Arrhythmia Panel

Updated
Summary
  • Is a 58 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical diagnosis or suspicion of a hereditary arrhythmia disorder.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

58

Test code

CA1601

Panel size

Large

CPT codes
81413

Summary

The Blueprint Genetics Arrhythmia Panel (test code CA1601):

ICD codes

Commonly used ICD-10 code(s) when ordering the Arrhythmia Panel

ICD-10 Disease
Q24.8 Brugada syndrome
I49.9 Catecholaminergic polymorphic ventricular tachycardia (CPVT)
I46.2 Cardiac arrest underlying cardiac condition
I46.9 Cardiac arrest cause unspecified
R55 Syncope and collapse
R94.31 Abnormal ECG
I45.81 Long QT syndrome
I42.8 Arrhythmogenic right ventricular cardiomyopathy (ARVC)
I49.9 Short QT syndrome

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)

Label the sample tube with your patient's name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. Read more about our sample requirements here.

Subpanel description

This comprehensive panel includes genes from the following panels: Long QT Syndrome (LQTS) Panel, Brugada Syndrome Panel, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Panel, Short QT Syndrome (SQTS) Panel and Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Panel.

All the diseases included in the Arrhythmia Panel manifest with similar symptoms such as palpitations, pre-syncope/syncope or sudden cardiac death. Although clinical evaluation, ECG and echocardiography are considered helpful, they rarely offer a definitive diagnosis of a specific arrhythmia disease. Effective and safe arrhythmia treatments have been challenging to develop as severe arrhythmias represent a heterogeneous group of diseases with diverse cellular mechanisms. The role of a molecular diagnosis is becoming increasingly important as it can inform the diagnosis, prognosis, and treatment of hereditary arrhythmia diseases for both the patient and their family members.

