Clarence Khoo, MD, FRCPC, Shubhayan Sanatani, MD, FRCPC, Laura Arbour, MD, FRCPC, Andrew Krahn, MD, FRCPC
The family members of a victim of sudden cardiac death (SCD) are being evaluated for their risk of an inherited arrhythmia. The proband was a 16-year-old girl who was found dead in her bed by her family one morning. She had returned home late from a party the night before. Following a negative autopsy, the immediate suspicion was that illicit substances were involved in her death, although the toxicology screen was subsequently negative. The family thus sought further medical evaluation after concerns were raised that an inherited cause may have contributed.
There was no history of syncope or other illness in the proband. She had been otherwise well up to the time of her demise. Her only medication was an over-the-counter antihistamine.
The family history was significant for multiple incidents of SCD. Her mother had experienced a previous syncopal episode and had four siblings who suffered SCD between the ages of 20 and 40 years. The proband’s maternal grandmother had also died shortly after the birth of her youngest child. ECGs from the proband’s mother and older sister demonstrated a prolonged corrected QT interval (Figure 51-1).
FIGURE 51-1 Twelve-lead electrocardiogram from a relative of the proband demonstrating prolongation of the QT interval at baseline.
• Up to 30% of cases of sudden death in young individuals have no identifiable etiology for death at autopsy, thus raising the possibility of a primary arrhythmic disorder.1
• The acquisition and retention of tissue samples from the deceased in such cases may help in identifying mutations responsible for an inherited channelopathy.
• At present, genetic testing can identify known pathogenic mutations associated with channelopathies such as long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and certain cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy (HCM).
• If a causal mutation is identified, all first-degree relatives should be tested.
The finding of the same mutation in a relative along with clinical testing for the relevant clinical condition to establish the severity of the phenotype to conduct risk stratification should be followed by appropriate interventions when necessary.
Mutation carriers without an expressed phenotype may be observed on a q 1 to 3 year basis for development of phenotypic changes requiring intervention. Relatively benign interventions such as lifestyle modification, avoidance of arrhythmia-provoking drugs (in the case of LQTS and Brugada syndrome), or the use of certain pharmacologic therapies (ie, β-blockers) may be employed in specific situations.2
Relatives without the causal mutation require no further evaluation.
• If no causal mutation is identified in the proband, then the role of further genetic testing in first-degree relatives is limited.
The lack of a causal mutation in the proband does not mean that an inherited etiology for SCD is absent, as genetic testing cannot identify all possible pathogenic mutations.
If an inherited channelopathy or cardiomyopathy is still suspected, then follow-up of relatives on a regular basis should be performed to detect for the development of an overt phenotype. The interval between assessments is unknown, but likely every 3 to 5 years unless there is rapid development at the adolescent stage.
DIAGNOSIS AND MANAGEMENT
• Suspicion of LQTS was raised based on the strong family history of SCD and the ECG findings from the decedent’s relatives. The family members were counselled with regards to genetic testing and were agreeable to proceed.
• Genetic testing performed from blood collected from the mother identified a pathogenic nonsense mutation in the KCNH2 gene (c. 1184C>T; p.Gln391X).
• Splenic tissue had been frozen following the autopsy, and DNA was isolated. The same mutation found in the family was identified in the decedent, suggesting it contributed to her sudden death.
• A pedigree of affected members is depicted in Figure 51-2.
FIGURE 51-2 Pedigree constructed from detailed family history taken from relatives of the proband. Results of genetic screening for mutation in KCNH2 causing phenotypic long QT syndrome are also depicted on the pedigree.
GENETIC TESTING IN THE SETTING OF SUDDEN UNEXPLAINED DEATH CASES
• Genetic testing for an inherited arrhythmic cause of death may be considered in autopsy-negative individuals who experience sudden death, especially if the circumstances are suggestive of primary arrhythmic conditions, for example, exercise induced, auditory stimuli, nocturnal death (particularly in Asian men) (Table 51-1), and if family members have evidence of a clinical phenotype.3
TABLE 51-1 Specific Circumstances Surrounding the Time of Death of the Decedent May Point to Certain Inheritable Arrhythmic Diagnoses
• In cases of unexplained SCD, tissue from the decedent should be obtained and stored using “DNA-friendly” preservation methods where possible.
• EDTA-preserved blood, fresh frozen tissue, and dried (Guthrie) blood spot cards, allow for the most ideal degree of DNA preservation for further analysis. However, the majority of specimens are currently archived as formalin-fixed tissue embedded in paraffin. Although extraction of DNA is still feasible from paraffin-embedded specimens, the yield of vital segments of DNA may be reduced by at least a third, thus hampering genetic analysis.1 Extraction from formalin fixed tissue is typically unsuccessful.
• Up to 35% of cases of sudden death may have an underlying arrhythmic etiology.4 This extends to suspect causes of death, including drownings and single-vehicle accidents.
• Genetic testing in family members should be reserved to cases where a pathogenic mutation is established in the decedent or a phenotype has been recognized in the relative, as in the described case scenario.
THE ROLE OF GENETIC TESTING OF HERITABLE ARRHYTHMIAS
• As the diagnostic yield of genetic testing for any condition is suboptimal, a negative test does not exclude the diagnosis of an inheritable arrhythmia.
• In most cases, the primary role of genetic testing is in screening family members for subclinical disease. However, in specific situations, genetic testing may also aid in diagnosis of equivocal cases by providing extra evidence for a disease process (Table 51-2).
TABLE 51-2 Summary of the Role of Genetic Testing of Inheritable Arrhythmias
• Genetic testing for a specific condition should be reserved for individuals with a reasonable clinical suspicion for that condition to minimize the risk of false-positives.
