Cardiomyopathy and Arrhythmia Panel, Sequencing and Deletion/Duplication

Last Literature 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 ClassAnalytic Sensitivity (PPA) Estimatea (%) and 95% Credibility RegionAnalytic Specificity (NPA)
SNVs>99 (96.9-99.4)>99.9
Deletions 1-10 bpb93.8 (84.3-98.2)>99.9
Insertions 1-10 bpb94.8 (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 duplications83.3 (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
      • 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

DisorderClinical CharacteristicsPrevalenceInheritanceComments
ARVCProgressive fibrofatty replacement of the myocardium predisposing to ventricular tachycardia and sudden death1/1,000ADCommonly implicated genes include PKP2, DSP, DSG2
BrSCardiac conduction abnormalities that can result in sudden deathUnknownAD, 1% de novoVariants in SCN5A account for 15-30% of BrS
CPVTEpisodic syncope or ventricular arrhythmias occurring during exercise or acute emotion without presence of structural cardiac abnormalities1/10,000AD or ARVariants in RYR2 account for 50-55% of all CPVT
DCMLeft ventricular enlargement and systolic dysfunction1/250-1/2,500Typically AD; AR/XL/Mitochondrial less common

~20-50% of cases are familial

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

HCMLeft ventricular hypertrophy with absence of other cardiovascular causes1/500ADVariants in MYH7 and MYBPC3 account for the majority of familial HCM 
LVNCHypertrophic and hypokinetic left ventricle with distinctive morphologyUnknownTypically ADMYH7 and MYBPC3 are commonly implicated genes
LQTSCardiac electrophysiologic disease with prolonged QT- and T-wave abnormalities on ECG associated with ventricular tachycardia (torsade de pointes)1/2,500ADIncomplete penetrance
SQTSCardiac arrhythmia with short QT interval on ECGUnknownADAssociated genes: KCNH2,
KCNJ2, KCNQ1
AD, autosomal dominant; AR, autosomal recessive; XL, X-linked

Genes Tested

GeneMIM NumberDisorderInheritance
ABCC9601439

Cantu syndrome

DCM 10

Familial atrial fibrillation 12

AD
ACTC1102540

HCM 11

Atrial septal defect 5

DCM 1R

AD
ACTN2102573

DCM 1AA with or without LVNC

HCM 23 with or without LVNC

AD
AGL610860Glycogen storage disease IIIa or IIIbAR
ALMS1606844Alstrom SyndromeAR
ALPK318052HCM 27AR
BAG3603883

Myofibrillar myopathy 6

DCM 1HH

AD
BRAF164757

Cardiofaciocutaneous syndrome 1

Noonan syndrome 7

AD
CACNA1C114205

Timothy syndrome

LGTS 8

AD
CALM1114180

LQTS 14

CPVT 4

AD
CALM2114182

LQTS 15

CPVT

AD
CALM3114183

LQTS 16

CPVT 6

AD
CASQ2114251CPVT 2AR
CAV3601253

Familial hypertrophic cardiomyopathy, 1

Long QT syndrome 9

AD
CRYAB123590

Myofibrillar myopathy, 2

DCM 1II

AD
Myofibrillar myopathy, fatal infantile hypertonic, alpha-B crystallin-relatedAR
CSRP3600824HCM 12AD
DES125660Myofibrillar myopathy, 1AD/AR
DCM 1IAD
DMD300377

Becker muscular dystrophy

DCM 3B

Duchenne muscular dystrophy

XL
DOLK610746Congenital disorder of glycosylation ImAR
DSC2125645ARVC 11AD
ARVC 11 with mild palmoplantar keratoderma and woolly hairAR
DSG2125671

ARVC 10

DCM 1BB

AD
DSP125647

ARVC 8

DCM with woolly hair, keratoderma, and tooth agenesis

AD
DCM with woolly hair and keratodermaAR
EMD300384Emery-Dreifuss muscular dystrophy 1XL
FHL1300163

