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Cardiac Abnormalities and Sudden Infant Death Syndrome
Paediatric Respiratory Reviews 15 (2014) 301–306
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Mini-Symposium: Sudden Infant Death Syndrome
Cardiac Abnormalities and Sudden Infant Death Syndrome Joanna Sweeting 1, Christopher Semsarian 1,2,3,* 1
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia Sydney Medical School, University of Sydney, Sydney, Australia 3 Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia 2
EDUCATIONAL AIMS To discuss the possible role of genetic heart disease as a cause of SIDS. To highlight cardiac arrhythmogenic syndromes, particularly long QT syndrome, as potentially implicated in SIDS. To illustrate the clinical implications of a possible cardiac genetic basis in some SIDS cases.
A R T I C L E I N F O
S U M M A R Y
Keywords: Genetic heart disease Long QT syndrome Genes SIDS
Many factors have been implicated in SIDS cases including environmental influences such as sleeping arrangements and smoking. Most recently, cardiac abnormalities have been hypothesised to play a role in some cases, particularly the primary genetic arrhythmogenic disorders such as familial long QT syndrome (LQTS). Both post-mortem and clinical studies of SIDS cases have provided supporting evidence for the involvement of cardiac genetic disorders in SIDS. This review provides a summary of this evidence focussing particularly on the primary hypothesis related to underlying familial LQTS. In addition, the current literature relating to other cardiac genetic conditions such as Brugada syndrome (BrS) and structural heart diseases such as hypertrophic cardiomyopathy (HCM) is briefly presented. Finally, the implications of a possible cardiac genetic cause of SIDS is discussed with reference to the need for genetic testing in SIDS cases and subsequent clinical and genetic testing in family members. ß 2014 Elsevier Ltd. All rights reserved.
INTRODUCTION It has been suggested that cardiac abnormalities, such as the inherited primary arrhythmogenic disorders, may be implicated in a proportion of SIDS cases. Many studies have been performed, primarily focused on post-mortem genetic analyses, to determine the proportion of SIDS cases that may be attributable to an underlying cardiac genetic cause. Pathogenic (disease-causing) mutations in cardiac genes have been hypothesised to be responsible for up to 10% of all SIDS cases [1–3]. This review will examine the current literature concerned with potential cardiac related causes of SIDS, with particular reference to the development of the primary hypothesis that genetic mutations may lead
* Corresponding author. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW, 2042 Australia. Tel.: +61 2 9565 6195. E-mail address: [email protected] (C. Semsarian). http://dx.doi.org/10.1016/j.prrv.2014.09.006 1526-0542/ß 2014 Elsevier Ltd. All rights reserved.
to arrhythmogenic events, such as life-threatening ventricular arrhythmias, resulting in SIDS.
GENETIC HEART DISEASES Genetic heart diseases include the arrhythmogenic conditions such as familial long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), as well as the structural disorders such as hypertrophic cardiomyopathy (HCM). These conditions have been shown to cause sudden death, particularly in young people aged 1-35 years [4]. In the case of the arrhythmogenic conditions, cardiac gene mutations lead to irregular cardiac ion channel function leading to arrhythmias and sudden death. In structural disorders, such as the cardiomyopathies, genetic mutations occur commonly in the sarcomere and cytoskeletal proteins leading to fibrosis and thickening of the heart muscle, providing an arrhythmogenic substrate for ventricular arrhythmias and sudden death. Overall, up to 95% of all cardiac genetic disorders are inherited in an
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autosomal dominant fashion, meaning at-risk relatives have a 1 in 2 chance of inheriting the disease gene [5]. Consequently, both clinical and genetic screening is recommended in all families where a relative is found to carry a disease gene, so-called predictive or cascade testing, to determine who else in the family carries the gene and to facilitate the opportunity to initiate appropriate treatment and management. CARDIAC ARRHYTHMIA SYNDROMES LINKING QT INTERVAL AND SIDS Genetic cardiac arrhythmias were first proposed as a mechanism of SIDS in 1976 by a group in the United States who suggested a potential role of QT interval prolongation in SIDS cases [6]. LQTS is an inherited cardiac condition characterised by QT interval prolongation on the electrocardiogram (ECG) that may lead to lethal arrhythmias. [2] Several mutations in genes encoding cardiac ion channels have been correlated with the various forms of LQTS (LQTS1-13) and these have formed the basis of postmortem genetic studies in SIDS cases [2,6–8]. In their landmark study from 1976, Maron et al. used electrocardiography (ECG) to study 42 sets of parents who had at least one infant die with a diagnosis of SIDS. They hypothesised that due to the inherited nature of the disease, if LQTS was to be implicated in SIDS, a proportion of parents with first hand experience of SIDS would also be affected by LQTS. Significantly, in the parents of infants who died from SIDS, one parent in each of ten parent pairs and two parents in one pair had prolongation of the QT interval on ECG. In a further key study by Schwartz et al. in 1998, SIDS cases over a 17-year period were studied, including correlation with recorded ECGs at birth [8]. Amongst 34,442 newborns, 24 deaths classified as SIDS occurred. Importantly, infants that died of SIDS had longer corrected QT intervals (QTc) than the surviving infants, suggesting a strong association between QT interval in the first week of life and SIDS. Collectively, these two key studies, coupled with other reported observations, provided the basis for the possibility that prolongation of the QT interval may predispose some babies to the development of SIDS. Furthermore, that genetic heart diseases which primarily affect the cardiac conduction system may be an underlying cause of SIDS in some cases.
