS 14

CPVT 4

AD
CALM2 114182

LQTS 15

CPVT

 AD
CALM3 114183

LQTS 16

CPVT 6

 AD

CASQ2

114251

CPVT 2

AR

CAV3

601253

Familial hypertrophic cardiomyopathy, 1

Long QT syndrome 9

AD

CRYAB

123590

Myofibrillar myopathy, 2

DCM 1II

AD

Myofibrillar myopathy, fatal infantile hypertonic, alpha-B crystallin-related

AR

CSRP3

600824

HCM 12

AD

DES

125660

Myofibrillar myopathy, 1

AD/AR

DCM 1I

AD

DMD

300377

Becker muscular dystrophy

DCM 3B

Duchenne muscular dystrophy

XL
DOLK 610746 Congenital disorder of glycosylation Im AR

DSC2

125645

ARVC 11

AD

ARVC 11 with mild palmoplantar keratoderma and woolly hair

AR

DSG2

125671

ARVC 10

DCM 1BB

AD

DSP

125647

ARVC 8

DCM with woolly hair, keratoderma, and tooth agenesis

AD

DCM with woolly hair and keratoderma

AR

EMD

300384

Emery-Dreifuss muscular dystrophy 1

XL

FHL1

300163

Uruguay faciocardiomusculoskeletal syndrome

Scapuloperoneal myopathy

Myopathy with postural muscle atrophy

Emery-Dreifuss muscular dystrophy 6

Reducing body myopathy 1B

XL

FKTN

607440

DCM 1X

Muscular dystrophy-dystroglycanopathy Ad4

AR
FLNC 102565

Myofibrillar myopathy 5

HCM 26

Restrictive cardiomyopathy 5

Distal myopathy 4

 AD

GAA

606800

Glycogen storage disease II

AR

GLA

300644

Fabry disease

XL

HCN4

605206

Sick sinus syndrome 2

AD
HRAS 190020 Costello syndrome AD

JPH2

605267

HCM 17

AD

JUP

173325

ARVC 12

AD

Naxos disease

AR

KCNE1

176261

LQTS 5

AD

Jervell and Lange-Nielsen syndrome 2

AR

KCNE2

603796

Familial atrial fibrillation 4

LQTS 6

AD

KCNH2

152427

LQTS 2

SQTS 1

AD

KCNJ2

600681

Andersen syndrome

SQTS 3

Familial atrial fibrillation 9

AD

KCNQ1

607542

LQT S 1

Familial atrial fibrillation 3

SQTS 2

AD

Jervell and Lange-Nielsen syndrome 1

AR

KRAS

190070

Cardiofaciocutaneous syndrome 2

Noonan syndrome 3

AD

LAMP2

309060

Danon disease

XL

LDB3

605906

DCM 1C with or without LVNC

Myofibrillar myopathy, 4

AD

LMNA

150330

DCM 1A

Emery-Dreifuss muscular dystrophy 2

Slovenian type heart-hand syndrome

Congenital muscular dystrophy

Malouf syndrome

AD

Emery-Dreifuss muscular dystrophy 3

AR
MAP2K1 176872 Cardiofaciocutaneous syndrome 3 AD
MAP2K2 601263 Cardiofaciocutaneous syndrome 4 AD

MYBPC3

600958

HCM 4

DCM 1MM

LVNC 10

AD

MYH6

160710

DCM 1EE

Sick sinus syndrome 3

Atrial septal defect 3

AD

MYH7

160760

DCM 1S

HCM 1

Laing distal myopathy

AD

Myosin storage myopathy

AR

MYL2

160781

HCM 10

AD

MYL3

160790

HCM 8

AD/AR

NEXN

613121

DCM 1CC

AD
NKX2-5 600584 Atrial septal defect with or without AV conduction defects AD
NRAS 164790 Noonan syndrome 6 AD

PKP2

602861

ARVC 9

AD

PLN

172405

DCM 1P

HCM 18

AD
PRDM16 605557 DCM 1LL AD

PRKAG2

602743

HCM 6

Glycogen storage disease of the heart, lethal congenital

Wolff-Parkinson-White syndrome

AD
PTPN11 176876

Noonan syndrome 1

LEOPARD syndrome 1

 AD
RAF1 164760

Noonan syndrome 5

DCM 1NN

LEOPARD syndrome 2

 AD

RBM20

613171

DCM 1DD

AD
RIT1 609591 Noonan syndrome 8 AD

RYR2

180902

ARVC 2

CPVT 1

AD

SCN5A

600163

Brugada syndrome 1

DCM 1E

Familial atrial fibrillation 10

Familial heart block

Familial paroxysmal ventricular fibrillation

LQTS 3

AD

Sick sinus syndrome 1

AR

SOS1

182530

Noonan syndrome 4

AD

TAFAZZIN

300394

Barth syndrome

XL

TCAP

604488

Limb-girdle muscular dystrophy 2G

AR

TECRL

617242

CPVT 3

AR

TMEM43

612048

ARVC 5

Emery-Dreifuss muscular dystrophy 7

AD

TNNC1

191040

DCM 1Z

HCM 13

AD

TNNI3

191044

DCM 1FF

Restrictive cardiomyopathy 1

HCM 7

AD

DCM 2A

AR
TNNI3K 613932 Cardiac conduction disease with or without DCM AD

TNNT2

191045

HCM 2

DCM 1D

Restrictive cardiomyopathy 3

AD

TPM1

191010

HCM 3

DCM 1Y

AD

TRDN

603283

Cardiac arrhythmia syndrome with or without skeletal muscle weakness

AR

TTN

188840

DCM 1G

Myofibrillar myopathy 9

AD

Salih myopathy

AR

TTR

176300

Transthyretin-related amyloidosis

AD

VCL

193065

DCM 1W

AD

AD, autosomal dominant; AR, autosomal recessive, XL, X-linked

References