Invitae Arrhythmia and Cardiomyopathy Comprehensive Panel

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  • Test code: 02101
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Test description

This test provides a comprehensive analysis of the genes associated with inherited arrhythmia and cardiomyopathy conditions. Given the clinical overlap between different arrhythmia and cardiomyopathy conditions, comprehensive testing enables a more efficient evaluation of multiple conditions based on a single indication for testing.

Individuals with clinical symptoms of an inherited arrhythmia or cardiomyopathy may benefit from diagnostic genetic testing to establish or confirm diagnosis, clarify risks, or inform management. Asymptomatic individuals within a family with a known pathogenic variant may also benefit by avoiding activities and medications that can trigger symptoms.

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Primary panel (67 genes)

ABCC9 ACTC1 ACTN2 AGL ANK2 BAG3 CACNA1C CACNB2 CALM1 CALM2 CALM3 CASQ2 CAV3 CRYAB CSRP3 DES DMD DOLK DSC2 DSG2 DSP EMD EYA4 FHL1 FKRP FKTN FLNC GAA GLA GPD1L HCN4 JUP KCNA5 KCNE1 KCNE2 KCNH2 KCNJ2 KCNQ1 LAMP2 LMNA MYBPC3 MYH7 MYL2 MYL3 MYL4 NKX2-5 PKP2 PLN PRKAG2 RAF1 RBM20 RYR2 SCN5A SGCD SLC22A5 TAZ TCAP TGFB3 TMEM43 TNNC1 TNNI3 TNNT2 TPM1 TRDN TTN TTR VCL

DMD: Analysis guarantees del/dup detection at single-exon resolution.
FKTN: Analysis includes the intronic variant NM_001079802.1:c.647+2084G>T as well as the 3 kb retrotransposon insertion in the 3' UTR at c.*4287_*4288ins3062.
GAA: Analysis includes the promoter variant NM_000152.3:c.-32-13T>G as well as the common exon 18 deletion.
GLA: Analysis includes the intronic variant NM_000169.2:c.IVS4+919G>A.
MYBPC3: Analysis includes the intronic variant NM_000256.3:c.3628-41_3628-17del25.
TTN: Deletion/duplication and sequencing analysis is not offered for exons 153-155 (NM_133378.4). Variants are named relative to the NM_001267550.2 (meta) transcript, but only variants in the coding sequence and intronic boundaries of the clinically relevant NM_133378.4 (N2A) isoform are reported (PMID: 25589632).

Add-on Preliminary-evidence Genes for Arrhythmia and Cardiomyopathy (46 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

AKAP9 ANKRD1 CACNA2D1 CALR3 CHRM2 CTF1 CTNNA3 DTNA FHL2 GATA4 GATA6 GATAD1 GJA5 ILK JPH2 KCND3 KCNE3 KCNE5 KCNJ5 KCNJ8 KCNK3 LAMA4 LDB3 LRRC10 MYH6 MYLK2 MYOM1 MYOZ2 MYPN NEBL NEXN NPPA PDLIM3 PLEKHM2 PRDM16 RANGRF SCN10A SCN1B SCN2B SCN3B SCN4B SLMAP SNTA1 TMPO TRPM4 TXNRD2

ANKRD1: Deletion/duplication analysis is not offered for exons 3 or 4.

Add-on RASopathy Genes (17 genes)

Structural heart defects or hypertrophic cardiomyopathy are also common features of RASopathy conditions. Clinicians can choose to include these genes for no additional charge.

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

Add-on Autosomal Recessive Syndromic Pediatric Cardiomyopathy Genes (8 genes)

Genes associated with early-onset cardiomyopathy as part of an autosomal recessive disorder may be included at no additional charge. Clinicians may wish to include these genes for patients who present in infancy or early childhood with clinical features of a multi-system disorder. Please note, SDHA is included due to its association with autosomal recessive mitochondrial complex II deficiency. However, SDHA is most commonly associated with autosomal dominant predisposition to cancer.