CARDIAC ION CHANNELOPATHIES AND SIDS Familial Long QT syndrome (LQTS) Following the clinical studies that linked QT interval changes with SIDS cases, numerous studies have subsequently examined the role of cardiac ion channel gene mutations in SIDS cases, primarily those impacting the sodium ion channel SCN5A. Cardiac ion channels play a pivotal role in cardiac excitability and conduction of the cardiac impulse [9], i.e., the cardiac action potential and electrophysiology of the heart [10]. Consequently, mutations in cardiac ion channel genes can lead to disruptions in the electrophysiology of the heart and irregular cardiac rhythms resulting in sudden cardiac death. Figure 1 shows the relationship between genotype and molecular, cellular, organ and clinical phenotype in the arrhythmogenic pathogenetic pathway for SIDS. In addition, the potential for environmental factors to interact with the genetic factors is shown with acidosis, autonomics and sleep position potentially playing a part at certain stages [11]. Many studies and case reports over the last two decades have supported the potential role of cardiac genetic abnormalities in SIDS cases. Schwartz et al. described an important case regarding a baby who had a near-miss SIDS event and his parents [1]. The infant was found by his parents in a cyanotic, apnoeic, pulseless state and was subsequently taken to hospital and found to have ventricular fibrillation (ECG trace shown in Figure 2). The infant was restored to sinus rhythm and marked prolongation of the QT interval was documented (QTc = 648msec). Following treatment for LQTS, the infant was monitored and five years later remained free of symptoms. Genetic testing in the infant uncovered a substitution mutation in exon 16 of the coding sequence of the SCN5A gene, one of the sodium channel genes associated with familial LQTS and also BrS. Neither parent was found to carry the mutation, suggesting the mutation in the baby was a de novo event. This case is one of several providing evidence for a cardiac origin in some SIDS cases. In this instance, as a near-miss case, the authors had to opportunity to perform an ECG post-event and determine the presence of a prolonged QT interval. In actual SIDS cases this is unfortunately not possible and in the absence of a prolonged QT interval or genetic mutation in the parents, the cause of death remains unknown. A further paper by Schwartz et al. described a
Figure 1. An arrhythmogenic pathogenetic pathway for SIDS: from genotype to phenotype. The genetic abnormality, a polymorphism in the cardiac Na+ channel SCN5A, causes a molecular phenotype of increased late Na+ current (INa) under the influence of environmental factors such as acidosis. Interacting with other ion currents that may themselves be altered by genetic and environmental factors, the late Na+ current causes a cellular phenotype of prolonged action potential duration as well as early after depolarizations. Prolonged action potential in the cells of the ventricular myocardium and further interaction with environmental factors such as autonomic innervation, which in turn may be affected by genetic factors, produce a tissue/organ phenotype of a prolonged QT interval on the ECG and torsade de pointes arrhythmia in the whole heart. If this is sustained or degenerates to ventricular fibrillation, the clinical phenotype of SIDS results. (Adapted from Makielski et al. [11])
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In addition to growing supportive data from case studies, several large post-mortem genetic analysis studies have been performed. Table 1 summarises 12 studies looking at 93 or more SIDS cases in each study, from 2001–2013. The studies consisted of post-mortem genetic analysis of specific genes or panels of genes using DNA extracted from infants who died from SIDS. The majority of the genes studied were those previously implicated in familial LQTS including SCN5A, KCNQ1, KCNH2, KCNE2, KCNJ8 and CAV3 (see Table 1). The study by Arnestad et al. found that in nearly 10% of 201 SIDS cases examined, a genetic variant was identified in one of five LQTS associated genes, using gene panels rather than studying single genes. Other studies have looked primarily at a single gene, such as the study by Cronk et al., which examined the incidence of CAV3 mutations within a cohort of 134 cases [16]. CAV3 mutations had previously been demonstrated to cause disturbances in SCN5A channel function, and given the previous studies showing the association of mutations in SCN5A with SIDS cases, Cronk et al. hypothesised that CAV3 mutations may also play a role in SIDS. They determined the presence of 3 mutations in their cohort giving a mutation rate of approximately 2%. Evans et al., looked primarily at potassium ion channel mutations and found a mutation rate of 4% in the small cohort of SIDS cases studied with two mutations in the HCN4 gene [17]. Three studies have been performed on a cohort of 292 SIDS cases [18–20]. The cohort for these three studies was the same and in each a different gene examined. In the 292 cases, 8 mutations were found in SNTA1, 3 mutations were found in SCN1B-4B and 2 mutations were found in KCNJ8. Combining these three studies the mutation rate is approximately 4.5%, however as not all LQTS genes were studied in this cohort it is plausible to consider that the mutation rate may be higher. Collectively, these studies provide further support linking genetic abnormalities in ion channel genes, LQTS, and SIDS in up to 10% of cases. Figure 2. Case of near-miss SIDS. Electrocardiograms at the Time of Admission to the Hospital (Panel A), after the Restoration of Sinus Rhythm (Panel B), and at the Time of the Last Follow-up Visit (Panel C). At hospital admission, the 44-day-old infant had ventricular fibrillation (Panel A). After the restoration of sinus rhythm, the corrected QT interval was found to be prolonged (648 msec) (Panel B). At the time of the last follow-up visit at the age of three years, the child’s corrected QT interval, albeit still prolonged, was shorter (510 msec), possibly as a result of continued treatment with propranolol and mexiletine (Panel C). (Adapted from Schwartz PJ et al. [1]).
SIDS case in which molecular diagnosis was made with the identification of a de novo mutation in the potassium channel gene KCNQ1. [12] Other case studies have been reported with identification of mutations in other potassium channel associated genes such as KCNH2 (HERG) [13] and further cases of mutations in SCN5A related genes [14–16].
