Comprehensive Cardiology Panel

Heart disease is a phenotypically and genetically heterogeneous group of diseases which impair the function and structure of the heart and are the leading cause of death worldwide (Roger et al. 2012). Genetic factors play a role in conferring risk for heart disease. The contribution of inheritance varies by disease and by other factors such as subtype of disease and onset age. Heart disease encompasses a broad range of disorders, such as Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, Brugada syndrome, Long QT syndrome, Short QT syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia and Left Ventricular Non-Compaction Cardiomyopathy.

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).

Brugada syndrome (BrS) is a potentially life-threating arrhythmia disorder without structural abnormalities and electrocardiographically characterized by a distinct ST-segment elevation in the right precordial leads (Antzelevitch et al. 2005).

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).

Long QT syndrome (LQTS) is characterized by a prolonged cardiac repolarization that may trigger ventricular arrhythmias (torsade de pointes), recurrent syncopes, seizure, or sudden cardiac death (Alders and Christiaans 2015).

Short QT syndrome (SQTS) is associated with marked shortening of QT intervals and sudden cardiac death in individuals with structurally normal hearts (Miyamoto A. et al. 2012).

Left Ventricular Noncompaction (LVNC) Cardiomyopathy is believed to be caused by an arrest in cardiac development during embryogenesis, resulting in a spongy, noncompacted appearance. The numerous trabeculations are most pronounced in the left ventricle (Oechslin et al. 2011; Hoedemaekers et al. 2010).

Dilated Cardiomyopathy (DCM) is a heterogeneous disease of the cardiac muscle characterized by dilatation of the left, right, or both ventricles, systolic dysfunction, and diminished myocardial contractility (Hershberger et al. 2013).

Hypertrophic Cardiomyopathy (HCM) is a primary disease of the cardiac muscle characterized by idiopathic hypertrophy of the left ventricle, although hypertrophy of the right ventricle may also occur. HCM is distinguished by extensive clinical variability between individuals, even within the same family (Cirino et al. 2014)

Inherited heart diseases are a group of genetically heterogeneous disorders with a relatively high population frequency, and substantial genetic component. Familial inheritance is common and can be autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL). The major of cardiac-related genes are associated with autosomal dominant disorders. The ABCG5, ABCG8, ALMS1, APOC2, CASQ2, CBS, COX15, DNAJC19, DOLK, EFEMP2, FKRP, FKTN, GAA, GATAD1, GPIHBP1, HADHA, HFE, LAMA2, LDLRAP1, LMF1, LTBP2, SCO2, SGCG, SLC2A10, TRDN and APOE* are associated with autosomal recessive cardiac-related disorders. The DSC2, DSP, ACTA1, JUP, KCNE1, KCNQ1, LMNA, LPL, NPPA, RYR1, SCN5A, SELENON (previously SEPN1), SLC25A4, TNNI3, TTN and APOA4* genes are associated with autosomal dominant and recessive cardiac-related disorders. The FHL1, GLA, LAMP2, DMD, EMD, TAZ and ZIC3 genes are associated with X-linked recessive cardiac-related disorders, except for LAMP2, which is involved in X-linked dominant cardiac-related disorders (OMIM; Human Gene Mutation Database, *limited cases). See individual gene test descriptions for information on molecular biology of gene products.

The sensitivity of this panel varies based on the type of disease. This test is predicted to detect causative variants in ~60% of Hypertrophic Cardiomyopathy patients (Morita et al. 2008; Hershberger et al. 2009), up to 20-30% of adults with Left Ventricular Noncompaction (Ichida et al 2001; Vatta et al. 2003; Hermida-Prieto et al. 2004; Klaassen et al. 2008; Hoedemaekers et al. 2010), 30-40% of patients with familial Dilated Cardiomyopathy (Hershberger and Morales 2013), ~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 98.9% 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).