Cardiomyopathy and Arrhythmia Panel, Sequencing and Deletion/Duplication

Indication for testing:

Confirm hereditary form of cardiomyopathy or arrhythmia.

Indication for testing:

  • Recommended test for a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s test result documenting the familial variant is required.

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). Genetic testing is used to confirm diagnosis.

DISEASE OVERVIEW

See Common Disorders table below.

TEST DESCRIPTION

See Genes Tested table for genes included in the panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

  • ARVC – 50 percent 
  • BrS – 15-30 percent 
  • CPVT – 60 percent 
  • DCM – 30-40 percent 
  • HCM (nonsyndromic familial) – 50-60 percent 
  • LQTS – 60-75 percent 

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 variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletions/duplications in BAG3, CRYAB, EMD, FHL1, GATAD1, TAZ, TRDN
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • TTN (NM_001267550) 172, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 215
      • TTN (NM_133378) 153, 154, 155
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1kb in the targeted genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
    • Gene Exon(s)

      ACTN2

      (NM_001103) 17

      CACNB2

      (NM_001167945) 7

      DMD

      (NM_000109) 1

      DSC2

      (NM_024422) 1

      DTNA

      (NM_001390) 16, 21

      KCNH2

      (NM_000238) 13

      KCNQ1

      (NM_000218) 16

      KCNQ1

      (NM_181798) 1

      MYBPC3

      (NM_000256) 10, 24

      MYH6

      (NM_002471) 24, 28

      MYH7

      (NM_000257) 29

      PKP2

      (NM_004572) 6

      PRKAG2

      (NM_001304527) 1

      PRKAG2

      (NM_001304531) 2

      PRKAG2

      (NM_016203) 5

      SGCB

      (NM_000232) 1

      SGCG

      (NM_000231) 8

      TGFB3

      (NM_003239) 7

      TRPM4

      (NM_001321285) 4

      TRPM4

      (NM_017636) 7

      TTN

      (NM_001267550) 158, 173, 176, 185, 191, 194

      TTN

      (NM_133378) 114, 148, 155, 156, 167, 170

    Analytical Sensitivity

    For massively parallel sequencing:

    Variant Class

    Analytical Sensitivity (PPA) Estimatea (%)

    Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

    SNVs

    99.2

    96.9-99.4

    Deletions 1-10 bp

    93.8

    84.3-98.2

    Deletions 11-44 bp

    100

    87.8-100

    Insertions 1-10 bp

    94.8

    86.8-98.5

    Insertions 11-23 bp

    100

    62.1-100

    aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

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

Common Disorders

Disorder Clinical Characteristics Prevalence Inheritance Comments
Arrhythmogenic right ventricular cardiomyopathy (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
Brugada syndrome (BrS)

Cardiac conduction abnormalities that can result in sudden death

Unknown

AD, 1% de novo

Variants in SCN5A account for 15-30% of BrS
Catecholaminergic polymorphic ventricular tachycardia (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
Dilated cardiomyopathy (DCM)

Left ventricular enlargement and systolic dysfunction

~1/500

Typically AD; AR/XL/Mitochondrial less common

~20-35% of isolated DCM is familial

Variants in TTN account for 10-20% of isolated DCM
Hypertrophic cardiomyopathy (HCM)

Left ventricular hypertrophy with absence of other cardiovascular causes

1/500

AD

Variants in MYH7 and MYBPC3 account for majority of familial HCM.

Variants in genes encoding for components of the sarcomere account for 55-70% of HCM with no multisystem involvement.

 
Left ventricular noncompaction (LVNC)

Hypertrophic and hypokinetic left ventricle with distinctive morphology

Unknown

Typically AD

MYH7 and MYBPC3 commonly implicated genes
Long QT syndrome (LQTS)

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

1/3,000

AD

Incomplete penetrance
Short QT syndrome (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