ACADVL ALMS1 CPT2 DNAJC19 ELAC2 MTO1 SDHA TMEM70

SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.

Add-on Sudden Unexpected Death in Epilepsy (SUDEP) Genes (10 genes)

The symptoms associated with arrhythmia and seizures can appear very similar and are known to co-occur in some cases. Some clinicians may wish to include a selection of genes associated with epilepsy for individuals with a differential diagnosis of arrhythmia vs. seizures, or a primary indication of arrhythmia and a family history of seizures.

DEPDC5 KCNQ2 KCNQ3 KCNT1 PCDH19 PRRT2 SCN1A SCN8A SCN9A SLC2A1

KCNT1: Deletion/duplication analysis is not offered for exons 26 or 27.
SCN8A: Analysis includes exon 6 of NM_001330260.1.

  • arrhythmogenic right ventricular cardiomyopathy (ARVC)
  • Brugada syndrome
  • catecholaminergic polymorphic ventricular tachycardia (CPVT)
  • dilated cardiomyopathy (DCM)
  • hypertrophic cardiomyopathy (HCM)
  • left ventricular cardiomyopathy (LVNC)
  • long QT syndrome (LQTS)
  • short QT syndrome (SQTS)

Arrhythmia and cardiomyopathy may present as isolated features, but they frequently occur together, as part of the same condition.

Arrhythmia is an irregular heart rhythm that occurs when there is a disturbance to the normal electrical impulses in the heart. These electrical disturbances can cause the heart to beat too fast, too slow, or erratically. Arrhythmia can lead to stroke, heart failure, or sudden cardiac arrest. Individuals with different inherited cardiac conditions may present with the same type of arrhythmia. The most common types of inherited arrhythmia include long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome.

Cardiomyopathy is a disease of the heart muscle that causes the heart to thicken, enlarge, or become rigid. These changes to the cardiac muscle cause the heart to weaken and may lead to heart failure. Cardiomyopathy can be acquired, often from another type of disease, or it can be inherited. The most common types of inherited cardiomyopathy include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular noncompaction (LVNC) and restrictive cardiomyopathy (RCM).

Cardiomyopathy may also be one feature of a multi-system disorder, such as Noonan syndrome, Fabry disease, Barth syndrome, Danon disease, glycogen storage disease, transthyretin amyloidosis, various types of muscular dystrophy or myopathy, or combined oxidative phosphorylation deficiency. Please note that the genes associated with Noonan syndrome and/or autosomal recessive syndromic pediatric cardiomyopathy can be included when placing an order for this test.

The clinical sensitivity of this test is dependent on the patient’s underlying genetic condition. This test covers all of the common genetic causes of the following hereditary arrhythmia and/or cardiomyopathy conditions: LQTS, SQTS, Brugada syndrome, CPVT, ARVC, HCM, DCM, and LVNC. For each condition, the chart below shows the percentage of clinical cases in which a pathogenic variant is expected to be identified through analysis of the genes on this panel.

Clinical sensitivity by underlying condition
ARVC Brugada CPVT DCM HCM LQTS LVNC SQTS
50% 15%-30% 65% 20%-40% 40%-60% 70% 20%-30% Unknown

Arrhythmia conditions
Most inherited arrhythmia disorders exhibit an autosomal dominant pattern. A small number of arrhythmias, such as LQTS due to Jervell and Lange-Nielsen syndrome (JLNS), CASQ2-related CPVT, TRDN-related arrhythmia, ARVC due to Naxos disease, and dilated cardiomyopathy due to Carvajal syndrome, are inherited in an autosomal recessive manner. EMD-related muscular dystrophy and variants in the gene KCNE5 are inherited in an X-linked manner.

Cardiomyopathy conditions
The majority of inherited cardiomyopathy conditions exhibit an autosomal dominant inheritance pattern. Cardiomyopathy due to Emery-Dreifuss muscular dystrophy, Duchenne muscular dystrophy, Fabry disease, and Barth syndrome exhibit X-linked inheritance. Some syndromic conditions, such as Alstrom syndrome, Naxos disease, Carvajal syndrome, Pompe disease, AGL-related glycogen storage disease, primary carnitine deficiency, DOLK-related congenital disorders of glycosylation, SGCD-related limb-girdle muscular dystrophy, and ELAC2, MTO1, and SDHA-related combined oxidative phosphorylation deficiency, are inherited in an autosomal recessive manner.

