Prospective In Vitro Models of Channelopathies and Cardiomyopathies

Table 1

HRS/EHRA Expert Consensus Statement on Genetic Testing (Heart Rhythm 2011; 8 : 1308–1339).

Cardiac Channelopathy; /Cardiomyopathy	Diagnostic implications of genetic testing	Class I	Class IIa	Class IIb	Class III	Testing genes	Common disease genes
		“is recommended”	“can be useful”	“may be considered”	“is not recommended”		Genes	% of disease
Long QT syndrome; (LQTS)	Patient in whom a cardiologist has established a strong clinical index of suspicion for LQTS	○				Comprehensive or LQT1-3
	Asymptomatic patient with QT prolongation in the absence of other clinical conditions that might prolong the QT interval on serial 12-lead ECGs defined as QTc >480 ms (prepuberty) or >500 ms (adults)	○					KCNQ1 (LQT1); KCNH2 (LQT2); SCN5A (LQT3); LQT4-13	30–35%; 25–40%; 5–10%; >5%
	Asymptomatic patient with otherwise idiopathic QTc values >460 ms (prepuberty) or >480 ms (adults) on serial 12-lead ECGs			○		Mutation-specific
	Family members and other appropriate relatives subsequently following the identification of the LQTS-causative mutation in an index case	○
Catecholaminergic polymorphic ventricular tachycardia (CPVT)	Patient in whom a cardiologist has established a clinical index of suspicion for CPVT	○				Comprehensive or CPVT1 and CPVT2	RYR2 (CPVT1)	60%
	Family members and appropriate relatives following identification of the CPVT-causative mutation in an index case	○				Mutation-specific	CASQ2 (CPVT2)	3–5%
Brugada syndrome (BrS)	Family members and appropriate relatives following identification of the BrS-causative mutation in an index case	○				Mutation-specific	SCN5A (BrS1)	20–30%
	Patient in whom a cardiologist has established a clinical index of suspicion for BrS		○			Comprehensive or SCN5A
	The setting of an isolated type2 or type3 Brugada ECG pattern				○	—
Progressive cardiac conduction disorders (CCD)	Family members and appropriate relatives following the identification of the CCD-causative mutation in an index case	○				Mutation-specific	SCN5A	5%
	Patients with either isolated CCD or CCD with concomitant congenital heart disease, especially when there is documentation of a positive family history of CCD			○		SCN5A and TRPM4
Short QT syndrome (SQTS)	Family members and appropriate relatives following the identification of the SQTS-causative mutation in an index case	○				Mutation-specific
							KCNH2 (SQT1); KCNQ1 (SQT2); KCNJ2 (SQT3)	>5%; >5%; >5%
	Patient in whom a cardiologist has established a strong clinical index of suspicion for SQTS based on examination of the patient's clinical history, family history, and electrocardiographic phenotype			○		Comprehensive or SQT1-3
Atrial fibrillation (AF)	Genetic testing is not indicated for atrial fibrillation at this time.				○	—	None of the known
							disease-associated
							genes has been
							shown to account
							for >5% of this disease.
Hypertrophic cardiomyopathy (HCM)	Patient in whom a cardiologist has established a clinical diagnosis of HCM	○				Comprehensive or targeted (MYBPC3, MYH7, TNNI3, TNNT2, and TPM1)	MYBPC3; MYH7; TNNT2; TNNI3; TPM1	20–45%; 15–20%; 1–7%; 1–7%; >5%
	Family members and appropriate relatives following identification of the HCM-causative mutation in an index case	○				Mutation-specific
Arrhythmogenic cardiomyopathy (ACM)/Arrhythmogenic right ventricular cardiomyopathy (ARVC)	Family members and appropriate relatives following identification of the ACM/ARVC-causative mutation in an index case	○				Mutation-specific	PKP2; DSG2; DSP; DSC2; TMEM43	25–40%; 5–10%; 2–12%; 2–7%; >5%
	Patients satisfying task force diagnostic criteria for ACM/ARVC		○			Comprehensive or targeted (DSC2, DSG2, DSP, JUP, PKP2, and TMEM43)
	Patients with possible ACM/ARVC (1 major or 2 minor criteria) according to the 2010 task force criteria (European Heart Journal)			○
	Patients with only a single minor criterion according to the 2010 task force criteria				○	—
Dilated cardiomyopathy (DCM)	Patients with DCM and significant cardiac conduction disease (i.e., first-, second-, or third-degree heart block) and/or a family history of premature unexpected sudden death	○
	Family members and appropriate relatives following the identification of a DCM-causative mutation in the index case	○				Comprehensive or targeted (LMNA and SCN5A)	LMNA; SCN5A	>5%; >5%
	Patients with familial DCM to confirm the diagnosis, to recognize those who are at highest risk of arrhythmia and syndromic		○			Mutation-specific
	features, to facilitate cascade screening within the family, and to help with family planning					Mutation-specific
Left ventricular noncompaction (LVNC)	Family members and appropriate relatives following the identification of an LVNC-causative mutation in the index case	○				Mutation-specific; LBD3, and so forth	LBD3	~5%
	Patients in whom a cardiologist has established a clinical diagnosis of LVNC		○
Restrictive cardiomyopathy (RCM)	Family members and appropriate relatives following the identification of an RCM—causative mutation in the index case	○				Mutation-specific	β-MHC	~5%
	Patients in whom a cardiologist has established a clinical index of suspicion for RCM			○		MYH7, TNNI3, TNNT2	TNNI3	~5%
Out-of-hospital cardiac arrest survivors	The survivor of an Unexplained Out-of-Hospital Cardiac Arrest	○				Appropriate genes following diagnosis of the survivor; —	RYR2; KCNQ1; KCNH2	10–15%; 5–10%; ~5%
	Routine genetic testing, in the absence of a clinical index of suspicion for a specific cardiomyopathy or channelopathy				○
Postmortem genetic; testing in sudden death cases (SUD/SIDS)	For all SUDS and SIDS cases, collection of a tissue sample	○
	In the setting of autopsy negative SUDS			○		comprehensive or targeted (RYR2, KCNQ1, KCNH2, and SCN5A); Mutation-specific	RYR2; KCNQ1; KCNH2; SCN5A	SCN5A: 3–5%
	Family members and other appropriate relatives following identification of a SUDS-causative mutation in the decedent	○

HRS: the Heart Rhythm Society, EHRA: European Heart Rhythm Association. We summarized their tables with permission.