Dilated cardiomyopathy, 1O

Familial atrial fibrillation, 12

AD

ACTC1

102540

Familial hypertrophic cardiomyopathy, 11

Atrial septal defect 5

Dilated cardiomyopathy, 1R

Left ventricular noncompaction 4

AD

ACTN2

102573

Dilated cardiomyopathy, 1AA, with or without LVNC

Hypertrophic cardiomyopathy, 23, with or without LVNC

AD

ANK2

106410

Cardiac arrhythmia, ankyrin-B-related

Long QT syndrome 4

AD

ANKRD1

609599

Dilated cardiomyopathy

AD

BAG3

603883

Myofibrillar myopathy, 6

Dilated cardiomyopathy, 1HH

AD

CACNA1C

114205

Timothy syndrome

Brugada syndrome 3

AD

CACNB2

600003

Brugada syndrome 4

AD

CASQ2

114251

Catecholaminergic polymorphic ventricular tachycardia, 2

AR

CAV3

601253

Familial hypertrophic cardiomyopathy, 1

Long QT syndrome 9

AD

CRYAB

123590

Myofibrillar myopathy, 2

Dilated cardiomyopathy, 1II

AD

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

AR

CSRP3

600824

Dilated cardiomyopathy, 1M

Familial hypertrophic cardiomyopathy, 12

AD

DES

125660

Myofibrillar myopathy, 1

Dilated cardiomyopathy, 1I

AD

Myofibrillar myopathy, 1

AR

DMD

300377

Becker muscular dystrophy

Dilated cardiomyopathy, 3B

Duchenne muscular dystrophy

XL

DSC2

125645

Arrhythmogenic right ventricular dysplasia, 11

AD

Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair

AR

DSG2

125671

Arrhythmogenic right ventricular dysplasia, 10

Dilated cardiomyopathy, 1BB

AD

DSP

125647

Arrhythmogenic right ventricular dysplasia, 8

Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis

AD

Dilated cardiomyopathy with woolly hair and keratoderma

AR

DTNA

601239

Left ventricular noncompaction 1

AD

EMD

300384

Emery-Dreifuss muscular dystrophy 1

XL

EYA4

603550

Dilated cardiomyopathy, 1J

AD

FHL1

300163

Uruguay faciocardiomusculoskeletal syndrome

Scapuloperoneal myopathy

Myopathy with postural muscle atrophy

Emery-Dreifuss muscular dystrophy 6

Reducing body myopathy 1B, with late childhood or adult onset

XL

FKRP

606596

Muscular dystrophy-dystroglycanopathy, type A, 5

Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5

AR

FKTN

607440

Dilated cardiomyopathy, 1X

Muscular dystrophy-dystroglycanopathy, type A, 4

AR

GAA

606800

Glycogen storage disease II

AR

GATAD1

614518

Dilated cardiomyopathy, 2B

AR

GLA

300644

Fabry disease

XL

GPD1L

611778

Brugada syndrome 2

AD

JPH2

605267

Hypertrophic cardiomyopathy, 17

AD

JUP

173325

Arrhythmogenic right ventricular dysplasia, 12

AD

Naxos disease

AR

KCNE1

176261

Long QT syndrome 5

AD

Jervell and Lange-Nielsen syndrome 2

AR

KCNE2

603796

Atrial fibrillation, familial, 4

Long QT syndrome 6

AD
KCNE3

604433

Brugada syndrome 6

AD

KCNH2

152427

Long QT syndrome 2

Short QT syndrome 1

AD

KCNJ2

600681

Andersen syndrome

Short QT syndrome 3

Atrial fibrillation, familial, 9

AD

KCNQ1

607542

Long QT syndrome 1

Atrial fibrillation, familial, 3

Short QT syndrome 2

AD

Jervell and Lange-Nielsen syndrome 1

AR

LAMA4

600133

Dilated cardiomyopathy, 1JJ

AD

LAMP2

309060

Danon disease

XL

LDB3

605906

Dilated cardiomyopathy, 1C, with or without LVNC

Hypertrophic cardiomyopathy, 24

Myofibrillar myopathy, 4

AD

LMNA

150330

Dilated cardiomyopathy, 1A

Emery-Dreifuss muscular dystrophy 2

Heart-hand syndrome, Slovenian type

Muscular dystrophy, congenital

Malouf syndrome

AD

Emery-Dreifuss muscular dystrophy 3

AR

MYBPC3

600958

Hypertrophic cardiomyopathy, 4

Dilated cardiomyopathy, 1MM

Left ventricular noncompaction 10

AD

MYH6

160710

Dilated cardiomyopathy, 1EE

Hypertrophic cardiomyopathy, 14

AD

MYH7

160760

Laing distal myopathy

Hypertrophic cardiomyopathy 1

