Cardiovascular Pathology 23 (2014) 107–109
Contents lists available at ScienceDirect
Cardiovascular Pathology
Case Report
Post-mortem genetic testing in a family with long-QT syndrome and hypertrophic cardiomyopathy David A. Kane a,⁎, John Triedman b a b
Department of Pediatric Cardiology, University of Massachusetts Medical School, Worcester, MA, USA Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA
a r t i c l e
i n f o
Article history: Received 29 July 2013 Received in revised form 6 November 2013 Accepted 8 November 2013 Keywords: Sudden cardiac arrest Long QT syndrome Hypertrophic cardiomyopathy Post-mortem genetic testing Familial cardiomyopathy screening
a b s t r a c t Pediatric sudden unexplained deaths are rare and tragic events that should be evaluated with all the tools available to the medical community. The current state of genetic testing is an excellent resource that improves our ability to diagnose cardiovascular disorders that can lead to sudden cardiac arrest. Postmortem genetic testing is not typically a covered benefit of health insurance and may not be offered to families in the setting of a negative autopsy. This unusual case includes two separate cardiovascular disorders that highlight the use of genetic testing and its role in diagnosis, screening, and risk stratification. The insurance company's decision to cover post-mortem testing demonstrated both compassion as well as an understanding of the long-term cost effectiveness. © 2014 Elsevier Inc. All rights reserved.
1. Case A family with 4 surviving children presented for cardiovascular screening after their 12-year-old son and brother died while playing soccer. The proband had collapsed on the field and emergency medical services arrived where defibrillation was performed within 3 minutes. Resuscitation efforts at the local pediatric emergency department were unsuccessful and he died. The preliminary report from the medical examiner was that the weight of the heart was increased, but there was no gross evidence of cardiomyopathy from a limited dissection of the heart. A cardiac pathologist would be reviewing the specimen at a later date. The surviving children were two girls aged 4 and 7 and two boys aged 9 and 14 (Fig. 1). They were all well and participated in a variety of activities and competitive athletics. The children and the parents did not have any symptoms related to their cardiovascular systems. There was no other family history of sudden death, hypertrophic or dilated cardiomyopathy, long-QT syndrome, congenital deafness, seizures, drowning, or family members with pacemakers or defibrillators. The history and physical exams of the four children were unremarkable.
Abbreviations: LQTS, Long QT Syndrome; HCM, Hypertrophic cardiomyopathy; SCD, Sudden cardiac death. Funding Source: No external funding was secured for this report. ⁎ Corresponding author. Department of Pediatric Cardiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Tel.:+1 508 856 4154. E-mail address: [email protected] (D.A. Kane). 1054-8807/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.carpath.2013.11.003
Electrocardiograms (ECG) and echocardiograms were performed on all of the children and the parents as well. There were no significant echocardiographic abnormalities identified. The proband’s 9-year-old brother, patient II-B, had an ECG with a prolonged corrected QT interval measuring 510 ms. Based on the presumption that his brother had suffered a cardiac arrest as a consequence of Long-QT syndrome (LQTS), genetic testing from this phenotypepositive proband was performed. Informed consent for genetic testing was obtained from the parents prior to the collection of every blood sample. Patient II-B was started on Nadolol and he was restricted from competitive athletics. Genetic testing of the deceased child was discussed with the insurance company, but it was their policy that post-mortem genetic testing was not a covered benefit. Several weeks later, the result of cardiac pathology examination of the proband, patient II-A, determined his cause of death to be hypertrophic cardiomyopathy (HCM). The autopsy report revealed a classic description of HCM: “The left ventricular myocardium (including the anterior, lateral, posterior, and septal aspects, as well as papillary muscles) shows cardiomyocyte disarray, arteriolar hypertrophy, perivascular and interstitial fibrosis, and patchy areas of replacement fibrosis. The cardiomyocyte disarray is particularly pronounced within the interventricular septum, where there is significant branching of cardiomyocytes often forming whorled or herringbone patterns, cardiomyocyte hypertrophy, marked nodular interstitial expansion with fibrosis and capillary proliferation, and marked arteriolar hypertrophy.” After extended discussions with the family and the insurance company regarding the presence of potentially two genetic cardiovascular disorders, we revisited the
108
D.A. Kane, J. Triedman / Cardiovascular Pathology 23 (2014) 107–109
I
A (44)
B (42)
II
A (12)
TNNI3 positive Arg204His
B (9)
C (14)
D (7)
E (4)
KCNH2 positive Phe627Leu
Fig. 1. Squares represent males and circles females. The patient’s ages are listed in years within parentheses. Diagonal line represents a deceased patient. The solid arrow represents the proband with hypertrophic cardiomyopathy (II-A). The dashed arrow represents the proband with long QT 2 syndrome (II-B). The shaded upper left corner represents the presence of a heterozygous GNA nucleotide substitution in exon 8 of the TNNI3 gene denoted as Arg204His. The shaded lower left corner represents the presence of a heterozygous CNA nucleotide substitution in exon 7 of the KCNH2 gene denoted as Phe627Leu.