Most hereditary arrhythmia and cardiomyopathy conditions exhibit reduced penetrance, meaning that not everyone who inherits a predisposition to develop arrhythmia or cardiomyopathy will go on to manifest the disorder.

The chance to develop an arrhythmia or acquired cardiomyopathy typically increases with age. Individuals with a genetic predisposition to develop arrhythmia or cardiomyopathy have an increased risk for arrhythmia at any age and frequently present with arrhythmia at younger ages compared to the general population. Symptoms are variable, even among affected members of the same family. Arrhythmia may occur spontaneously or be triggered by certain factors such as exercise, emotional stress, certain medications, fever, dehydration, or electrolyte imbalance.

Arrhythmia may also be the presenting feature of arrhythmogenic cardiomyopathy conditions. Individuals with a genetic predisposition to develop arrhythmogenic cardiomyopathy may initially have conduction disease, atrial fibrillation, ventricular tachycardia or ventricular fibrillation along with an increased risk to develop cardiomyopathy over the lifespan.

Autosomal recessive Jervell and Lange-Nielsen syndrome, CASQ2-related CPVT, Naxos disease, and Carvajal syndrome have higher penetrance, with most affected individuals developing signs and symptoms during their lifetime and often at young ages. The age of onset and penetrance of syndromic causes of cardiomyopathy is dependent on the disorder. Barth syndrome and Duchenne or Becker muscular dystrophy commonly present in males in childhood, while cardiomyopathy due to Fabry disease or transthyretin amyloidosis often does not present until mid- to late adulthood.

The prevalence of genetic forms of arrhythmia or cardiomyopathy is dependent on the underlying condition.

ConditionEstimated prevalenceAdditional information
HCM~1 in 500Recently, the prevalence has been suggested to be as high as 1 in 200 individuals.
LQTS~1 in 2,000 
DCM~1 in 2,500 to ~1 in 3,000 
ARVC~1 in 2,000 to ~1:5,000Prevalence is increased in Italy and Greece, where it can be as high as 1 in 125 to 1 in 250.
CPVT~1 in 10,000 
BrugadaNo precise data availablePrevalence is much higher in Asian and Southeast Asian countries—especially Thailand, the Philippines, and Japan—and reaches 0.5–1 in 1,000 persons.

The specific prevalence of other inherited arrhythmias is unknown at this time.

This test may be considered for individuals with:

  • arrhythmia in the absence of clear structural heart disease
  • unexplained arrhythmia that may be consistent with multiple genetic arrhythmia conditions
  • unexplained sudden cardiac arrest
  • unexplained cardiomyopathy
  • cardiomyopathy that may be consistent with multiple genetic cardiomyopathy conditions