Catecholaminergic polymorphic ventricular tachycardia (CPVT) Along with LQTS, other arrhythmogenic conditions have been implicated in SIDS, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT has been described as similar to LQTS, and manifests with exertion, extreme stress or emotioninduced syncope [21]. Mutations in the calcium ion channel gene RyR2 (ryanodine receptor) have been shown to cause CPVT in up to 60% of cases. Tester et al reported two distinct and novel RyR2 mutations in two cases of SIDS [21]. Following functional studies, the authors established that the RyR2 mutations altered the RyR2 channels making them ‘leaky’, potentially leading to fatal cardiac arrhythmias and SIDS in some cases. In addition to studies in humans, murine models have been developed to help elucidate the role of genetic mutations in RyR2 in SIDS [22]. These studies
Table 1 Post-Mortem genetic analyses of SIDS cases (number of deaths 93) Study
Year
Study type
SIDS Deaths
Likely causative mutation (%)
Mutation Genes
Reference
Ackerman et al
2001
PM analysis, SCN5A screen
93
2 (2%)
SCN5A
[7]
Arnestad et al Brion et al Brion et al Cheng et al Cronk et al Evans et al Plant et al Tan et al Tester et al Tester et al Van Norstrand
2007 2009 2012 2009 2007 2013 2006 2010 2011 2007 2007
PM PM PM PM PM PM PM PM PM PM PM
201 140 286 292 134 226 133 292 292 134 83, 221
19 (9.5%) 14 (10%) 11 (4%) 8(3%) 3 (2%) 2/46 (4%) 3 (2%) 3 (1%) 2 (<1%) 2 (1.5%) 1/83 (1%), 2/221 (<1%)
KCNQ1, KCNH2, SCN5A, CAV3, KCNE2 TNNT2, MYBPC3, MYH6, TNNI3 MYBPC3, MYH6, TNNI3 SNTA1 CAV3 HCN4 SCN5A SCN1B-4B KCNJ8 RyR2 GPD1-L
[2] [26] [27] [18] [16] [17] [37] [19] [20] [21] [38]
analysis, analysis, analysis, analysis, analysis, analysis, analysis, analysis, analysis, analysis, analysis,
LQTS screen HCM gene screen HCM gene screen SNTA1 screen CAV3 screen HCN4 screen SCN5A screen SCN1B-4B screen KCNJ8 screen RyR2 screen GPD1-L screen
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provide some evidence for a potential role of RyR2 mutations in some cases of SIDS. Brugada syndrome (BrS) In addition to LQTS and CPVT, BrS has also been implicated in some SIDS cases. As well as causing LQTS, mutations in cardiac ion channel genes such as SCN5A may lead to BrS, which is characterised by changes in the ST segment of the ECG, as opposed to the QT interval in LQTS [23]. Similar to the case study reported by Schwartz et al., [1] another near-miss SIDS case provided evidence for a cardiac role in some SIDS cases. In this instance the infant gave a sharp cry before being taken to hospital where the infant became apnoeic and pulseless [24]. At hospital the ECG showed coarse ventricular tachycardia that was eventually resolved with the infant being restored to sinus rhythm. The QTc interval of the infant was only marginally prolonged. Since the event and treatment with beta-blockers, the authors reported that the infant was developing normally with no further events. Genetic testing identified a mutation in the SCN5A gene, in both the infant and mother. This gene has been associated with BrS as well as idiopathic ventricular fibrillation and the authors suggested that the infant did in fact have BrS. A family studied by Priori et al., [25] also found an SCN5A mutation scattered throughout a family with five sudden deaths in children aged 3 or under. It is likely that in some cases of SIDS, the true underlying cause may be BrS. It should be noted that in all SIDS cases where an underlying gene mutation has been implicated, the precise pathogenic role of that mutation often remains uncertain. Furthermore, in some of the studies which have previously reported the genetic variant as being disease causing, subsequent knowledge and genetic information from databases have shown the particular variant not to be disease causing. OTHER CARDIAC GENETIC ASSOCIATIONS WITH SIDS Apart from the primary arrythmogenic disorders outlined previously, structural cardiac disorders have also been implicated in SIDS cases, albeit less frequently [26,27]. In the two studies by Brion et al., (Table 1), mutations in sarcomere genes were examined as a possible cause of SIDS. Such mutations have been shown to cause cardiomyopathies such as hypertrophic cardiomyopathy (HCM) in adults, resulting in cardiac arrest or sudden death. However, in these cases, the cause of death is usually clearly evident at autopsy with macroscopic left ventricular hypertrophy and classical histopathology with myocyte disarray present [28]. In the 2009 study by Brion et al.,140 SIDS cases were screened for a panel of ten sarcomere and five other genes [26]. 14 SIDS cases were found to carry genetic variants in the following four sarcomere genes; TNNT2, MYBPC3, MYH6 and TNNI3. Similarly, in their 2012 study, 286 SIDS cases were screened for 11 sarcomere genes and five other genes [27]. They found 10 mutations in sarcomere genes (predominately MYBPC3). These two studies suggest cardiomyopathy-related genes may be associated with SIDS cases despite the lack of cardiac hypertrophy or histological abnormalities at post-mortem. In addition to these genetic cardiac causes, it has also been hypothesised that primary cardiac conduction system disease resulting in bradycardia (slow heart rate) may also play a role in some SIDS deaths. Meny et al. reported on six SIDS deaths where the infant had died while on memory-equipped cardiorespiratory monitors [29]. In all six deaths bradycardia was observed to play a significant role in the death of the infant, preceding or occurring simultaneously with central apnoea [29]. These few reports suggest bradycardia may be the final event in some cases of SIDS, although the preceding events remain poorly understood.