importance of post-mortem genetic testing. The insurance company decided to cover this testing. We performed HCM genetic testing in the phenotype positive proband, II-A, and we would await the results of II-B’s LQT testing before performing site-specific LQT gene testing on the siblings and the deceased child. II-B’s gene testing revealed a previously published heterozygous missense mutation (CNA nucleotide substitution) in exon 7 of the KCNH2 gene (Phe627Leu) which is consistent with an autosomal dominant form of LQTS 2 [1–3]. This mutation was located in the pore region of the channel protein and has been classified by Shimizu et al. as a higher risk gene abnormality [4]. The HCM gene testing results returned from the deceased patient later, revealing a previously published heterozygous GNA substitution in exon 8 of the cardiac troponin I (TNNI3) gene resulting in Arg204His. This is consistent with an autosomal dominant form of HCM [5]. Gene testing was performed on whole blood in an EDTA tube that was collected at the time of the autopsy and subsequently frozen. This gene abnormality was consistent with the histopathologic diagnosis of HCM that was made at autopsy. Although there were no other siblings or parents with any phenotypic evidence of LQTS or HCM, site-specific gene testing would be the only way to identify those siblings at risk. Site specific testing for the KCNH2 mutation and the TNNI3 mutation revealed no abnormalities in the parents or the other surviving siblings. The TNNI3 mutation was absent in patient II-B, and the KCNH2 mutation was absent in the deceased child. Thus, both of these autosomal-dominant disease causing genetic mutations appeared to be de novo mutations. Haplotype segregation analysis to confirm common paternity was not performed, and germ-line mosaic mutations were not tested for in the parents as they were not planning to have any other children. These are two potential limitations of the genetic analysis when considering de novo mutations.
2. Discussion This challenging case touches on issues including familial sudden death cardiovascular screening, LQTS, HCM, and the role of genetic testing in Pediatric Cardiology. It began with a tragic occurrence of sudden unexpected cardiac arrest secondary to HCM. With the initial belief (prior to qualified cardiac pathologic examination) that this lethal event may be unexplained by autopsy, it seemed quite likely that an underlying channelopathy would be the etiology of his sudden death. Drs. Michael Ackerman and David Tester have published extensively on the benefits of molecular autopsy and that an underlying channelopathy can be diagnosed in up to 30% of children without a pathologic diagnosis at autopsy [6–9]. Unfortunately, sudden cardiac death (SCD) often is the sentinel event that uncovers a genetic channelopathy within a family. Previous reports looking at families of SCD victims have found an incidence of 22–28% of inherited cardiac disease such as LQTS and catecholaminergic polymorphic ventricular tachycardia [10,11]. In this case, the proband was subsequently found to have HCM, the most common cause of sudden cardiac death in athletes and another familial cause of SCD [12]. The current screening guidelines of family members with a malignant family history of HCM would be annual echocardiography until the ages of 18–21 years and then at least every 5 years thereafter [13]. Longitudinal cardiac evaluation is necessary because the phenotypic expression and penetrance of HCM is quite variable and often does not present until adolescence. This clearly poses a significant financial cost to the insurance company, society, and the family. More importantly, the unknown risk to the surviving family members creates increased anxiety that can lead to unnecessary sports restriction, behavioral, and academic difficulties. The finding of a specific sarcomeric mutation in the proband allowed for site-specific gene testing of siblings and parents, which was
D.A. Kane, J. Triedman / Cardiovascular Pathology 23 (2014) 107–109
