RhythmFirst and RhythmNext

RhythmFirstTM and RhythmNextTM are targeted panels that can be ordered individually or on a reflex basis for patients with inherited arrhythmias. Often, these can be asymptomatic and sudden death is the first and only symptom. Therefore, genetic testing may be the most effective way of identifying at-risk individuals, or confirming a diagnosis.

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RhythmFirstTM and RhythmNextTM are targeted panels that can be ordered individually or on a reflex basis for patients with inherited arrhythmias. Often, these can be asymptomatic and sudden death is the first and only symptom. Therefore, genetic testing may be the most effective way of identifying at-risk individuals, or confirming a diagnosis.

RhythmFirst is a panel including 12 genes commonly associated with long QT syndrome (LQTS), Brugada syndrome (BrS), and short QT syndrome (SQTS): AKAP9, ANK2, CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, SCN4B, SCN5A, SNTA1. These genes are implicated in over 80% of known genetic causes of LQTS and BrS, so RhythmFirst is an excellent first-tier testing option. 

RhythmNext is a panel including 36 genes associated with arrhythmogenic right ventricular dysplasia (ARVD), BrS, catecholaminergic polymorphic ventricular tachycardia (CPVT), LQTS, SQTS, other arrhythmias/channelopathies, as well as sudden cardiac arrest. Genes in RhythmNext include: AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2, CALM1, CASQ2, CAV3, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCND3, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ8, KCNQ1, LMNA, NKX2.5, PKP2, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, SNTA1, TBX5, TGFB3, TMEM43, TRDN, and TRPM4.  

Both testing options include next generation sequencing (NGS) and deletion/duplication analysis.

Inherited arrhythmias/channelopathies and clinical descriptions:

INHERITED ARRHYTHMIA CLINICAL DESCRIPTION

Arrhythmogenic
right ventricular
dysplasia (ARVD)*

Progressive fibrofatty replacement of the myocardium in the right ventricle
Brugada syndrome (BrS) Right precordial ST wave elevation on an electrocardiogram (EKG), causing potential for sudden cardiac arrest
Catecholaminergic
polymorphic
ventricular tachycardia (CPVT)
Bidirectional or polymorphic ventricular tachycardia causing syncope and sudden cardiac arrest during exercise or stress
Long QT syndrome (LQTS) Prolonged QT wave interval and T-wave abnormalities on an EKG, ventricular tachycardia, syncope
Short QT syndrome (SQTS) Extremely short QT wave interval, T-wave abnormalities, atrial fibrillation, syncope

*Also known as ARVC: Arrhythmogenic right ventricular cardiomyopathy

 

Target Populations for RhythmFirst and RhythmNext

  • Patients with a strong clinical suspicion for LQTS, based on clinical and family history and prolonged QT interval on EKG defined as QTc>480 ms (adolescents) or >500 ms (adults)*
  • Asymptomatic patients with QT prolongation in the absence of other clinical explanations*
  • Patients with a strong clinical suspicion for BrS or SQTS, based on clinical/family history and EKG pattern
  • Patients with personal or family history of unexplained sudden cardiac arrest/death, with structurally normal heart and normal physical exam/autopsy

* Recommendations from 2011 Heart Rhythm Society (HRS) and European Heart Rhythm Association (EHRA) Expert Consensus Statement

 

Genetic Testing for Long QT syndrome and Brugada syndrome 

rhythmfirst rhythmnext identification of inherited mutations in long qt and brugada syndrome

 

Disease Name 
Arrhythmogenic right ventricular dysplasia (ARVD)
Brugada syndrome (BrS)
Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Long QT syndrome (LQTS)
Short QT syndrome (SQTS)
Inherited arrhythmias/channelopathies
Sudden cardiac arrest
Testing Benefits & Indication 
  • Clarify diagnosis and risk for sudden cardiac arrest
  • Target cardiac event triggers, cardiac event incidence, and management plan to an individual’s genotype
  • Adjust management in those with LQTS due to conditions like Jervell and Lange-Nielsen and Andersen-Tawil syndromes
  • May identify the cause of a sudden unexplained death after a normal autopsy
  • Offer family members genetic testing (for a familial mutation) and implement medical surveillance to only those that need it
  • Reduce healthcare costs, resources, and anxiety for families
Test Description 

RhythmFirst includes 12 genes commonly associated with inherited arrhythmias (listed above).  RhythmNext includes 36 genes that cause LQTS, other arrhythmias, and sudden cardiac arrest (listed earlier). These genes are also included in the comprehensive cardiovascular genetics panel (CardioNext). Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized kit and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology using long biotinylated oligonucleotide probes, followed by polymerase chain reaction (PCR) and NGS. Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing  This assay targets all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. Gross deletion/duplication analysis for all genes is performed utilizing a targeted chromosomal microarray.

Mutation Detection Rate 

~70% of patients with a diagnosis of LQTS have a mutation in one of the RhythmFirst genes, which represents over 95% of known genetic causes (clinical sensitivity). 16-30% of patients with a diagnosis of BrS have a mutation in one of the RhythmFirst genes, which represents over 80% of known genetic causes (clinical sensitivity). RhythmFirst and RhythmNext will detect >99.9% of described mutations in the included genes, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
TEST CODE TECHNIQUE TURNAROUND TIME (Weeks)
8888 RhythmFirst  2-3 
8900 RhythmNext 4-5 
8901 RhythmNext Reflex (RhythmFirst with reflex to RhythmNext) 4-5 
9520 CustomNext-Cardio
Up to 106 cardiovascular genes of your choice
4-5 weeks

 

Specialty 
Genes 
LMNA
SCN5A
DSG2
DSP
DSC2
JUP
PKP2
TGFB3
TMEM43
RYR2
ANK2
CALM1
CASQ2
KCNJ2
TRDN
AKAP9
CACNA1C
CACNA2D1
CACNB2
CAV3
GPD1L
HCN4
KCND3
KCNE1
KCNE2
KCNE3
KCNH2
KCNJ8
KCNQ1
SCN1B
SCN4B
SCN3B
SNTA1
TRPM4
NKX2.5
TBX5
References 
  1. Adapted from Ackerman MJ et al. HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies. Heart Rhythm. 2011 Aug;8(8):1308-39.
  2. McNally E, MacLeod H, Dellefave-Castillo L. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. 2005 Apr 18 [Updated 2014 Jan 9]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. 
  3. Napolitano C, Priori SG, Bloise R. Catecholaminergic Polymorphic Ventricular Tachycardia. 2004 Oct 14 [Updated 2014 Mar 6]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. 
  4. Alders M, Mannens MMAM. Long QT Syndrome. 2003 Feb 20 [Updated 2012 May 31]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. 
  5. Brugada R, Campuzano O, Brugada P et al. Brugada Syndrome. 2005 Mar 31 [Updated 2014 Apr 10]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. 
  6. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.