CLINICAL IMPLICATIONS The possibility that there may be an underlying cardiac genetic basis in some SIDS cases has some significant implications for family screening. These include: Clinical screening of family members, including the possibility of performing an ECG in both parents of a SIDS case. Consideration of genetic testing in SIDS cases, with the potential for predictive genetic testing in at-risk relatives. Possibility of neonatal or prenatal cardiac screening. Targeted management in subsequent pregnancies for families who have a previous history of SIDS.
Clinical screening may be undertaken in family members of an infant who has died from SIDS if an arrhythmogenic disorder is suspected. Family members should be screened clinically, including a detailed medical and family history, physical examination, and a 12-lead ECG in order to pick up any irregularities. In addition to clinical screening, a genetic investigation may be considered. Given the strong and mounting evidence implicating cardiac ion channel gene mutations in SIDS cases, questions regarding genetic testing arise in families. With the knowledge that up to 10% of SIDS cases may harbour an underlying causative LQTS gene mutation [30], genetic testing may be indicated. Guidelines released by the Heart Rhythm Society and the European Heart Rhythm Association in 2011 [31] state that in all cases of SIDS, collection of a tissue sample (whole blood, blood spot card or a frozen sample of heart, liver, or spleen) is recommended for subsequent DNA testing. A second recommendation states ‘‘In the setting of autopsy negative sudden unexplained death, comprehensive or targeted (RYR2, KCNQ1, KCNH2, and SCN5A) ion channel genetic testing may be considered in an attempt to establish probable cause and manner of death and to facilitate the identification of potentially at-risk relatives and is recommended if circumstantial evidence points toward a clinical diagnosis of LQTS or CPVT specifically’’ [31]. Although it is recommended in all cases that tissue samples be taken from SIDS victims, the need for genetic testing is determined by a multidisciplinary team including the forensic pathologist, cardiologist and genetic counsellor, and is not requested in every case. As mentioned, genetic testing in SIDS cases is considered an important step in managing family members [32]. If a mutation is found in the infant, family members can then be screened and either released from the need for further testing if genotype negative or, if genotype positive, undergo clinical screening, diagnosis and treatment aimed to reduce their risk of sudden death. In addition to post-SIDS event screening, neonatal screening has been proposed given the hypothesised incidence of genetic cardiac disorders in SIDS cases. An Italian study looking at the prevalence of congenital Long QT syndrome enrolled over 40,000 newborns in 18 maternity hospitals [33]. The investigators performed an ECG on every infant (15 to 25 days old) and in infants with a QTc > 450ms, repeated the ECG within 1 to 2 weeks. For infants with a QTc of > 470ms or between 461 and 470ms, genetic testing using a LQTS gene panel was performed. The study found a mutation detection rate of 43% in infants with a QTc > 470ms and 29% in infants with QTc 461-470ms. As well as providing a concept of prevalence of LQTS in newborns (1:2534) this finding implies a place for ECG screening of newborns [33]. However, large-scale ECG screening has both monetary and psychosocial costs, and so whether it is a cost-effective measure needs to be established. Quaglini et al., performed a cost-effectiveness analysis for neonatal screening for LQTS and found it to be a ‘highly cost-effective’
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screening programme allowing for appropriate therapy in affected individuals and preventing unnecessary deaths [34]. Another point of consideration regarding the implications of a genetic cardiac factor in SIDS, in particular shown with LQTS, relates to the possibility of miscarriage or stillbirth due to a genetic heart disease in the foetus. If a foetus has a genetic mutation in a cardiac gene it is plausible to hypothesise that in at least some cases, a prenatal arrhythmia may cause death to the foetus. This is supported by a recent study that reported the identification of pathogenic LQTS and LQTS-associated ion channel gene mutations in 12% of cases of intrauterine foetal death [35]. This is further supported by the recent development of magnetocardiography technology, which allows detection of foetal arrhythmias in utero during development [36]. In a recently published study, 30 foetuses were referred for magnetocardiography studies due to a history of familial LQTS, neonatal/childhood sudden death or prenatal LQTS rhythms [36]. Magnetocardiography was an accurate method for identifying foetuses with LQTS in utero and thus may be able to play a role in the diagnosis and management of foetuses at risk of LQTS, and therefore at risk of SIDS after birth. CONCLUSION SIDS is a complex syndrome with numerous aetiological factors, including environmental and genetic influences. An underlying cardiac abnormality may play a role in some cases of SIDS. Mutations in LQTS associated genes such as SCN5A, HERG, KCNQ1, KCNH2 and other cardiac genes such as RYR2 have been found in SIDS cohorts, leading researchers to propose that up to 10% of all SIDS cases may be due to an underlying cardiac genetic cause. Identification of a cardiac basis for SIDS has important implications for the surviving family, and may prompt both clinical screening of family members, as well as targeted genetic analysis. Defining the precise causes of SIDS has the potential to identify families at risk of SIDS, and subsequent initiation of appropriate treatment and prevention strategies, with the ultimate goal to prevent SIDS in our communities. DISCLOSURES Nil FUTURE RESEARCH DIRECTIONS Clinical cardiac screening for family members of an infant who has died from SIDS. Further consideration of genetic investigations in SIDS cases. Potential for neonatal screening for ECG changes or key cardiac arrhythmia genes. Acknowledgements CS is the recipient of a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (#571084). JS is the recipient of the Elizabeth and Henry Hamilton Browne Scholarship from the University of Sydney. References [1] Schwartz PJ, Priori SG, Dumaine R, Napolitano C, Antzelevitch C, StrambaBadiale M, Richard TA, Berti MR, Bloise R. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 2000;343: 262–7. [2] Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Wang DW, Rhodes TE, George Jr AL, Schwartz PJ. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007;115:361–7.