reassuringly negative. Because sarcomeric mutations are found in only 60–70% of adult and pediatric patients with a family history of HCM [14], in the absence of a specific genotype from the deceased child a negative HCM gene panel from a surviving family member would not definitively exclude the development of HCM. Thus, the approach of post-mortem testing was less expensive and more definitive compared to the cost of annual monitoring for the development of a clinical phenotype or for performance of entire HCM or LQT gene panels on the surviving family members. Using the above mentioned screening guidelines, post-mortem genetic testing will prevent us from performing over fifty unnecessary echocardiograms on the four surviving siblings until they reach the age of 21. This will also help guide cardiac surveillance of future generations in this family. Although this case ultimately had a phenotypic and genotypic diagnosis of HCM, the identification of a genotype-positive/phenotype-positive LQT2 sibling within days of the event itself raised the possibility that the diagnostic impression from the autopsy was incorrect. Given the substantial possibility that this genotype was shared between the siblings and the association of LQTS with SCD in sports, it was initially considered reasonably likely that LQTS was in fact the etiology of the proband’s sudden death. The presence of a mutation demonstrated to have lethal potential would be important information that could affect the subsequent management of other affected family members in risk stratification. By confirming the phenotypic diagnosis with post-mortem gene testing, we were able to evaluate the phenotypes and genotypes of the surviving family members. Three of the siblings are able to participate free of restrictions and cardiac evaluation of the extended family (aunts, uncles, cousins) is unnecessary. It is our belief that targeted cardiac gene testing should be performed on all children and young adults that suffer a SCD and it should be covered by health insurance. Patients that suffer a SCD with a pathologic diagnosis of HCM, arrhythmogenic right ventricular dysplasia, or dilated cardiomyopathy should be tested for genetic mutations in that specific cardiac panel. Pediatric patients that do not have a pathologic diagnosis at the time of autopsy should have a molecular autopsy performed that focuses on channelopathies. Pathologists should freeze a blood sample in an EDTA tube to provide the option for families to pursue genetic testing in these circumstances. This information will allow the treating physician of the surviving family members to provide the best care and to hopefully protect the family from further tragedy. It remains imperative that
109
families discuss these issues and undergo screening from cardiac trained providers that are aware of the limitations of gene testing and the phenotypic expression of these inherited cardiac diseases. The final conclusion that these two patients with LQT2 and HCM were isolated de novo mutations was extremely unlikely, but from the perspective of the family it was in fact the most favorable outcome possible: no other family member has HCM, and patient II-B has been diagnosed with LQTS and treated appropriately, prior to any cardiac event. The willingness of the insurance company to cover postmortem genetic testing allowed for us to ultimately deliver the most reassuring news we could to the family. This targeted gene testing has reduced anxiety and fear in the surviving family members and will reduce cost and resource utilization. References [1] Splawski, et al. Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000;102:1178–85. [2] Moss, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go related gene potassium panel. Circulation 2002;105:794–9. [3] Lin, et al. In utero onset of long QT syndrome with atrioventricular block and spontaneous or lidocaine-induced ventricular tachycardia: compound effects of hERG pore region mutation and SCN5A N-terminus variant. Heart Rhythm Soc 2008;5:1567–74. [4] Shimizu, et al. Genotype-phenotype aspects of Type 2 long QT syndrome. J Am Coll Cardiol 2009;54:2052–62. [5] Doolan, et al. Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy; clinical, genetic, and functional consequences. J Mol Cell Cardiol 2005;38:387–93. [6] Tester DJ, Ackerman MJ. The role of molecular autopsy in unexplained sudden cardiac death. Curr Opin Cardiol 2006;21:166–72. [7] Ackerman, et al. Molecular autopsy of sudden unexplained death in the young. Am J Forensic Med Pathol 2001;22:105–11. [8] Tester DJ, Ackerman MJ. The molecular autopsy: should the evaluation continue after the funeral? Pediatr Cardiol 2012;33(3):461–70. [9] Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol 2007;49(2):240–6. [10] Tan, et al. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation 2005;112:207–13. [11] Behr, et al. Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome. Lancet 2003;362:1457. [12] Maron, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation 2009;119:1085–92. [13] Gersh, et al. ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:2761–96. [14] Ho C. Hypertrophic cardiomyopathy in 2012. Circulation 2012;125:1432–8.
