Comprehensive Cardiac Arrhythmia Panel

Cardiac arrhythmia is a group of conditions in which the heartbeat is irregular, too fast, or too slow. Some arrhythmia disorders are inherited, including Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Brugada syndrome, Long QT syndrome, and Short QT syndrome.

Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) primarily affects the right ventricle. It is characterized by myocardial atrophy, fibrofatty replacement of the ventricular myocardium and inflammatory infiltrates (McNally et al. 2014). With disease progression and occasional left ventricle involvement, heart failure may result. ARVC/D is present in ~20% of young sudden cardiac death victims (Corrado et al. 1998). ARVC/D affects between 1/1000 and 1/5000 people worldwide with a higher prevalence in men compared to women (Corrado and Thiene 2006).

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by life-threatening electrical instability induced by physical or emotional stress without any structural cardiac abnormalities (Napolitano et al. 2014). The electrical instability may degenerate into cardiac arrest and sudden death. CPVT typically onsets during childhood and often presents as syncope.

Long QT syndrome (LQTS) is a heritable channelopathy characterized by a prolonged cardiac repolarization that may trigger ventricular arrhythmias (torsade de pointes), recurrent syncopes, seizure, or sudden cardiac death (Cerrone et al. 2012). LQTS can manifest with syncope, and cardiac arrest that is commonly triggered by adrenergic stress, often precipitated by emotion or exercise. Roughly 10% to 15% of patients experience symptoms at rest or during the night (Schwartz et al. 2001).

Brugada syndrome (BrS) is a potentially life-threating arrhythmia disorder without structural abnormalities, characterized by dizziness, syncope, nocturnal agonal respiration and sudden death. The classic electrocardiographic findings associated with BrS include ST segment elevation in leads V1 to V3, right bundle branch block, first degree AV block, and intraventricular conduction delay. BrS is much more common in men than in women, and many people who have BrS are asymptomatic.

Short QT Syndrome (SQTS) is an inherited arrhythmia disorder which affects the movement of ions through channels within the cell membrane and is associated with marked shortening of QT intervals and sudden cardiac death in individuals with structurally normal hearts. Typical electrocardiogram (ECG) findings associated with SQTS include an abnormally short QT interval (usually <360 msec with a range of 220 to 360 msec), absence of the ST segment, and tall and peaked T waves in the precordial leads. The clinical presentation of SQTS is variable, and many patients are asymptomatic. Most patients present with one or more of the following symptoms: SCD, palpitations, syncope, and atrial fibrillation (Patel et al. 2010).

Cardiac arrhythmia disorder is a heterogeneous disease usually inherited in an autosomal dominant (AD), but occasionally in an autosomal recessive (AR) manner with age- and gender-dependent penetrance. Most of the genes involved encode subunits of ion channels (sodium, potassium calcium channels) or the proteins that regulate them in cardiac contraction unit or conduction system. A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported. Large deletions/duplications and complex genomic rearrangements have also been reported in a few genes (CACNA2D1, CACNB2, CAV, DES, DSP, GJA5, GPD1L, KCNA5, KCNH2, KCNJ2, KCNQ1, NKX2-5, PKP2, RYR2 and SCN5A) (Human Gene Mutation Database). See individual gene test descriptions for more information on molecular biology of gene products.

The following Table indicates chromosome location and mode of inheritance by gene.

*Limited cases

It is estimated that use of this NGS panel will allow detection of a pathogenic variant in: ~73% of patients with autosomal dominant or sporadic Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (McNally et al. 2014; Bhuiyan et al. 2009), ~52%-60% of Catecholaminergic Polymorphic Ventricular Tachycardia cases (Napolitano et al. 2014), ~ 80% of patients with Long QT syndrome (Splawski et al. 2000; Taggart et al 2007; Ackerman et al. 2011); 20%-35% of Brugada syndrome cases (Kapplinger et al 2010; Crotti et al. 2012); and 15%-20% of Short QT Syndrome cases (Schimpf et al. 2008).

Gross deletions or duplications not detectable by Sanger sequencing have been reported in CACNA2D1, CACNB2, CAV3, DES, DSP, GJA5, GPD1L, KCNA5, KCNH2, KCNJ2, KCNQ1, NKX2-5, PKP2, RYR2 and SCN5A as individual cases (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.4% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).