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Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Mini-Symposium: Sudden Infant Death Syndrome
Cardiac Abnormalities and Sudden Infant Death Syndrome Joanna Sweeting 1, Christopher Semsarian 1,2,3,* 1
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, Australia Sydney Medical School, University of Sydney, Sydney, Australia 3 Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia 2
EDUCATIONAL AIMS To discuss the possible role of genetic heart disease as a cause of SIDS. To highlight cardiac arrhythmogenic syndromes, particularly long QT syndrome, as potentially implicated in SIDS. To illustrate the clinical implications of a possible cardiac genetic basis in some SIDS cases.
A R T I C L E I N F O
S U M M A R Y
Keywords: Genetic heart disease Long QT syndrome Genes SIDS
Many factors have been implicated in SIDS cases including environmental influences such as sleeping arrangements and smoking. Most recently, cardiac abnormalities have been hypothesised to play a role in some cases, particularly the primary genetic arrhythmogenic disorders such as familial long QT syndrome (LQTS). Both post-mortem and clinical studies of SIDS cases have provided supporting evidence for the involvement of cardiac genetic disorders in SIDS. This review provides a summary of this evidence focussing particularly on the primary hypothesis related to underlying familial LQTS. In addition, the current literature relating to other cardiac genetic conditions such as Brugada syndrome (BrS) and structural heart diseases such as hypertrophic cardiomyopathy (HCM) is briefly presented. Finally, the implications of a possible cardiac genetic cause of SIDS is discussed with reference to the need for genetic testing in SIDS cases and subsequent clinical and genetic testing in family members. ß 2014 Elsevier Ltd. All rights reserved.
INTRODUCTION It has been suggested that cardiac abnormalities, such as the inherited primary arrhythmogenic disorders, may be implicated in a proportion of SIDS cases. Many studies have been performed, primarily focused on post-mortem genetic analyses, to determine the proportion of SIDS cases that may be attributable to an underlying cardiac genetic cause. Pathogenic (disease-causing) mutations in cardiac genes have been hypothesised to be responsible for up to 10% of all SIDS cases [1–3]. This review will examine the current literature concerned with potential cardiac related causes of SIDS, with particular reference to the development of the primary hypothesis that genetic mutations may lead
* Corresponding author. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW, 2042 Australia. Tel.: +61 2 9565 6195. E-mail address: [email protected] (C. Semsarian). http://dx.doi.org/10.1016/j.prrv.2014.09.006 1526-0542/ß 2014 Elsevier Ltd. All rights reserved.
to arrhythmogenic events, such as life-threatening ventricular arrhythmias, resulting in SIDS.
GENETIC HEART DISEASES Genetic heart diseases include the arrhythmogenic conditions such as familial long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), as well as the structural disorders such as hypertrophic cardiomyopathy (HCM). These conditions have been shown to cause sudden death, particularly in young people aged 1-35 years [4]. In the case of the arrhythmogenic conditions, cardiac gene mutations lead to irregular cardiac ion channel function leading to arrhythmias and sudden death. In structural disorders, such as the cardiomyopathies, genetic mutations occur commonly in the sarcomere and cytoskeletal proteins leading to fibrosis and thickening of the heart muscle, providing an arrhythmogenic substrate for ventricular arrhythmias and sudden death. Overall, up to 95% of all cardiac genetic disorders are inherited in an
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autosomal dominant fashion, meaning at-risk relatives have a 1 in 2 chance of inheriting the disease gene [5]. Consequently, both clinical and genetic screening is recommended in all families where a relative is found to carry a disease gene, so-called predictive or cascade testing, to determine who else in the family carries the gene and to facilitate the opportunity to initiate appropriate treatment and management. CARDIAC ARRHYTHMIA SYNDROMES LINKING QT INTERVAL AND SIDS Genetic cardiac arrhythmias were first proposed as a mechanism of SIDS in 1976 by a group in the United States who suggested a potential role of QT interval prolongation in SIDS cases [6]. LQTS is an inherited cardiac condition characterised by QT interval prolongation on the electrocardiogram (ECG) that may lead to lethal arrhythmias. [2] Several mutations in genes encoding cardiac ion channels have been correlated with the various forms of LQTS (LQTS1-13) and these have formed the basis of postmortem genetic studies in SIDS cases [2,6–8]. In their landmark study from 1976, Maron et al. used electrocardiography (ECG) to study 42 sets of parents who had at least one infant die with a diagnosis of SIDS. They hypothesised that due to the inherited nature of the disease, if LQTS was to be implicated in SIDS, a proportion of parents with first hand experience of SIDS would also be affected by LQTS. Significantly, in the parents of infants who died from SIDS, one parent in each of ten parent pairs and two parents in one pair had prolongation of the QT interval on ECG. In a further key study by Schwartz et al. in 1998, SIDS cases over a 17-year period were studied, including correlation with recorded ECGs at birth [8]. Amongst 34,442 newborns, 24 deaths classified as SIDS occurred. Importantly, infants that died of SIDS had longer corrected QT intervals (QTc) than the surviving infants, suggesting a strong association between QT interval in the first week of life and SIDS. Collectively, these two key studies, coupled with other reported observations, provided the basis for the possibility that prolongation of the QT interval may predispose some babies to the development of SIDS. Furthermore, that genetic heart diseases which primarily affect the cardiac conduction system may be an underlying cause of SIDS in some cases.
