Published online October 1, 2007
PEDIATRICS Vol. 120 No. 4 October 2007, pp. e967-e973 (doi:10.1542/peds.2006-3751)
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ARTICLE

Contribution of Inherited Heart Disease to Sudden Cardiac Death in Childhood

Nynke Hofman, MSca, Hanno L. Tan, MD, PhDb, Sally-Ann Clur, MDc, Mariel Alders, PhDd, Irene M. van Langen, MD, PhDa and Arthur A. M. Wilde, MD, PhDb

a Departments of Clinical Genetics
b Cardiology
c Pediatric Cardiology
d Molecular Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 STUDY LIMITATIONS
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. In children aged 1 to 18 years, the causes of sudden cardiac death may remain unresolved when autopsy results are negative. Because inherited cardiac diseases are likely, cardiologic and genetic investigations of relatives may still yield the diagnosis in these cases. Moreover, these investigations provide timely identification of relatives who are also at risk of sudden cardiac death. We aimed to establish the cause of sudden cardiac death in the children of whom the family was referred to our cardiogenetics department and the diagnostic yield of these investigations.

METHODS AND RESULTS. We genetically counseled 25 consecutive, unrelated families after sudden cardiac death of a child (aged 1 to 18 years) who was disease-free during lifetime and in whose family there was no known inherited heart disease. We performed cardiac investigation (electrocardiography, exercise testing, and echocardiography) of first-degree and second-degree relatives and performed diagnosis-directed DNA analysis. Autopsy was performed in 20 case subjects. A diagnosis was identified in 14 of 25 families. In addition, we studied 10 children after aborted sudden cardiac death; in 6 of them, a diagnosis was made. Overall, in 17 of the 19 families in whom an inherited disease was diagnosed, a disease-causing mutation in either a first-degree relative or the index patient confirmed the diagnosis.

CONCLUSIONS. Sudden cardiac death in children seems to be caused often by inherited cardiac diseases. Cardiac and genetic examination of relatives combined, if possible, with postmortem analysis after sudden cardiac death of a child has a high diagnostic yield (14 of 25), comparable to analysis in surviving victims of sudden cardiac death (6 of 10). Because sudden cardiac death can be prevented by timely treatment, these results warrant active family screening after unexplained sudden cardiac death of a child.

Key Words: sudden cardiac death • children • molecular genetics • arrhythmia • genetic counseling

Abbreviations: SCD—sudden cardiac death • VT—ventricular tachycardia • HCM—hypertrophic cardiomyopathy • ARVC—arrhythmogenic right ventricular cardiomyopathy • LQTS—long QT syndrome • CPVT—catecholaminergic polymorphic ventricular tachycardia • ECG—electrocardiography • LQT—long QT

Sudden cardiac death (SCD) is usually caused by ventricular fibrillation or ventricular tachycardia (VT). In adults, SCD is most often secondary to coronary artery disease. SCD in children is uncommon at an estimated yearly rate of 500 to 1000 patients aged <21 years in the United States.1

The causes of SCD in children aged 1 to 18 years are ill defined when autopsy does not reveal a diagnosis.2–4 Children who fall prey to SCD often had no previous medical history. Postmortem analysis often reveals structural cardiac abnormalities, such as hypertrophic cardiomyopathy (HCM), myocarditis, and congenital coronary artery anomalies.5,6 However, structural abnormalities are not always found. SCD in young adults (aged <40 years) without previous medical history is often caused by inherited heart disease. In addition to structural diseases, such as HCM and arrhythmogenic right ventricular cardiomyopathy (ARVC),7–10 primary electrical disease may be the cause, for example, long QT syndrome (LQTS), Brugada syndrome, and catecholaminergic polymorphic VT (CPVT).10–12 Inherited diseases may be diagnosed by analyzing survivors of aborted SCD or relatives of deceased individuals.11,12 These diseases have an autosomal dominant mode of inheritance, rendering establishment of the diagnosis crucial, because other disease carriers must receive timely treatment to avert SCD.13 Conversely, the heritability of these diseases allows for a diagnosis in SCD cases when postmortem analysis provides no clues, because cardiologic and genetic analysis in surviving relatives may reveal presymptomatic disease carriers.

Our primary aim was to define the causes of SCD in children of families which were referred to our Cardiogenetics department. Second, with the assumption that SCD in children is generally caused by inherited heart disease, we aimed to establish the diagnostic yield (ie, the capability to diagnose the underlying disease) of cardiologic and genetic assessment of surviving relatives.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 STUDY LIMITATIONS
 CONCLUSIONS
 REFERENCES
 
Inclusion of Families and Surviving Relatives
We included all 25 of the unrelated families who were consecutively referred to our cardiogenetics department from 1996 to 2006, in whom a child aged 1 to 18 years had died suddenly and unexpectedly (SCD group). Eight of these families were studied in an analysis of unexplained SCD in subjects aged ≤40 years.12 All of the SCD victims (the probands) were disease-free during lifetime, and there was no known inherited heart disease in the family. Most first-degree relatives (parents and siblings) were referred by their general practitioners or medical specialists, whereas some contacted us directly after they had read laymen publications. To study how the diagnostic yield of studying surviving relatives compares with the diagnostic yield of studying children who sustained aborted SCD, we also studied 10 children with aborted SCD who came to our attention in the same period (aborted SCD group). Aborted SCD was defined as cardiac arrest with VT/ventricular fibrillation, as documented by electrocardiography (ECG), which was aborted by cardiopulmonary resuscitation. These children underwent elaborate cardiologic and genetic assessment themselves. Before any investigation, all of the studied relatives received the opportunity of informed choice after extensive genetic counseling that included discussions of potential advantages and disadvantages of presymptomatic cardiologic and genetic screening. This study was performed in accordance with the Declaration of Helsinki and with written, informed consent of all of the patients/parents.

