Arrhythmia Panel

Last modified: Jun 12, 2018

Summary

  • Is a 57 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
  • SEQ
  • DEL/DUP

Availability

3-4 weeks

Number of genes

57

Test code

CA1601

CPT codes

SEQ 81413
DEL/DUP 81414

Summary

The Blueprint Genetics Arrhythmia Panel (test code CA1601):

  • Is a 57 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

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
I45.81 Long QT syndrome
I42.8 Arrhythmogenic right ventricular cardiomyopathy (ARVC)
I49.9 Short QT syndrome

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

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.

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 25 40
AKAP9 Long QT syndrome AD 4 33
ANK2 Cardiac arrhythmia, Long QT syndrome AD 7 70
BAG3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 36 60
CACNA1C* Brugada syndrome, Timothy syndrome AD 20 62
CACNB2 Brugada syndrome AD 3 22
CALM1* Ventricular tachycardia, catecholaminergic polymorphic, Recurrent cardiac arrest, infantile, Long QT syndrome AD 9 10
CALM2 Long QT syndrome AD 7 10
CALM3 Catecholaminergic polymorphic ventricular tachycardia AD/AR 4 4
CASQ2 Ventricular tachycardia, catecholaminergic, polymorphic AR 24 33
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/Digenic 21 49
CDH2 Arrhythmogenic right ventricular cardiomyopathy (ARVC) AD 5
CTNNA3 Arrhythmogenic right ventricular dysplasia AD 6 41
DBH Dopamine beta-hydroxylase deficiency AR 10 13
DES Dilated cardiomyopathy (DCM), Myopathy, myofibrillar, Scapuloperoneal syndrome, neurogenic, Kaeser type AD/AR 61 117
DSC2 Arrhythmogenic right ventricular dysplasia with palmoplantar keratoderma and woolly hair, Arrhythmogenic right ventricular dysplasia AD/AR 25 85
DSG2 Arrhythmogenic right ventricular dysplasia, Dilated cardiomyopathy (DCM) AD 40 125
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 155 281
FLNC* Myopathy AD 29 101
GATA6 Heart defects, congenital, and other congenital anomalies, Atrial septal defect 9, atrioventricular septal defect 5, Persistent truncus arteriosus, Tetralogy of Fallot AD 16 79
HADHA Trifunctional protein deficiency, Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency AR 50 70
HCN4 Sick sinus syndrome, Brugada syndrome AD 9 28
JUP Arrhythmogenic right ventricular dysplasia, Naxos disease AD/AR 8 43
KCNA5 Atrial fibrillation AD 4 23
KCNE1 Long QT syndrome, Jervell and Lange-Nielsen syndrome AD/AR/Digenic 7 45
KCNE2 Long QT syndrome, Atrial fibrillation, familial AD 6 23
KCNH2 Short QT syndrome, Long QT syndrome AD 346 925
KCNJ2 Short QT syndrome, Andersen syndrome, Long QT syndrome, Atrial fibrillation AD 41 87
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 285 604
LDB3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 9 14
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 231 553
MYH6 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM), Atrial septal defect 3 AD 13 114
MYH7 Hypertrophic cardiomyopathy (HCM), Myopathy, myosin storage, Myopathy, distal, Dilated cardiomyopathy (DCM) AD 285 950
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 43 102
NOS1AP Romano-Ward syndrome AD/AR 4
NUP155 Atrial fibrillation 15 AR 2 1
PKP2* Arrhythmogenic right ventricular dysplasia AD 141 275
PLN Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD/AR 8 29
PPA2 Sudden cardiac failure, infantile AR 8 8
RYR2 Ventricular tachycardia, catecholaminergic polymorphic, Arrhythmogenic right ventricular dysplasia AD 113 353
SALL4 Acro-renal-ocular syndrome, Duane-radial ray/Okohiro syndrome AD 19 55
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 15 29
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 225 829
SCN10A Paroxysmal extreme pain disorder, Channelopathy-associated congenital insensitivity to pain, Primary erythermalgia, Sodium channelopathy-related small fiber neuropathy, Brugada syndrome AD/AR 1 70
TBX5 Holt-Oram syndrome AD 55 126
TECRL Ventricular tachycardia, catecholaminergic polymorphic, 3 AR 2 2
TGFB3 Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasia AD 17 22
TMEM43 Arrhythmogenic right ventricular dysplasia, Emery-Dreifuss muscular dystrophy AD 5 24
TNNI3 Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM) AD/AR 54 127
TNNI3K Cardiac conduction disease with or without dilated cardiomyopathy AD 1 2
TNNT2 Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM) AD 57 140
TRDN Ventricular tachycardia, catecholaminergic polymorphic AR 10 6
TRPM4 Progressive familial heart block AD 5 29
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 725 304

* 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 the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
DSC2 Chr18:28683379 c.-1445G>C NM_024422.4 rs75494355
GATA6 Chr18:19749272 c.-409C>G NM_005257.4
GATA6 Chr18:19749151 c.-530A>T NM_005257.4
KCNE2 Chr21:35736455 c.-13+5G>A NM_172201.1 rs786205806
KCNH2 Chr7:150646165 c.2399-28A>G NM_000238.3
LMNA Chr1:156107037 c.1608+14G>A NM_170707.3
LMNA Chr1:156107433 c.1609-12T>G NM_170707.3 rs267607582
LMNA Chr1:156100609 c.513+45T>G NM_170707.3
LMNA Chr1:156105681 c.937-11C>G NM_170707.3 rs267607645
NKX2-5 Chr5:172672291 c.-10205G>A .
NKX2-5 Chr5:172672303 c.-10217G>C .
PLN Chr6:118869417 c.-236C>G NM_002667.4 rs188578681
PLN Chr6:118869382 c.-271A>G NM_002667.4
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
ABCC9
BAG3
CDH2
FLNC
HADHA
MYH7
MYL4
NUP155
PPA2
SALL4
TECRL
TNNI3K
ABCB4
CACNA2D4
GJA5
KCND3
KCNE3

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • 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 publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG 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

The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: *PPA2* (11, 12). 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. 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
  • 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 Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

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 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 such as, 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, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to 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 of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen 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 used, congress abstracts and mutation databases to help our customers 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 within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. 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.