CARDIAC ION CHANNELOPATHIES AND SIDS Familial Long QT syndrome (LQTS) Following the clinical studies that linked QT interval changes with SIDS cases, numerous studies have subsequently examined the role of cardiac ion channel gene mutations in SIDS cases, primarily those impacting the sodium ion channel SCN5A. Cardiac ion channels play a pivotal role in cardiac excitability and conduction of the cardiac impulse [9], i.e., the cardiac action potential and electrophysiology of the heart [10]. Consequently, mutations in cardiac ion channel genes can lead to disruptions in the electrophysiology of the heart and irregular cardiac rhythms resulting in sudden cardiac death. Figure 1 shows the relationship between genotype and molecular, cellular, organ and clinical phenotype in the arrhythmogenic pathogenetic pathway for SIDS. In addition, the potential for environmental factors to interact with the genetic factors is shown with acidosis, autonomics and sleep position potentially playing a part at certain stages [11]. Many studies and case reports over the last two decades have supported the potential role of cardiac genetic abnormalities in SIDS cases. Schwartz et al. described an important case regarding a baby who had a near-miss SIDS event and his parents [1]. The infant was found by his parents in a cyanotic, apnoeic, pulseless state and was subsequently taken to hospital and found to have ventricular fibrillation (ECG trace shown in Figure 2). The infant was restored to sinus rhythm and marked prolongation of the QT interval was documented (QTc = 648msec). Following treatment for LQTS, the infant was monitored and five years later remained free of symptoms. Genetic testing in the infant uncovered a substitution mutation in exon 16 of the coding sequence of the SCN5A gene, one of the sodium channel genes associated with familial LQTS and also BrS. Neither parent was found to carry the mutation, suggesting the mutation in the baby was a de novo event. This case is one of several providing evidence for a cardiac origin in some SIDS cases. In this instance, as a near-miss case, the authors had to opportunity to perform an ECG post-event and determine the presence of a prolonged QT interval. In actual SIDS cases this is unfortunately not possible and in the absence of a prolonged QT interval or genetic mutation in the parents, the cause of death remains unknown. A further paper by Schwartz et al. described a
Figure 1. An arrhythmogenic pathogenetic pathway for SIDS: from genotype to phenotype. The genetic abnormality, a polymorphism in the cardiac Na+ channel SCN5A, causes a molecular phenotype of increased late Na+ current (INa) under the influence of environmental factors such as acidosis. Interacting with other ion currents that may themselves be altered by genetic and environmental factors, the late Na+ current causes a cellular phenotype of prolonged action potential duration as well as early after depolarizations. Prolonged action potential in the cells of the ventricular myocardium and further interaction with environmental factors such as autonomic innervation, which in turn may be affected by genetic factors, produce a tissue/organ phenotype of a prolonged QT interval on the ECG and torsade de pointes arrhythmia in the whole heart. If this is sustained or degenerates to ventricular fibrillation, the clinical phenotype of SIDS results. (Adapted from Makielski et al. [11])
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In addition to growing supportive data from case studies, several large post-mortem genetic analysis studies have been performed. Table 1 summarises 12 studies looking at 93 or more SIDS cases in each study, from 2001–2013. The studies consisted of post-mortem genetic analysis of specific genes or panels of genes using DNA extracted from infants who died from SIDS. The majority of the genes studied were those previously implicated in familial LQTS including SCN5A, KCNQ1, KCNH2, KCNE2, KCNJ8 and CAV3 (see Table 1). The study by Arnestad et al. found that in nearly 10% of 201 SIDS cases examined, a genetic variant was identified in one of five LQTS associated genes, using gene panels rather than studying single genes. Other studies have looked primarily at a single gene, such as the study by Cronk et al., which examined the incidence of CAV3 mutations within a cohort of 134 cases [16]. CAV3 mutations had previously been demonstrated to cause disturbances in SCN5A channel function, and given the previous studies showing the association of mutations in SCN5A with SIDS cases, Cronk et al. hypothesised that CAV3 mutations may also play a role in SIDS. They determined the presence of 3 mutations in their cohort giving a mutation rate of approximately 2%. Evans et al., looked primarily at potassium ion channel mutations and found a mutation rate of 4% in the small cohort of SIDS cases studied with two mutations in the HCN4 gene [17]. Three studies have been performed on a cohort of 292 SIDS cases [18–20]. The cohort for these three studies was the same and in each a different gene examined. In the 292 cases, 8 mutations were found in SNTA1, 3 mutations were found in SCN1B-4B and 2 mutations were found in KCNJ8. Combining these three studies the mutation rate is approximately 4.5%, however as not all LQTS genes were studied in this cohort it is plausible to consider that the mutation rate may be higher. Collectively, these studies provide further support linking genetic abnormalities in ion channel genes, LQTS, and SIDS in up to 10% of cases. Figure 2. Case of near-miss SIDS. Electrocardiograms at the Time of Admission to the Hospital (Panel A), after the Restoration of Sinus Rhythm (Panel B), and at the Time of the Last Follow-up Visit (Panel C). At hospital admission, the 44-day-old infant had ventricular fibrillation (Panel A). After the restoration of sinus rhythm, the corrected QT interval was found to be prolonged (648 msec) (Panel B). At the time of the last follow-up visit at the age of three years, the child’s corrected QT interval, albeit still prolonged, was shorter (510 msec), possibly as a result of continued treatment with propranolol and mexiletine (Panel C). (Adapted from Schwartz PJ et al. [1]).
SIDS case in which molecular diagnosis was made with the identification of a de novo mutation in the potassium channel gene KCNQ1. [12] Other case studies have been reported with identification of mutations in other potassium channel associated genes such as KCNH2 (HERG) [13] and further cases of mutations in SCN5A related genes [14–16].
