Cardiomyopathy and Arrhythmia Panel, Sequencing and Deletion/Duplication

Indication for testing:

Confirm hereditary form of cardiomyopathy or arrhythmia.

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

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 (McNally, 2017)
  • BrS – 15-30 percent (Brugada, 2016)
  • CPVT – 60 percent (Napolitano, 2016)
  • DCM – 30-40 percent (Hershberger, 2018)
  • HCM (nonsyndromic familial) – 50-60 percent (Cirino, 2014)
  • LQTS – 60-75 percent (Alders, 2016)

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 

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

    Brugada Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Nov 2016; Accessed: Nov 2018]

    Cirino A, Ho C. Hypertrophic Cardiomyopathy Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Jan 2014; Accessed: Nov 2018]

    Hershberger R, Morales A. Dilated Cardiomyopathy Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Aug 2018; Accessed: Nov 2018]

    McNally E, MacLeod H, Dellefave-Castillo L. Arrhythmogenic Right Ventricular Cardiomyopathy. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: May 2017; Accessed: Nov 2018]

    Napolitano C, Priori S, Bloise R. Catecholaminergic Polymorphic Ventricular Tachycardia. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Oct 2016; Accessed: Nov 2018]

    Last Update: January 2019