RhythmFirst / RhythmNext

RhythmFirst:
Long QT syndrome, Brugada syndrome, and short QT syndrome are inherited arrhythmias that are often asymptomatic and can lead to sudden cardiac death. RhythmFirst is a 12 gene panel that analyzes genes most commonly associated with these inherited arrhythmias. The test can be an effective way to confirm an arrhythmia disorder and direct medical management and treatment decisions.

RhythmNext:
Inherited arrhythmias such as ARVD, BrS, CPVT, LQTS, and SQTS can often lead to sudden cardiac death. RhythmNext, a 36-gene panel analyzes genes associated with these arrhythmias and can be an effective way of confirming a diagnosis. At-risk individuals in the family are identified, providing vital information for management and intervention options for both the patient and their family.

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Quick Reference
Test Code: 8888 Test Name: RhythmFirst TAT 14-21 days Genes: 12
Test Code: 8900 Test Name: RhythmNext TAT 4-5 weeks Genes: 36
Test Code: 8901 Test Name: RhythmNext reflex TAT 4-5 weeks Genes: 36

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Why Is This Important?

Knowing if your patient has a hereditary cardiovascular disorder can help you determine their future cardiovascular disease risks and guide your medical management recommendations. Key benefits include:

  1. Clarify diagnosis and risk for sudden cardiac arrest
  2. Target cardiac event triggers, cardiac event incidence, and management plan to an individual’s genotype
  3. Adjust management in those with LQTS due to conditions like Jervell and Lange-Nielsen and Andersen-Tawil syndromes
  4. May identify the cause of a sudden unexplained death after a normal autopsy
  5. Offer family members genetic testing (for a familial mutation) and implement medical surveillance to only those that need it
  6. Reduce healthcare costs, resources, and anxiety for families

When To Consider Testing

  • Patient has 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)*
  • Patient is asymptomatic with QT prolongation in the absence of other clinical explanations*
  • Patient has a strong clinical suspicion for BrS or SQTS, based on clinical/family history and EKG patter
  • Patient has a 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

Mutation Distribution and Detection Rates

~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).

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.1 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.

 

1. 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.

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