  1. Ackerman MJ, 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). 2011 Heart Rhythm Aug; 8(8):1308-1339. PMID: 21787999
  2. Hershberger RE, et al. Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. 2009 J Card Fail. Mar; 15(2):83-97. PMID: 19254666
  3. Hershberger et al. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med. 2010 Nov;12(11):655-67. PMID: 20864896
  4. Hershberger, RE, Morales, A. Dilated Cardiomyopathy Overview. 2007 Jul 27. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301486
  5. Hoedemaekers YM, et al. The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. 2010 Circ Cardiovasc Genet Jun;3(3):232-239 PMID: 20530761
  6. Hsiao PY, et al. Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies. 2013 Appl Clin Genet. Jan; 18 6:1-13. PMID: 23837003
  7. January CT, et al. AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. 2014 J Am Coll Cardiol. Dec; 2:64(21):e1-76. PMID: 24685669
  8. McNally EM, et al. Genetic mutations and mechanisms in dilated cardiomyopathy. 2013 J Clin Invest. Jan;123(1):19-26. PMID: 23281406
  9. Mizusawa Y, et al. Genetics and clinical advances in congenital long QT syndrome. 2014 Circ J 78(12):2827-2833. PMID: 25274057
  10. NCBI GeneReviews. Hypertrophic Cardiomyopathy Overview. PMID: 20301725
  11. Nyegaard M, et al. Mutations in calmodulin cause ventricular tachycardia and sudden cardiac death. 2012 Am J Hum Genet. Oct; 91(4):703-712. PMID: 23040497
  12. Pinamonti B, et al. Arrhythmogenic right ventricular cardiomyopathy: From genetics to diagnostic and therapeutic challenges. 2014 World J Cardiol. Dec 26:6(12):1234-44. PMID: 25548613
  13. Priori, SG, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of individuals with inherited primary arrhythmia syndromes. 2013. Heart Rhythm, Dec;10(12):e85-108. PMID: 23916535
  14. Pugh TJ, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. 2014 Genet Med Aug; 16(8):601-608. PMID: 24503780
  15. Schwartz PJ, et al. Impact of genetics on the clinical management of channelopathies. 2013 J Am Coll Cardiol. Jul 16:62(3):169-180. PMID: 23684683
  16. Semsarian C, et al. New perspectives on the prevalence of hypertrophic cardiomyopathy. 2015 J Am Coll Cardiol. Mar 31;65(12):1249-1254. PMID: 25814232
  17. Tester DJ, et al. Genetics of long QT syndrome. 2014 Methodist Debakey Cardiovasc J. Jan-Mar 10(1):29-33. PMID: 24932360