Catecholaminergic polymorphic ventricular tachycardia (CPVT) Along with LQTS, other arrhythmogenic conditions have been implicated in SIDS, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT has been described as similar to LQTS, and manifests with exertion, extreme stress or emotioninduced syncope [21]. Mutations in the calcium ion channel gene RyR2 (ryanodine receptor) have been shown to cause CPVT in up to 60% of cases. Tester et al reported two distinct and novel RyR2 mutations in two cases of SIDS [21]. Following functional studies, the authors established that the RyR2 mutations altered the RyR2 channels making them ‘leaky’, potentially leading to fatal cardiac arrhythmias and SIDS in some cases. In addition to studies in humans, murine models have been developed to help elucidate the role of genetic mutations in RyR2 in SIDS [22]. These studies
Table 1 Post-Mortem genetic analyses of SIDS cases (number of deaths 93) Study
Year
Study type
SIDS Deaths
Likely causative mutation (%)
Mutation Genes
Reference
Ackerman et al
2001
PM analysis, SCN5A screen
93
2 (2%)
SCN5A
[7]
Arnestad et al Brion et al Brion et al Cheng et al Cronk et al Evans et al Plant et al Tan et al Tester et al Tester et al Van Norstrand
2007 2009 2012 2009 2007 2013 2006 2010 2011 2007 2007
PM PM PM PM PM PM PM PM PM PM PM
201 140 286 292 134 226 133 292 292 134 83, 221
19 (9.5%) 14 (10%) 11 (4%) 8(3%) 3 (2%) 2/46 (4%) 3 (2%) 3 (1%) 2 (<1%) 2 (1.5%) 1/83 (1%), 2/221 (<1%)
KCNQ1, KCNH2, SCN5A, CAV3, KCNE2 TNNT2, MYBPC3, MYH6, TNNI3 MYBPC3, MYH6, TNNI3 SNTA1 CAV3 HCN4 SCN5A SCN1B-4B KCNJ8 RyR2 GPD1-L
[2] [26] [27] [18] [16] [17] [37] [19] [20] [21] [38]
analysis, analysis, analysis, analysis, analysis, analysis, analysis, analysis, analysis, analysis, analysis,
LQTS screen HCM gene screen HCM gene screen SNTA1 screen CAV3 screen HCN4 screen SCN5A screen SCN1B-4B screen KCNJ8 screen RyR2 screen GPD1-L screen
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provide some evidence for a potential role of RyR2 mutations in some cases of SIDS. Brugada syndrome (BrS) In addition to LQTS and CPVT, BrS has also been implicated in some SIDS cases. As well as causing LQTS, mutations in cardiac ion channel genes such as SCN5A may lead to BrS, which is characterised by changes in the ST segment of the ECG, as opposed to the QT interval in LQTS [23]. Similar to the case study reported by Schwartz et al., [1] another near-miss SIDS case provided evidence for a cardiac role in some SIDS cases. In this instance the infant gave a sharp cry before being taken to hospital where the infant became apnoeic and pulseless [24]. At hospital the ECG showed coarse ventricular tachycardia that was eventually resolved with the infant being restored to sinus rhythm. The QTc interval of the infant was only marginally prolonged. Since the event and treatment with beta-blockers, the authors reported that the infant was developing normally with no further events. Genetic testing identified a mutation in the SCN5A gene, in both the infant and mother. This gene has been associated with BrS as well as idiopathic ventricular fibrillation and the authors suggested that the infant did in fact have BrS. A family studied by Priori et al., [25] also found an SCN5A mutation scattered throughout a family with five sudden deaths in children aged 3 or under. It is likely that in some cases of SIDS, the true underlying cause may be BrS. It should be noted that in all SIDS cases where an underlying gene mutation has been implicated, the precise pathogenic role of that mutation often remains uncertain. Furthermore, in some of the studies which have previously reported the genetic variant as being disease causing, subsequent knowledge and genetic information from databases have shown the particular variant not to be disease causing. OTHER CARDIAC GENETIC ASSOCIATIONS WITH SIDS Apart from the primary arrythmogenic disorders outlined previously, structural cardiac disorders have also been implicated in SIDS cases, albeit less frequently [26,27]. In the two studies by Brion et al., (Table 1), mutations in sarcomere genes were examined as a possible cause of SIDS. Such mutations have been shown to cause cardiomyopathies such as hypertrophic cardiomyopathy (HCM) in adults, resulting in cardiac arrest or sudden death. However, in these cases, the cause of death is usually clearly evident at autopsy with macroscopic left ventricular hypertrophy and classical histopathology with myocyte disarray present [28]. In the 2009 study by Brion et al.,140 SIDS cases were screened for a panel of ten sarcomere and five other genes [26]. 14 SIDS cases were found to carry genetic variants in the following four sarcomere genes; TNNT2, MYBPC3, MYH6 and TNNI3. Similarly, in their 2012 study, 286 SIDS cases were screened for 11 sarcomere genes and five other genes [27]. They found 10 mutations in sarcomere genes (predominately MYBPC3). These two studies suggest cardiomyopathy-related genes may be associated with SIDS cases despite the lack of cardiac hypertrophy or histological abnormalities at post-mortem. In addition to these genetic cardiac causes, it has also been hypothesised that primary cardiac conduction system disease resulting in bradycardia (slow heart rate) may also play a role in some SIDS deaths. Meny et al. reported on six SIDS deaths where the infant had died while on memory-equipped cardiorespiratory monitors [29]. In all six deaths bradycardia was observed to play a significant role in the death of the infant, preceding or occurring simultaneously with central apnoea [29]. These few reports suggest bradycardia may be the final event in some cases of SIDS, although the preceding events remain poorly understood.