Dilated cardiomyopathy, 1S

Left ventricular noncompaction 5

AD

Myopathy, myosin storage

AR

MYL2

160781

Hypertrophic cardiomyopathy, 10

AD

MYL3

160790

Hypertrophic cardiomyopathy, 8

AD/AR

MYLK2

606566

Hypertrophy cardiomyopathy, 1

AD

MYOT

604103

Myofibrillar myopathy, 3

AD

MYOZ2

605602

Hypertrophic cardiomyopathy, 16

AD

MYPN

608517

Dilated cardiomyopathy, 1KK

Familial restrictive cardiomyopathy 4

Hypertrophic cardiomyopathy 22

AD

Nemaline myopathy 11

AR

NEXN

613121

Dilated cardiomyopathy, 1CC

Hypertrophic cardiomyopathy, 20

AD

PKP2

602861

Arrhythmogenic right ventricular dysplasia, 9

AD

PLN

172405

Dilated cardiomyopathy, 1P

Hypertrophic cardiomyopathy, 18

AD

PRKAG2

602743

Hypertrophic cardiomyopathy, 6

Glycogen storage disease of the heart, lethal congenital

Wolff-Parkinson-White syndrome

AD

RBM20

613171

Dilated cardiomyopathy, 1DD

AD

RYR2

180902

Arrhythmogenic right ventricular dysplasia, 2

Catecholaminergic polymorphic ventricular tachycardia, 1

AD

SCN1B

600235

Brugada syndrome 5

Cardiac conduction defect, nonspecific

Atrial fibrillation, familial, 13

AD

SCN2B

601327

Atrial fibrillation, familial, 14

AD

SCN3B

608214

Brugada syndrome 7

Atrial fibrillation, familial, 16

AD

SCN4B

608256

Long QT syndrome 10

Atrial fibrillation, familial, 17

AD

SCN5A

600163

Heart block, progressive, type IA

Heart block, nonprogressive

Brugada syndrome 1

Cardiomyopathy, dilated, 1E

Ventricular fibrillation, paroxysmal familial, 1

Long QT syndrome 3

Atrial fibrillation, familial, 10

AD

Sick sinus syndrome 1

AR

SGCA

600119

Muscular dystrophy, limb-girdle, type 2D

AR

SGCB

600900

Muscular dystrophy, limb-girdle, type 2E

AR

SGCD

601411

Muscular dystrophy, limb-girdle, type 2F

AR

Dilated cardiomyopathy, 1L

AD

SGCG

608896

Muscular dystrophy, limb-girdle, type 2C

AR

SLC25A4

103220

Mitochondrial DNA depletion syndrome 12A

AD

Mitochondrial DNA depletion syndrome 12B

AR

SNTA1

601017

Long QT syndrome 12

AD

TAZ

300394

Barth syndrome

XL

TCAP

604488

Hypertrophic cardiomyopathy, 25

AD

Muscular dystrophy, limb-girdle, type 2G

AR

TGFB3

190230

Arrhythmogenic right ventricular dysplasia, 1

AD

TMEM43

612048

Arrhythmogenic right ventricular dysplasia, 5

Emery-Dreifuss muscular dystrophy 7

AD

TNNC1

191040

Dilated cardiomyopathy, 1Z

Hypertrophic cardiomyopathy, 13

AD

TNNI3

191044

Dilated cardiomyopathy, 1FF

Cardiomyopathy, familial restrictive, 1

Hypertrophic cardiomyopathy, 7

AD

Dilated cardiomyopathy, 2A

AR

TNNT2

191045

Hypertrophic cardiomyopathy, 2

Dilated cardiomyopathy, 1D

Left ventricular noncompaction 6

Cardiomyopathy, familial restrictive, 3

AD

TPM1

191010

Hypertrophic cardiomyopathy, 3

Dilated cardiomyopathy, 1Y

Left ventricular noncompaction 9

AD

TRDN

603283

Catecholaminergic polymorphic ventricular tachycardia, 5, with or without muscle weakness

AR

TRPM4

606936

Progressive familial heart block, type IB

AD

TTN

188840

Dilated cardiomyopathy, 1G

Hypertrophic cardiomyopathy, 9

AD

Salih myopathy

AR

TTR

176300

Amyloidosis, hereditary, transthyretin-related

AD

VCL

193065

Hypertrophic cardiomyopathy, 15

Dilated cardiomyopathy, 1W

AD

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

References

  1. GeneReviews - Brugada Syndrome

    Brugada R, Campuzano O, Sarquella-Brugada G, et al. Brugada Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Nov 2016; Accessed: Feb 2020]

    Online

  2. GeneReviews - Long QT Syndrome

    Alders M, Bikker H, Christiaans I. Long QT Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Feb 2018; Accessed: Feb 2020]

    Online