Uruguay faciocardiomusculoskeletal syndrome

Scapuloperoneal myopathy

Myopathy with postural muscle atrophy

Emery-Dreifuss muscular dystrophy 6

Reducing body myopathy 1B

XL
FKTN607440

DCM 1X

Muscular dystrophy-dystroglycanopathy Ad4

AR
FLNC102565

Myofibrillar myopathy 5

HCM 26

Restrictive cardiomyopathy 5

Distal myopathy 4

AD
GAA606800Glycogen storage disease IIAR
GLA300644Fabry diseaseXL
HCN4605206Sick sinus syndrome 2AD
HRAS190020Costello syndromeAD
JPH2605267HCM 17AD
JUP173325ARVC 12AD
Naxos diseaseAR
KCNE1176261LQTS 5AD
Jervell and Lange-Nielsen syndrome 2AR
KCNE2603796

Familial atrial fibrillation 4

LQTS 6

AD
KCNH2152427

LQTS 2

SQTS 1

AD
KCNJ2600681

Andersen syndrome

SQTS 3

Familial atrial fibrillation 9

AD
KCNQ1607542

LQT S 1

Familial atrial fibrillation 3

SQTS 2

AD
Jervell and Lange-Nielsen syndrome 1AR
KRAS190070

Cardiofaciocutaneous syndrome 2

Noonan syndrome 3

AD
LAMP2309060Danon diseaseXL
LDB3605906

DCM 1C with or without LVNC

Myofibrillar myopathy, 4

AD
LMNA150330

DCM 1A

Emery-Dreifuss muscular dystrophy 2

Slovenian type heart-hand syndrome

Congenital muscular dystrophy

Malouf syndrome

AD
Emery-Dreifuss muscular dystrophy 3AR
MAP2K1176872Cardiofaciocutaneous syndrome 3AD
MAP2K2601263Cardiofaciocutaneous syndrome 4AD
MYBPC3600958

HCM 4

DCM 1MM

LVNC 10

AD
MYH6160710

DCM 1EE

Sick sinus syndrome 3

Atrial septal defect 3

AD
MYH7160760

DCM 1S

HCM 1

Laing distal myopathy

AD
Myosin storage myopathyAR
MYL2160781HCM 10AD
MYL3160790HCM 8AD/AR
NEXN613121DCM 1CCAD
NKX2-5600584Atrial septal defect with or without AV conduction defectsAD
NRAS164790Noonan syndrome 6AD
PKP2602861ARVC 9AD
PLN172405

DCM 1P

HCM 18

AD
PRDM16605557DCM 1LLAD
PRKAG2602743

HCM 6

Glycogen storage disease of the heart, lethal congenital

Wolff-Parkinson-White syndrome

AD
PTPN11176876

Noonan syndrome 1

LEOPARD syndrome 1

AD
RAF1164760

Noonan syndrome 5

DCM 1NN

LEOPARD syndrome 2

AD
RBM20613171DCM 1DDAD
RIT1609591Noonan syndrome 8AD
RYR2180902

ARVC 2

CPVT 1

AD
SCN5A600163

Brugada syndrome 1

DCM 1E

Familial atrial fibrillation 10

Familial heart block

Familial paroxysmal ventricular fibrillation

LQTS 3

AD
Sick sinus syndrome 1AR
SOS1182530Noonan syndrome 4AD
TAFAZZIN300394Barth syndromeXL
TCAP604488Limb-girdle muscular dystrophy 2GAR
TECRL617242CPVT 3AR
TMEM43612048

ARVC 5

Emery-Dreifuss muscular dystrophy 7

AD
TNNC1191040

DCM 1Z

HCM 13

AD
TNNI3191044

DCM 1FF

Restrictive cardiomyopathy 1

HCM 7

AD
DCM 2AAR
TNNI3K613932Cardiac conduction disease with or without DCMAD
TNNT2191045

HCM 2

DCM 1D

Restrictive cardiomyopathy 3

AD
TPM1191010

HCM 3

DCM 1Y

AD
TRDN603283Cardiac arrhythmia syndrome with or without skeletal muscle weaknessAR
TTN188840

DCM 1G

Myofibrillar myopathy 9

AD
Salih myopathyAR
TTR176300Transthyretin-related amyloidosisAD
VCL193065DCM 1WAD
AD, autosomal dominant; AR, autosomal recessive, XL, X-linked

References