Genes in the Arrhythmia Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCC9 Atrial fibrillation, Cantu syndrome, Dilated cardiomyopathy (DCM) AD 27 46
AKAP9 Long QT syndrome AD 4 38
ANK2 Cardiac arrhythmia, Long QT syndrome AD 6 73
BAG3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 39 62
CACNA1C* Brugada syndrome, Timothy syndrome AD 19 68
CACNB2 Brugada syndrome AD 4 22
CALM1* Ventricular tachycardia, catecholaminergic polymorphic, Recurrent cardiac arrest, infantile, Long QT syndrome AD 10 10
CALM2 Long QT syndrome AD 8 10
CALM3 Catecholaminergic polymorphic ventricular tachycardia AD/AR 4 4
CASQ2 Ventricular tachycardia, catecholaminergic, polymorphic AR 24 34
CAV3 Creatine phosphokinase, elevated serum, Hypertrophic cardiomyopathy (HCM), Long QT syndrome, Muscular dystrophy, limb-girdle, type IC, Myopathy, distal, Tateyama type, Rippling muscle disease 2 AD/AR 23 50
CDH2 Arrhythmogenic right ventricular cardiomyopathy (ARVC) AD 1 6
CTNNA3 Arrhythmogenic right ventricular dysplasia AD 7 46
DBH Dopamine beta-hydroxylase deficiency AR 10 11
DES Dilated cardiomyopathy (DCM), Myopathy, myofibrillar, Scapuloperoneal syndrome, neurogenic, Kaeser type AD/AR 64 124
DSC2 Arrhythmogenic right ventricular dysplasia with palmoplantar keratoderma and woolly hair, Arrhythmogenic right ventricular dysplasia AD/AR 32 87
DSG2 Arrhythmogenic right ventricular dysplasia, Dilated cardiomyopathy (DCM) AD 44 129
DSP Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, Arrhythmogenic right ventricular dysplasia, familial, Cardiomyopathy, dilated, with wooly hair and keratoderma, Keratosis palmoplantaris striata II, Epidermolysis bullosa, lethal acantholytic AD/AR 177 296
FLNC* Myopathy AD 54 109
GATA6 Heart defects, congenital, and other congenital anomalies, Atrial septal defect 9, atrioventricular septal defect 5, Persistent truncus arteriosus, Tetralogy of Fallot AD 16 82
HADHA Trifunctional protein deficiency, Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency AR 65 71
HCN4 Sick sinus syndrome, Brugada syndrome, Left ventricular non-compaction cardiomyopathy (LVNC) AD 8 34
JUP Arrhythmogenic right ventricular dysplasia, Naxos disease AD/AR 8 46
KCNA5 Atrial fibrillation AD 4 25
KCNE1 Long QT syndrome, Jervell and Lange-Nielsen syndrome AD/AR/Digenic 11 46
KCNE2 Long QT syndrome, Atrial fibrillation, familial AD 5 24
KCNH2 Short QT syndrome, Long QT syndrome AD 371 933
KCNJ2 Short QT syndrome, Andersen syndrome, Long QT syndrome, Atrial fibrillation AD 41 93
KCNJ5 Long QT syndrome, Hyperaldosteronism, familial AD 7 15
KCNQ1 Short QT syndrome, Long QT syndrome, Atrial fibrillation, Jervell and Lange-Nielsen syndrome AD/AR/Digenic 298 631
LDB3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 9 14
LEMD2 Cataract 46, juvenile onset, Arrhythmogenic right ventricular cardiomyopathy (ARVC), Dilated cardiomyopathy (DCM) AR 1 1
LMNA Heart-hand syndrome, Slovenian, Limb-girdle muscular dystrophy, Muscular dystrophy, congenital, LMNA-related, Lipodystrophy (Dunnigan), Emery-Dreiffus muscular dystrophy, Malouf syndrome, Dilated cardiomyopathy (DCM), Mandibuloacral dysplasia type A, Progeria Hutchinson-Gilford type AD/AR 250 564
MYH6 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM), Atrial septal defect 3 AD 14 123
MYH7 Hypertrophic cardiomyopathy (HCM), Myopathy, myosin storage, Myopathy, distal, Dilated cardiomyopathy (DCM) AD 305 986
MYL4 Atrial fibrillation, familial, 18 AD 2 2
NKX2-5 Conotruncal heart malformations, Hypothyroidism, congenital nongoitrous,, Atrial septal defect, Ventricular septal defect 3, Conotruncal heart malformations, variable, Tetralogy of Fallot AD 45 108
NOS1AP Romano-Ward syndrome AD/AR 4
NUP155 Atrial fibrillation 15 AR 2 1
PKP2#* Arrhythmogenic right ventricular dysplasia AD 150 289
PLN Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD/AR 8 30
PPA2 Sudden cardiac failure, infantile AR 8 8
RYR2 Ventricular tachycardia, catecholaminergic polymorphic, Arrhythmogenic right ventricular dysplasia AD 124 372
SALL4 Acro-renal-ocular syndrome, Duane-radial ray/Okohiro syndrome AD 21 56
SCN10A Paroxysmal extreme pain disorder, Channelopathy-associated congenital insensitivity to pain, Primary erythermalgia, Sodium channelopathy-related small fiber neuropathy, Brugada syndrome AD/AR 2 76
SCN1B Atrial fibrillation, Brugada syndrome, Generalized epilepsy with febrile seizures plus, Epilepsy, generalized, with febrile seizures plus, type 1, Epileptic encephalopathy, early infantile, 52 AD 16 31
SCN3B Atrial fibrillation, familial, Brugada syndrome AD 3 7
SCN5A Heart block, nonprogressive, Heart block, progressive, Long QT syndrome, Ventricular fibrillation, Atrial fibrillation, Sick sinus syndrome, Brugada syndrome, Dilated cardiomyopathy (DCM) AD/AR/Digenic 234 899
TBX5 Holt-Oram syndrome AD 61 127
TECRL Ventricular tachycardia, catecholaminergic polymorphic, 3 AR 2 3
TGFB3 Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasia AD 19 26
TMEM43 Arrhythmogenic right ventricular dysplasia, Emery-Dreifuss muscular dystrophy AD 4 24
TNNI3 Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM) AD/AR 56 129
TNNI3K Cardiac conduction disease with or without dilated cardiomyopathy AD 1 3
TNNT2 Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM) AD 61 148
TRDN Ventricular tachycardia, catecholaminergic polymorphic AR 19 6
TRPM4 Progressive familial heart block AD 5 32
TTN* Dilated cardiomyopathy (DCM), Tibial muscular dystrophy, Limb-girdle muscular dystrophy, Hereditary myopathy with early respiratory failure, Myopathy, early-onset, with fatal cardiomyopathy (Salih myopathy), Muscular dystrophy, limb-girdle, type 2J AD 818 327

