Table 2:

Current Recommendations and Clinical Utility of Commercially-Available Genetic Tests for Commonly Encountered Heritable Cardiac Channelopathies and Familial Hypercholesterolemia

Class	Disorder	Genes	Clinical Impact	Society Recommendationsb	Ref.
Channelopathies	BrS	Major: SCN5A(BrS1)c Minor: ABCC9, CACNA1Cc, CACNA2D1, CACNB2, FGF12, GPD1L, HCN4, KCND2, KCND3, KCNE3, KCNE5, KCNJ8, PKP2 MOG1, SCN1B, SCN2B, SCN3B, SCN10A, SLMAP, SEMA3A, and TRPM4	Diagnosis Risk-stratification	HRS/ERHA guidelines: 1) Mutation-specific cascade screening recommended (class I). 2) Genetic testing can be useful when there is clinical suspicion (class IIa).d	6
	CPVTe	Major: RYR2(CPVT1)c and CASQ2 (CPVT2)c Minor: CALM1, CALM2, CALM3, KCNJ2, and TRDN	Diagnosis Risk-stratification	HRS/EHRA guidelines: 1) Genetic testing recommended when there is clinical suspicion (class I). 2) Mutation-specific cascade screening recommended (class I).	6
	LQTSe	Major: KCNQ1(LQT1)c, KNCH2(LQT2)c, and SCN5A (LQT3)c Minor: AKAP9, ANKB, CACNA1C, CALM1, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1 and TRDN	Diagnosis Risk-stratification Management	HRS/EHRA guidelines: 1)Genetic testingrecommended when there is either clinical suspicion or in asymptomatic patients with unexplained QT prolongation (QTc > 480 ms pre-puberty or QTc > 500 ms post-puberty, class I). 2) Mutation-specific cascade screening recommended (class I). 3) Genetic testing may be considered in asymptomatic patients with otherwise unexplained QT prolongation (QTc > 460 ms pre-puberty or QTc >480 ms post-puberty, class IIb)d	6
Familial Hypercholesterole mia	FHe	Major: LDLRc, APOBc, and PCSK9c Minor: APOE, LDLRAPc, and STAP1	Diagnosis Risk-stratification	AHA, EAS, and NLA statements/guidelines: 1) Genetic testing strongly recommended for individuals with a definite or probable diagnosis of FH based on validated clinical scorecards (DLCN, Simon-Broome, etc.). 2) Mutation-specific cascade screening provides a diagnostic gold-standard in families with an identified disease-causative mutation(s).	8,47, 48

^aAHA = American Heart Association; BrS = Brugada syndrome; CPVT = catecholaminergic polymorphic ventricular tachycardia; DLCN = Dutch Lipid Clinic Network; EAS = European Atherosclerosis Society; EHRA = European Heart Rhythm Association; FH = familial hypercholesterolemia; HRS = Heart Rhythm Society; LQTS = long QT syndrome; and NLA = National Lipid Association.

^bClass of evidence indicated when available.

^cDenotes commonly encountered genes with strong evidence that disease-causative mutations within these genes contribute directly to disease pathogenesis.

^dUse of large gene panels in weak/borderline clinical cases substantially increases the risk of encountering a non-diagnostic VUS.

^eDenotes the most clinically useful monogenic cardiovascular genetic tests.