Contents lists available at ScienceDirect
Cardiovascular Pathology
Case Report
Post-mortem genetic testing in a family with long-QT syndrome and hypertrophic cardiomyopathy David A. Kane a,⁎, John Triedman b a b
Department of Pediatric Cardiology, University of Massachusetts Medical School, Worcester, MA, USA Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA
a r t i c l e
i n f o
Article history: Received 29 July 2013 Received in revised form 6 November 2013 Accepted 8 November 2013 Keywords: Sudden cardiac arrest Long QT syndrome Hypertrophic cardiomyopathy Post-mortem genetic testing Familial cardiomyopathy screening
a b s t r a c t Pediatric sudden unexplained deaths are rare and tragic events that should be evaluated with all the tools available to the medical community. The current state of genetic testing is an excellent resource that improves our ability to diagnose cardiovascular disorders that can lead to sudden cardiac arrest. Postmortem genetic testing is not typically a covered benefit of health insurance and may not be offered to families in the setting of a negative autopsy. This unusual case includes two separate cardiovascular disorders that highlight the use of genetic testing and its role in diagnosis, screening, and risk stratification. The insurance company's decision to cover post-mortem testing demonstrated both compassion as well as an understanding of the long-term cost effectiveness. © 2014 Elsevier Inc. All rights reserved.
1. Case A family with 4 surviving children presented for cardiovascular screening after their 12-year-old son and brother died while playing soccer. The proband had collapsed on the field and emergency medical services arrived where defibrillation was performed within 3 minutes. Resuscitation efforts at the local pediatric emergency department were unsuccessful and he died. The preliminary report from the medical examiner was that the weight of the heart was increased, but there was no gross evidence of cardiomyopathy from a limited dissection of the heart. A cardiac pathologist would be reviewing the specimen at a later date. The surviving children were two girls aged 4 and 7 and two boys aged 9 and 14 (Fig. 1). They were all well and participated in a variety of activities and competitive athletics. The children and the parents did not have any symptoms related to their cardiovascular systems. There was no other family history of sudden death, hypertrophic or dilated cardiomyopathy, long-QT syndrome, congenital deafness, seizures, drowning, or family members with pacemakers or defibrillators. The history and physical exams of the four children were unremarkable.
Abbreviations: LQTS, Long QT Syndrome; HCM, Hypertrophic cardiomyopathy; SCD, Sudden cardiac death. Funding Source: No external funding was secured for this report. ⁎ Corresponding author. Department of Pediatric Cardiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Tel.:+1 508 856 4154. E-mail address: [email protected] (D.A. Kane). 1054-8807/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.carpath.2013.11.003
Electrocardiograms (ECG) and echocardiograms were performed on all of the children and the parents as well. There were no significant echocardiographic abnormalities identified. The proband’s 9-year-old brother, patient II-B, had an ECG with a prolonged corrected QT interval measuring 510 ms. Based on the presumption that his brother had suffered a cardiac arrest as a consequence of Long-QT syndrome (LQTS), genetic testing from this phenotypepositive proband was performed. Informed consent for genetic testing was obtained from the parents prior to the collection of every blood sample. Patient II-B was started on Nadolol and he was restricted from competitive athletics. Genetic testing of the deceased child was discussed with the insurance company, but it was their policy that post-mortem genetic testing was not a covered benefit. Several weeks later, the result of cardiac pathology examination of the proband, patient II-A, determined his cause of death to be hypertrophic cardiomyopathy (HCM). The autopsy report revealed a classic description of HCM: “The left ventricular myocardium (including the anterior, lateral, posterior, and septal aspects, as well as papillary muscles) shows cardiomyocyte disarray, arteriolar hypertrophy, perivascular and interstitial fibrosis, and patchy areas of replacement fibrosis. The cardiomyocyte disarray is particularly pronounced within the interventricular septum, where there is significant branching of cardiomyocytes often forming whorled or herringbone patterns, cardiomyocyte hypertrophy, marked nodular interstitial expansion with fibrosis and capillary proliferation, and marked arteriolar hypertrophy.” After extended discussions with the family and the insurance company regarding the presence of potentially two genetic cardiovascular disorders, we revisited the
108
D.A. Kane, J. Triedman / Cardiovascular Pathology 23 (2014) 107–109
I
A (44)
B (42)
II
A (12)
TNNI3 positive Arg204His
B (9)
C (14)
D (7)
E (4)
KCNH2 positive Phe627Leu
Fig. 1. Squares represent males and circles females. The patient’s ages are listed in years within parentheses. Diagonal line represents a deceased patient. The solid arrow represents the proband with hypertrophic cardiomyopathy (II-A). The dashed arrow represents the proband with long QT 2 syndrome (II-B). The shaded upper left corner represents the presence of a heterozygous GNA nucleotide substitution in exon 8 of the TNNI3 gene denoted as Arg204His. The shaded lower left corner represents the presence of a heterozygous CNA nucleotide substitution in exon 7 of the KCNH2 gene denoted as Phe627Leu.
