GeneSeq®: Cardio Familial Arrhythmia Profile

CPT: 81413
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Test Details

Test Includes

This test covers all coding nucleotides of 29 genes: ANK2, ATP1B1, CACNA1C, CACNB2, CASQ2, CAV3, DSC2, DSG2, DSP, GINS3, GPD1L,JUP, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, LIG3, NOS1AP, NPPA, PKP2, PLN, RYR2, SCN1B, SCN4B, SCN5A, SNTA1, TGFB3, and TMEM43; exon 18 of AKAP9; plus at least two and typically 10 flanking intronic nucleotides upstream and downstream of each coding exon, covering the conserved donor and acceptor splice sites, as well as typically 10 flanking nucleotides in the 5′ and 3′ UTR.

Use

Confirm a clinical diagnosis of Arrhythmia and identify presymptomatic family members, guiding prophylactic measures.

Limitations

This analysis does not rule out germline mosaicism, the presence of large chromosomal aberrations (including deletions, insertions, and rearrangements), mutations in regions or genes not included in this test, and possible inter/intragenic interactions between sequence variants. False-positive or false-negative results may occur for reasons that include genetic variants, blood transfusions, bone marrow transplantation, mislabeled specimens, or erroneous representation of family relationships.

Methodology

Select XT® enrichment method and the Illumina® next-generation sequencing platform. Regions of the interest include all exons and splice junctions for each gene and limited regions for the following: SHOC2 (exon 2), APOB (556bp of exon 26), and AKAP9 (exon 18). Sequencing reads are aligned with the hg19 build of the human genome reference sequence. Analytical sensitivity is based on the depth of coverage across the regions of the interest and is provided separately for each gene. Greater than 98% of target bases are synonymous variants not previously recorded at greater than or equal to 20x coverage. Sanger sequencing is used to confirm mutation identity and analyze regions with low coverage. Variants are reported using numbering and nomenclature recommended by the Human Genome Variation Society (HGVS). Variants known to be benign and synonymous variants not previously recorded in our internal variant data bases are not reported.

Additional Information

Cardiac arrhythmias are generally characterized by abnormal electrical activity in the heart that puts patients at high risk for embolic stroke and/or sudden cardiac death (SCD). Commonly recognized arrhythmic disorders include atrial fibrillation (AF), long QT syndrome(LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), and Brugada syndrome (BrS).

Genetic testing for mutations in genes known to be associated with LQTS, CPVT, ARVD/C, AF, and BrS can be used in conjunction with standard cardiac testing to help:

• Confirm a diagnosis.

• Differentiate between arrhythmic disorders.

• Clarify the prognosis, alerting patients and physicians to the most common arrhythmia triggers, which may be specific to the underlying genetic cause.

• Guide therapeutic strategies.

• Identify family members who are at increased risk for arrhythmic disorder and may benefit from cardiac screening.

An estimated 30% to 50% of arrhythmia cases are familial. Mutations responsible for arrhythmias are typically acquired in an autosomal-dominant manner. Carrier screening for mutations in at-risk family members may help identify individuals - particularly those who do not have clinical signs or symptoms of disease - who would benefit from early intervention to reduce the risk of cardiac events.

Specimen Requirements

Specimen

Whole blood

Volume

10 mL whole blood or 30 mL if ordering multiple tests

Container

Yellow-top (ACD) tube or lavender-top (EDTA) tube

Storage Instructions

Maintain specimen at room temperature.

Causes for Rejection

Frozen specimen; container broken or leaking; container not labeled or label not legible; improper anticoagulant

Clinical Information

Special Instructions

Test orders must include an attestation that the provider has the patient's informed consent for genetic testing. See sample physician office consent form: Consent for Genetic Testing. Please call customer service at 866-647-0735 before submitting specimens for family testing (ie, known mutations).

References

Ackerman MJ, Priori SG, Willems S, 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) Heart Rhythm. 2011;8(8):1308-1339.21787999
Darbar D, Herron KJ, Ballew JD, et al. Familial atrial fibrillation is a genetically heterogeneous disorder. J Am Coll Cardiol. 2003 Jun 18; 41(12):2185-2192.12821245
Fox CS, Parise H, D'Agostino RB Sr, et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004 Jun 16; 291(23): 2851-2855.15199036
Hamid MS, Norman M, Quraishi A, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol. 2002 Oct 16; 40(8):1445-1450.12392835
Napolitano C, Priori SG, Bloise R. Catecholaminergic polymorphic ventricular tachycardia. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1289/. Accessed December 16, 2011.
Pérez MV, Wheeler M, Ho M, Pavlovic A, Wang P, Ashley EA. Genetics of arrhythmia: disease pathways beyond ion channels. J Cardiovasc Transl Res. 2008 Jun; 1(2):155-165.20559910
Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: the Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2015;36:2793-2867.26320108
Roberts R. Mechanisms of disease: Genetic mechanisms of atrial fibrillation. Nat Clin Pract Cardiovasc Med. 2006; 3:276-282.16645668
Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol. 2006 Feb 21; 47(4):764-768.16487842
Tzou WS, Gerstenfeld EP. Genetic testing in the management of inherited arrhythmia syndromes. Curr Cardiol Rep. 2009; 11:343-351.19709494
Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006 Sep 5; 114(10):e385-e484.16935995

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
451412 GeneSeq: Familial Arrhythmia 451331 Specimen Type: 31208-2
451412 GeneSeq: Familial Arrhythmia 451424 Results: 48003-8
451412 GeneSeq: Familial Arrhythmia 451323 Key Findings 53037-8
451412 GeneSeq: Familial Arrhythmia 451322 Additional Information 49549-9
451412 GeneSeq: Familial Arrhythmia 451321 Gene Information 51968-6
451412 GeneSeq: Familial Arrhythmia 451320 Tech Spec Results 51958-7
451412 GeneSeq: Familial Arrhythmia 451387 Seq Variants Detected 69548-6
451412 GeneSeq: Familial Arrhythmia 451409 Disclaimer N/A
451412 GeneSeq: Familial Arrhythmia 451389 Director Review: 48672-0
451412 GeneSeq: Familial Arrhythmia 451428 PDF 51969-4
451412 GeneSeq: Familial Arrhythmia 451425 GenSeq: Familial Arrhythmia N/A

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