CLINICAL IMPLICATIONS The possibility that there may be an underlying cardiac genetic basis in some SIDS cases has some significant implications for family screening. These include: Clinical screening of family members, including the possibility of performing an ECG in both parents of a SIDS case. Consideration of genetic testing in SIDS cases, with the potential for predictive genetic testing in at-risk relatives. Possibility of neonatal or prenatal cardiac screening. Targeted management in subsequent pregnancies for families who have a previous history of SIDS.
Clinical screening may be undertaken in family members of an infant who has died from SIDS if an arrhythmogenic disorder is suspected. Family members should be screened clinically, including a detailed medical and family history, physical examination, and a 12-lead ECG in order to pick up any irregularities. In addition to clinical screening, a genetic investigation may be considered. Given the strong and mounting evidence implicating cardiac ion channel gene mutations in SIDS cases, questions regarding genetic testing arise in families. With the knowledge that up to 10% of SIDS cases may harbour an underlying causative LQTS gene mutation [30], genetic testing may be indicated. Guidelines released by the Heart Rhythm Society and the European Heart Rhythm Association in 2011 [31] state that in all cases of SIDS, collection of a tissue sample (whole blood, blood spot card or a frozen sample of heart, liver, or spleen) is recommended for subsequent DNA testing. A second recommendation states ‘‘In the setting of autopsy negative sudden unexplained death, comprehensive or targeted (RYR2, KCNQ1, KCNH2, and SCN5A) ion channel genetic testing may be considered in an attempt to establish probable cause and manner of death and to facilitate the identification of potentially at-risk relatives and is recommended if circumstantial evidence points toward a clinical diagnosis of LQTS or CPVT specifically’’ [31]. Although it is recommended in all cases that tissue samples be taken from SIDS victims, the need for genetic testing is determined by a multidisciplinary team including the forensic pathologist, cardiologist and genetic counsellor, and is not requested in every case. As mentioned, genetic testing in SIDS cases is considered an important step in managing family members [32]. If a mutation is found in the infant, family members can then be screened and either released from the need for further testing if genotype negative or, if genotype positive, undergo clinical screening, diagnosis and treatment aimed to reduce their risk of sudden death. In addition to post-SIDS event screening, neonatal screening has been proposed given the hypothesised incidence of genetic cardiac disorders in SIDS cases. An Italian study looking at the prevalence of congenital Long QT syndrome enrolled over 40,000 newborns in 18 maternity hospitals [33]. The investigators performed an ECG on every infant (15 to 25 days old) and in infants with a QTc > 450ms, repeated the ECG within 1 to 2 weeks. For infants with a QTc of > 470ms or between 461 and 470ms, genetic testing using a LQTS gene panel was performed. The study found a mutation detection rate of 43% in infants with a QTc > 470ms and 29% in infants with QTc 461-470ms. As well as providing a concept of prevalence of LQTS in newborns (1:2534) this finding implies a place for ECG screening of newborns [33]. However, large-scale ECG screening has both monetary and psychosocial costs, and so whether it is a cost-effective measure needs to be established. Quaglini et al., performed a cost-effectiveness analysis for neonatal screening for LQTS and found it to be a ‘highly cost-effective’
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screening programme allowing for appropriate therapy in affected individuals and preventing unnecessary deaths [34]. Another point of consideration regarding the implications of a genetic cardiac factor in SIDS, in particular shown with LQTS, relates to the possibility of miscarriage or stillbirth due to a genetic heart disease in the foetus. If a foetus has a genetic mutation in a cardiac gene it is plausible to hypothesise that in at least some cases, a prenatal arrhythmia may cause death to the foetus. This is supported by a recent study that reported the identification of pathogenic LQTS and LQTS-associated ion channel gene mutations in 12% of cases of intrauterine foetal death [35]. This is further supported by the recent development of magnetocardiography technology, which allows detection of foetal arrhythmias in utero during development [36]. In a recently published study, 30 foetuses were referred for magnetocardiography studies due to a history of familial LQTS, neonatal/childhood sudden death or prenatal LQTS rhythms [36]. Magnetocardiography was an accurate method for identifying foetuses with LQTS in utero and thus may be able to play a role in the diagnosis and management of foetuses at risk of LQTS, and therefore at risk of SIDS after birth. CONCLUSION SIDS is a complex syndrome with numerous aetiological factors, including environmental and genetic influences. An underlying cardiac abnormality may play a role in some cases of SIDS. Mutations in LQTS associated genes such as SCN5A, HERG, KCNQ1, KCNH2 and other cardiac genes such as RYR2 have been found in SIDS cohorts, leading researchers to propose that up to 10% of all SIDS cases may be due to an underlying cardiac genetic cause. Identification of a cardiac basis for SIDS has important implications for the surviving family, and may prompt both clinical screening of family members, as well as targeted genetic analysis. Defining the precise causes of SIDS has the potential to identify families at risk of SIDS, and subsequent initiation of appropriate treatment and prevention strategies, with the ultimate goal to prevent SIDS in our communities. DISCLOSURES Nil FUTURE RESEARCH DIRECTIONS Clinical cardiac screening for family members of an infant who has died from SIDS. Further consideration of genetic investigations in SIDS cases. Potential for neonatal screening for ECG changes or key cardiac arrhythmia genes. Acknowledgements CS is the recipient of a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (#571084). JS is the recipient of the Elizabeth and Henry Hamilton Browne Scholarship from the University of Sydney. References [1] Schwartz PJ, Priori SG, Dumaine R, Napolitano C, Antzelevitch C, StrambaBadiale M, Richard TA, Berti MR, Bloise R. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med 2000;343: 262–7. [2] Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Wang DW, Rhodes TE, George Jr AL, Schwartz PJ. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007;115:361–7.
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