importance of post-mortem genetic testing. The insurance company decided to cover this testing. We performed HCM genetic testing in the phenotype positive proband, II-A, and we would await the results of II-B’s LQT testing before performing site-specific LQT gene testing on the siblings and the deceased child. II-B’s gene testing revealed a previously published heterozygous missense mutation (CNA nucleotide substitution) in exon 7 of the KCNH2 gene (Phe627Leu) which is consistent with an autosomal dominant form of LQTS 2 [1–3]. This mutation was located in the pore region of the channel protein and has been classified by Shimizu et al. as a higher risk gene abnormality [4]. The HCM gene testing results returned from the deceased patient later, revealing a previously published heterozygous GNA substitution in exon 8 of the cardiac troponin I (TNNI3) gene resulting in Arg204His. This is consistent with an autosomal dominant form of HCM [5]. Gene testing was performed on whole blood in an EDTA tube that was collected at the time of the autopsy and subsequently frozen. This gene abnormality was consistent with the histopathologic diagnosis of HCM that was made at autopsy. Although there were no other siblings or parents with any phenotypic evidence of LQTS or HCM, site-specific gene testing would be the only way to identify those siblings at risk. Site specific testing for the KCNH2 mutation and the TNNI3 mutation revealed no abnormalities in the parents or the other surviving siblings. The TNNI3 mutation was absent in patient II-B, and the KCNH2 mutation was absent in the deceased child. Thus, both of these autosomal-dominant disease causing genetic mutations appeared to be de novo mutations. Haplotype segregation analysis to confirm common paternity was not performed, and germ-line mosaic mutations were not tested for in the parents as they were not planning to have any other children. These are two potential limitations of the genetic analysis when considering de novo mutations.
2. Discussion This challenging case touches on issues including familial sudden death cardiovascular screening, LQTS, HCM, and the role of genetic testing in Pediatric Cardiology. It began with a tragic occurrence of sudden unexpected cardiac arrest secondary to HCM. With the initial belief (prior to qualified cardiac pathologic examination) that this lethal event may be unexplained by autopsy, it seemed quite likely that an underlying channelopathy would be the etiology of his sudden death. Drs. Michael Ackerman and David Tester have published extensively on the benefits of molecular autopsy and that an underlying channelopathy can be diagnosed in up to 30% of children without a pathologic diagnosis at autopsy [6–9]. Unfortunately, sudden cardiac death (SCD) often is the sentinel event that uncovers a genetic channelopathy within a family. Previous reports looking at families of SCD victims have found an incidence of 22–28% of inherited cardiac disease such as LQTS and catecholaminergic polymorphic ventricular tachycardia [10,11]. In this case, the proband was subsequently found to have HCM, the most common cause of sudden cardiac death in athletes and another familial cause of SCD [12]. The current screening guidelines of family members with a malignant family history of HCM would be annual echocardiography until the ages of 18–21 years and then at least every 5 years thereafter [13]. Longitudinal cardiac evaluation is necessary because the phenotypic expression and penetrance of HCM is quite variable and often does not present until adolescence. This clearly poses a significant financial cost to the insurance company, society, and the family. More importantly, the unknown risk to the surviving family members creates increased anxiety that can lead to unnecessary sports restriction, behavioral, and academic difficulties. The finding of a specific sarcomeric mutation in the proband allowed for site-specific gene testing of siblings and parents, which was
D.A. Kane, J. Triedman / Cardiovascular Pathology 23 (2014) 107–109