• Family screening of all first-degree relatives should be offered if a causative mutation is identified in the index case.
• The finding of a potentially disease-causing mutation in an otherwise asymptomatic family member may prompt initiation of preventative measures including avoidance of triggers or the use of pharmacologic therapy (ie, β-blockers in LQTS or CPVT).
• Due to the numerous subtleties in ordering and interpreting the results of genetic tests, this should be reserved for physician experts and specialized inherited arrhythmia clinics. Genetic counselling is imperative prior to the consideration of any genetic testing because of personal, employment, and insurance implications.
Long QT Syndrome (LQTS)
• LQTS is usually inherited in an autosomal-dominant pattern (Romano-Ward syndrome) but in rare cases may be autosomal-recessive (Jervell and Lange-Nielsen syndrome). Spontaneous de novo mutations leading to LQTS may account for <10% of cases.5
• While mutations in ≥13 genetic loci have been attributed to LQTS, the majority result from mutations in the slow delayed rectifier potassium current (KCNQ1; LQT1), the rapid delayed rectifier potassium current (KCNH2; LQT2), or the inward sodium current (SCN5A; LQT3).
• Genetic testing should be performed in all patients with a confirmed diagnosis of LQTS to allow appropriate risk stratification and gene-specific therapies. There is evidence for mutation-specific therapeutic and prognostic implications; mutation details predict response to β-blockade and may influence exercise recommendations.
• Genetic testing is also recommended for asymptomatic adult patients with prolongation of the QTc (in the absence of secondary causes) >500 ms and may be considered if >480 ms. In prepubescent patients, cut-offs of >460 to 480 ms are suggested.5
• As QT-prolonging medications may unmask latent LQTS, patients with drug-induced torsades de pointes (TdP) may be considered for genetic testing as well.
• Diagnostic yield of genetic testing for LQTS may be improved to 70% to 80% by reserving genetic testing for only those with a high clinical suspicion for LQTS.6
• Among patients with clinically definite LQTS, 75% to 80% will have mutations in genes responsible for LQT1 to LQT3. Less than 5% are due to mutations in other LQTS-associated genes.5
Short QT Syndrome (SQTS)
• SQTS is caused by autosomal-dominant mutations in genes encoding cardiac potassium channels (KCNH2/SQT1, KCNQ1/SQT2, KCNJ2/SQT3) caused by much less common gain of function mutations.
• Genetic testing may be offered for individuals with a high clinical index of suspicion for SQTS.
• No specific QT cut-offs currently exist to prompt investigation of asymptomatic individuals, although diagnostic criteria incorporating QTc measurements, clinical history, and family history have been proposed.7
Catecholaminergic Polymorphic VT (CPVT) Syndrome
• The genetic cause for CPVT has been attributed to either autosomal-dominant mutations in the cardiac ryanodine receptor gene (RYR2) or autosomal-recessive mutations in the cardiac calsequestrin gene (CASQ2) as well as other proteins involved in calcium handling.
• Genetic testing identifies a mutation in up to 65% of CPVT patients, with the highest yield in those with documented bidirectional VT.5
• All patients with confirmed CPVT or a high clinical index of suspicion should be offered genetic testing.
Brugada Syndrome (BrS)
• Genetic testing is able to identify a causative mutation in as low as 5% of cases if the pattern is sporadic (as is the norm) or 20% to 25% of cases of BrS if familial. Of these, a mutation in the inward sodium channel gene (SCN5A) is responsible in >75% of cases.5
• Patients with a high clinical suspicion for BrS may benefit from genetic testing.
• Genetic testing is not indicated in patients with either an isolated type 2 or type 3 Brugada pattern.
Hypertrophic Cardiomyopathy (HCM)
• Autosomal-dominant mutations in sarcomeric proteins are responsible for HCM.
• Patients with a high clinical suspicion for HCM should be offered genetic testing.
• At present, the diagnostic yield of genetic testing for established HCM is ~60%.5
• There is as yet no evidence for mutation-specific prognostic implications.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
• ARVC is transmitted as an autosomal-dominant condition with variable penetrance. Numerous genetic mutations largely involving desmosomal proteins (see Table 51-2) are implicated.5
• Genetic testing can be considered in patients with either a probable or possible diagnosis of ARVC based on task force diagnostic criteria.8
• There is also utility of genetic testing in confirming the diagnosis of ARVC in those who do not meet task force criteria but exhibit some features consistent with ARVC.
• The current diagnostic yield of genetic testing in probable cases of ARVC is ~50%.5
• ARVC is the most likely of the inherited arrhythmia conditions to return a variant of unknown significance genetic test result.
1. Carturan E, Tester DJ, Brost BC, et al. Postmortem genetic testing for conventional autopsy-negative sudden unexplained death: an evaluation of different DNA extraction protocols and the feasibility of mutational analysis from archival paraffin-embedded heart tissue. Am J Clin Pathol. 2008;129(3):391-397.
2. Vincent GM, Schwartz PJ, Denjoy I, et al. High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment “failures.” Circulation. 2009;119(2): 215-221.
3. Gollob MH, Blier L, Brugada R, et al. Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position paper. Can J Cardiol. 2011;27(2):232-245.
4. Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol. 2007;49(2):240-246.
5. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308-1339.
6. Modell SM, Bradley DJ, Lehmann MH. Genetic testing for long QT syndrome and the category of cardiac ion channelopathies. PLoS Curr. 2012;e4f9995f9969e9996c9997. doi: 10.1371/4f9995f69e6c7.
7. Gollob MH, Redpath CJ, Roberts JD. The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol. 2011;57(7):802-812.
8. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010;121(13):1533-1541.