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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 |
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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 | ○ | | | |
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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% |
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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 | | | | ○ | — |
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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 |
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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%
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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 |
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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. |
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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%
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Family members and appropriate relatives following identification of the HCM-causative mutation in an index case | ○ | | | | Mutation-specific |
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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%
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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 | | | | ○ | — |
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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%
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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 | | |
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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 | | ○ | | |
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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% |
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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%
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Routine genetic testing, in the absence of a clinical index of suspicion for a specific cardiomyopathy or channelopathy | | | | ○ |
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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 | ○ | | | | | | |
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