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by Arrhythmia Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
DSC2 Chr18:28683379 c.-1445G>C NM_024422.4 rs75494355
GATA6 Chr18:19749151 c.-530A>T NM_005257.4
GATA6 Chr18:19749272 c.-409C>G NM_005257.4
KCNH2 Chr7:150646165 c.2399-28A>G NM_000238.3
KCNQ1 Chr11:2484803 c.386+18089T>C NM_000218.2
LMNA Chr1:156100609 c.513+45T>G NM_170707.3
LMNA Chr1:156105681 c.937-11C>G NM_170707.3 rs267607645
LMNA Chr1:156107037 c.1608+14G>A NM_170707.3
LMNA Chr1:156107433 c.1609-12T>G NM_170707.3 rs267607582
NKX2-5 Chr5:172662741 NM_004387.3
NKX2-5 Chr5:172672291 c.-10205G>A .
NKX2-5 Chr5:172672303 c.-10217G>C .
PLN Chr6:118869382 c.-271A>G NM_002667.4
PLN Chr6:118869417 c.-236C>G NM_002667.4 rs188578681
RYR2 Chr1:237730106 c.3423+32dupG NM_001035.2
SCN5A Chr3:38639469 c.2024-11T>A NM_198056.2 rs777987317
SCN5A Chr3:38691021 c.-53+1G>A NM_198056.2
TBX5 Chr12:114704515 c.*88822C>A NM_000192.3 rs141875471
TGFB3 Chr14:76425035 c.*495C>T NM_003239.2 rs387906514
TGFB3 Chr14:76447266 c.-30G>A NM_003239.2 rs770828281
TRDN Chr6:123957870 c.22+29A>G NM_006073.3 rs774068079

Added and removed genes from the panel

Genes added Genes removed
LEMD2

Test Strengths

The strengths of this test include:
  • CAP and ISO-15189 accredited laboratory
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publicly available analytic validation demonstrating complete details of test performance
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test Limitations

Variants in the KCNE1 gene should not be used for risk assessment at the moment. Specifically, KCNE1 c.253G>A, p.(Asp85Asn) variant has been considered to be a mild risk factor for acquired long QT syndrome. However, in the newest version of the reference genome GRCh38, a gene KCNE1B, nearly identical to KCNE1 has appeared. By using standard NGS technologies, as well as Sanger sequencing, it is not possible to get reliable region-specific sequences for these genes. It is likely that reads that have been earlier mapped to KCNE1 actually belong to KCNE1B. Moreover, it is currently unclear whether KCNE1B produces a protein product, and if a protein is produced, whether the gene is expressed in heart. More independent data characterizing KCNE1B and its function are needed. Currently, all KCNE1 sequence data and the literature related to KCNE1 variants should be interpreted with caution. The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: PKP2 (NM_001254727:6). Genes with suboptimal coverage in our assay are marked with number sign (#) and genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. Gene is considered to have suboptimal coverage when >90% of the gene’s target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).
This test may not reliably detect the following:
  • Low level mosaicism (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics arrhythmia panel covers classical genes associated with Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac arrest underlying cardiac condition, cardiac arrest cause unspecified, syncope and collapse, abnormal ECG, Long QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Short QT syndrome. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.89% (99,153/99,266) >99.9999
Insertions, deletions and indels by sequence analysis
1-10 bps 96.9% (7,563/7,806) >99.9999
11-50 bps 99.13% (2,524/2,546) >99.9999
Copy number variants (exon level dels/dups)
1 exon level deletion (heterozygous) 100% (20/20) NA
1 exon level deletion (homozygous) 100% (5/5) NA
1 exon level deletion (het or homo) 100% (25/25) NA
2-7 exon level deletion (het or homo) 100% (44/44) NA
1-9 exon level duplication (het or homo) 75% (6/8) NA
Simulated CNV detection
5 exons level deletion/duplication 98.7% 100.00%
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 143X
Nucleotides with >20x sequencing coverage (%) 99.86%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding and regulatory variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases including, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as  SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with <20X sequencing depth if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a true positive call.
Reported heterozygous and homo/hemizygous copy number variations with a size <10 and <3 target exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen and confirmed less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references, abstracts and variant databases used to help ordering providers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. Our laboratory is therefore well-positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.

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