reassuringly negative. Because sarcomeric mutations are found in only 60–70% of adult and pediatric patients with a family history of HCM [14], in the absence of a specific genotype from the deceased child a negative HCM gene panel from a surviving family member would not definitively exclude the development of HCM. Thus, the approach of post-mortem testing was less expensive and more definitive compared to the cost of annual monitoring for the development of a clinical phenotype or for performance of entire HCM or LQT gene panels on the surviving family members. Using the above mentioned screening guidelines, post-mortem genetic testing will prevent us from performing over fifty unnecessary echocardiograms on the four surviving siblings until they reach the age of 21. This will also help guide cardiac surveillance of future generations in this family. Although this case ultimately had a phenotypic and genotypic diagnosis of HCM, the identification of a genotype-positive/phenotype-positive LQT2 sibling within days of the event itself raised the possibility that the diagnostic impression from the autopsy was incorrect. Given the substantial possibility that this genotype was shared between the siblings and the association of LQTS with SCD in sports, it was initially considered reasonably likely that LQTS was in fact the etiology of the proband’s sudden death. The presence of a mutation demonstrated to have lethal potential would be important information that could affect the subsequent management of other affected family members in risk stratification. By confirming the phenotypic diagnosis with post-mortem gene testing, we were able to evaluate the phenotypes and genotypes of the surviving family members. Three of the siblings are able to participate free of restrictions and cardiac evaluation of the extended family (aunts, uncles, cousins) is unnecessary. It is our belief that targeted cardiac gene testing should be performed on all children and young adults that suffer a SCD and it should be covered by health insurance. Patients that suffer a SCD with a pathologic diagnosis of HCM, arrhythmogenic right ventricular dysplasia, or dilated cardiomyopathy should be tested for genetic mutations in that specific cardiac panel. Pediatric patients that do not have a pathologic diagnosis at the time of autopsy should have a molecular autopsy performed that focuses on channelopathies. Pathologists should freeze a blood sample in an EDTA tube to provide the option for families to pursue genetic testing in these circumstances. This information will allow the treating physician of the surviving family members to provide the best care and to hopefully protect the family from further tragedy. It remains imperative that
109
families discuss these issues and undergo screening from cardiac trained providers that are aware of the limitations of gene testing and the phenotypic expression of these inherited cardiac diseases. The final conclusion that these two patients with LQT2 and HCM were isolated de novo mutations was extremely unlikely, but from the perspective of the family it was in fact the most favorable outcome possible: no other family member has HCM, and patient II-B has been diagnosed with LQTS and treated appropriately, prior to any cardiac event. The willingness of the insurance company to cover postmortem genetic testing allowed for us to ultimately deliver the most reassuring news we could to the family. This targeted gene testing has reduced anxiety and fear in the surviving family members and will reduce cost and resource utilization. References [1] Splawski, et al. Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000;102:1178–85. [2] Moss, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go related gene potassium panel. Circulation 2002;105:794–9. [3] Lin, et al. In utero onset of long QT syndrome with atrioventricular block and spontaneous or lidocaine-induced ventricular tachycardia: compound effects of hERG pore region mutation and SCN5A N-terminus variant. Heart Rhythm Soc 2008;5:1567–74. [4] Shimizu, et al. Genotype-phenotype aspects of Type 2 long QT syndrome. J Am Coll Cardiol 2009;54:2052–62. [5] Doolan, et al. Cardiac troponin I mutations in Australian families with hypertrophic cardiomyopathy; clinical, genetic, and functional consequences. J Mol Cell Cardiol 2005;38:387–93. [6] Tester DJ, Ackerman MJ. The role of molecular autopsy in unexplained sudden cardiac death. Curr Opin Cardiol 2006;21:166–72. [7] Ackerman, et al. Molecular autopsy of sudden unexplained death in the young. Am J Forensic Med Pathol 2001;22:105–11. [8] Tester DJ, Ackerman MJ. The molecular autopsy: should the evaluation continue after the funeral? Pediatr Cardiol 2012;33(3):461–70. [9] Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol 2007;49(2):240–6. [10] Tan, et al. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation 2005;112:207–13. [11] Behr, et al. Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome. Lancet 2003;362:1457. [12] Maron, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation 2009;119:1085–92. [13] Gersh, et al. ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:2761–96. [14] Ho C. Hypertrophic cardiomyopathy in 2012. Circulation 2012;125:1432–8.