For links to published management guidelines for cardiology conditions, please refer to our Management guidelines page.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
A2ML1 NM_144670.4
ABCC9 NM_005691.3
ACADVL NM_000018.3
ACTC1 NM_005159.4
ACTN2 NM_001103.3
AGL NM_000642.2
AKAP9 NM_005751.4
ALMS1 NM_015120.4
ANK2 NM_001148.4
ANKRD1* NM_014391.2
BAG3 NM_004281.3
BRAF NM_004333.4
CACNA1C NM_000719.6
CACNA2D1 NM_000722.3
CACNB2 NM_201590.2
CALM1 NM_006888.4
CALM2 NM_001743.4
CALM3 NM_005184.2
CALR3 NM_145046.4
CASQ2 NM_001232.3
CAV3 NM_033337.2
CBL NM_005188.3
CHRM2 NM_000739.2
CPT2 NM_000098.2
CRYAB NM_001885.2
CSRP3 NM_003476.4
CTF1 NM_001330.3
CTNNA3 NM_013266.3
DEPDC5 NM_001242896.1
DES NM_001927.3
DMD* NM_004006.2
DNAJC19 NM_145261.3
DOLK NM_014908.3
DSC2 NM_024422.4
DSG2 NM_001943.3
DSP NM_004415.2
DTNA NM_032978.6
ELAC2 NM_018127.6
EMD NM_000117.2
EYA4 NM_004100.4
FHL1 NM_001449.4; NM_001159702.2
FHL2 NM_201555.1
FKRP NM_024301.4
FKTN* NM_001079802.1
FLNC NM_001458.4
GAA* NM_000152.3
GATA4 NM_002052.3
GATA6 NM_005257.5
GATAD1 NM_021167.4
GJA5 NM_005266.6
GLA* NM_000169.2
GPD1L NM_015141.3
HCN4 NM_005477.2
HRAS NM_005343.2
ILK NM_004517.3
JPH2 NM_020433.4
JUP NM_002230.2
KCNA5 NM_002234.3
KCND3 NM_004980.4
KCNE1 NM_000219.5
KCNE2 NM_172201.1
KCNE3 NM_005472.4
KCNE5 NM_012282.2
KCNH2 NM_000238.3; NM_172057.2
KCNJ2 NM_000891.2
KCNJ5 NM_000890.3
KCNJ8 NM_004982.3
KCNK3 NM_002246.2
KCNQ1 NM_000218.2
KCNQ2 NM_172107.2
KCNQ3 NM_004519.3
KCNT1* NM_020822.2
KRAS NM_004985.4
LAMA4 NM_002290.4
LAMP2 NM_002294.2; NM_013995.2
LDB3 NM_001080116.1; NM_001171610.1; NM_007078.2
LMNA NM_170707.3; NM_005572.3
LRRC10 NM_201550.3
MAP2K1 NM_002755.3
MAP2K2 NM_030662.3
MTO1 NM_012123.3
MYBPC3* NM_000256.3
MYH6 NM_002471.3
MYH7 NM_000257.3
MYL2 NM_000432.3
MYL3 NM_000258.2
MYL4 NM_001002841.1
MYLK2 NM_033118.3
MYOM1 NM_003803.3
MYOZ2 NM_016599.4
MYPN NM_032578.3
NEBL NM_006393.2
NEXN NM_144573.3
NF1 NM_000267.3
NKX2-5 NM_004387.3; NM_004387.3
NPPA NM_006172.3
NRAS NM_002524.4
PCDH19 NM_001184880.1
PDLIM3 NM_014476.5
PKP2 NM_004572.3
PLEKHM2 NM_015164.2
PLN NM_002667.3
PRDM16 NM_022114.3
PRKAG2 NM_016203.3
PRRT2 NM_145239.2
PTPN11 NM_002834.3
RAF1 NM_002880.3
RANGRF NM_016492.4
RASA1 NM_002890.2
RBM20 NM_001134363.2
RIT1 NM_006912.5
RRAS NM_006270.4
RYR2 NM_001035.2
SCN10A NM_006514.3
SCN1A NM_001165963.1
SCN1B NM_199037.3; NM_001037.4
SCN2B NM_004588.4
SCN3B NM_018400.3
SCN4B NM_174934.3
SCN5A NM_198056.2
SCN8A* NM_014191.3; NM_001330260.1
SCN9A NM_002977.3
SDHA* NM_004168.3
SGCD NM_000337.5
SHOC2 NM_007373.3
SLC22A5 NM_003060.3
SLC2A1 NM_006516.2
SLMAP NM_007159.2
SNTA1 NM_003098.2
SOS1 NM_005633.3
SOS2 NM_006939.2
SPRED1 NM_152594.2
TAZ NM_000116.4
TCAP NM_003673.3
TGFB3 NM_003239.3
TMEM43 NM_024334.2
TMEM70 NM_017866.5
TMPO NM_003276.2
TNNC1 NM_003280.2
TNNI3 NM_000363.4
TNNT2 NM_001001430.2; NM_000364.3
TPM1 NM_001018005.1
TRDN NM_006073.3
TRPM4 NM_017636.3
TTN* NM_001267550.2
TTR NM_000371.3
TXNRD2 NM_006440.4
VCL NM_014000.2

ANKRD1: Deletion/duplication analysis is not offered for exons 3 or 4.
DMD: Analysis guarantees del/dup detection at single-exon resolution.
FKTN: Analysis includes the intronic variant NM_001079802.1:c.647+2084G>T as well as the 3 kb retrotransposon insertion in the 3' UTR at c.*4287_*4288ins3062.
GAA: Analysis includes the promoter variant NM_000152.3:c.-32-13T>G as well as the common exon 18 deletion.
GLA: Analysis includes the intronic variant NM_000169.2:c.IVS4+919G>A.
KCNT1: Deletion/duplication analysis is not offered for exons 26 or 27.
MYBPC3: Analysis includes the intronic variant NM_000256.3:c.3628-41_3628-17del25.
SCN8A: Analysis includes exon 6 of NM_001330260.1.
SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.
TTN: Deletion/duplication and sequencing analysis is not offered for exons 153-155 (NM_133378.4). Variants are named relative to the NM_001267550.2 (meta) transcript, but only variants in the coding sequence and intronic boundaries of the clinically relevant NM_133378.4 (N2A) isoform are reported (PMID: 25589632).