Cardiologic and Genetic Assessment
We studied demographic variables, medical histories, and triggers/circumstances of SCD (exercise, stress, swimming, and rest). Autopsy results were analyzed if available. In addition, we performed cardiac investigation (12-lead ECG, echocardiography, exercise testing, and Holter recording) of first-degree (n = 84) and second-degree (n = 9) relatives. When a particular diagnosis was suspected or the circumstances of SCD were specific for a particular disease (eg, SCD during swimming or exercise is highly suggestive of long QT; LQT1), DNA analysis was conducted in the proband or an affected relative (if DNA of the proband was not available). DNA was extracted from peripheral blood lymphocytes (relatives) or from stored tissue specimens after autopsy (probands). The polymerase chain reaction technique amplified the genomic DNA, and mutation detection was performed either by direct sequencing, by single-stranded conformational polymorphism, or by denaturing high-performance liquid chromatography, followed by direct sequencing of fragments with an abnormal elution profile. To determine whether a particular DNA variant was disease causing, ≥100 control subjects were screened to exclude the variant as a common polymorphism. Furthermore, literature was searched for previously published information about the specific DNA variant, the nature of the DNA/amino acid change was determined (nonsense, missense, insertion/deletion, frameshift, or splice site), and the degree of conservation among different species was studied, in addition to the chemical changes in the protein, caused by the mutation. When a DNA variant contained pathogenic properties, segregation with the phenotype in the family was analyzed.

Statistical Analysis
Statistical analysis was performed with SPSS 12.0.1 (SPSS Inc, Chicago, IL). Continuous variables were expressed as mean ± SD. Group comparisons were made with the {chi}2 or Fisher's exact test. P values of <.05 were considered statistically significant.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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 REFERENCES
 
The mean age of the 25 probands in the SCD group was 12.3 ± 3.8 years; 15 were boys. Fifteen probands died during physical exercise (7 during swimming) and 10 at rest (Table 1). Postmortem analysis was performed in 20 (Fig 1). This revealed HCM in 2 and viral myocarditis in 1. Cardiologic assessment in 93 first-degree and second-degree relatives revealed a diagnosis in another 11 families. This included primary electrical diseases in 10 (LQTS: n = 7; CPVT: n = 3) and ARVC in 1. Overall, we identified an inherited disease in 13 (52%) of 25 families and the likely cause of SCD of the proband in 14 (56%) of 25.


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  		TABLE 1 Families Studied After SCD of Proband

 

Figure 1
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  		FIGURE 1 Algorithm to establish postmortem diagnosis in a victim of SCD.

 
The mean age of the 10 children who we studied after aborted SCD was 11.8 ± 5.0 years; 7 were boys. In 6 children, a diagnosis of LQTS (n = 4) and CPVT (n = 2; Table 2) was obtained (60%). This diagnostic yield was not significantly different from the yield in families in whom analysis was limited to surviving relatives (P = .567).


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  		TABLE 2 Probands Studied After Aborted SCD

 
We investigated whether the trigger of SCD (distinguishing the general categories "rest associated" and "exercise associated") modified the likelihood of establishing the diagnosis. Taking the SCD and aborted SCD groups together (n = 35), a diagnosis was made in 14 (67%) of 21 of children who sustained (aborted) SCD during exercise, whereas this proportion was 6 (43%) of 14 among those who sustained (aborted) SCD at rest. These proportions were not significantly different (P = .163). Among 9 (aborted) SCD cases specifically related to swimming, a (molecular genetic) diagnosis was made in 7. In the 2 remaining cases, no DNA of the SCD victims was available.

Combining the SCD and aborted SCD groups, a disease-causing mutation in either a first-degree relative or the index patient confirmed the diagnosis in 17 of 19 families (LQTS: n = 9 of 11; CPVT: n = 5 of 5; HCM: n = 2 of 2; ARVC: n = 1 of 1; Tables 1 and 2). All of the CPVT families had mutations in RYR2 (cardiac ryanodine receptor). In the LQTS families, mutations in KCNQ1, KCNH2, and SCN5A (LQT1, LQT2, and LQT3, respectively) were found. In the HCM and ARVC families, mutations were found in MYBPC3 (myosin-binding protein C) and PKP2 (plakophilin-2), respectively. In 3 children (both patients with HCM and 1 patient with LQTS), DNA analysis revealed compound heterozygote mutations.


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
STUDY LIMITATIONS
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 REFERENCES
 
Inherited heart diseases are found in significant proportions (≥50%–60%) in children aged 1 to 18 years who sustained (aborted) SCD whose families were referred to our cardiogenetics department. Of note, we identified similarly high proportions of such inherited diseases in the SCD group (where diagnosis relied on autopsy and/or investigation of surviving relatives) and the aborted SCD group (where the children with aborted SCD episodes could be studied themselves). Thus, elaborate cardiologic and genetic evaluation of surviving relatives of a child who sustained SCD seems to have the maximally achievable diagnostic yield and is, therefore, strongly recommended even when the SCD victim can no longer be studied.

We found striking differences in the types of diagnoses and the number of relatives available for a cardiologic assessment when we compared these results with previous studies in which SCD in adults was studied. Ten of the present 14 diagnoses are primary electrical diseases (LQTS: n = 7; CPVT: n = 3). In contrast, studies in adults found that the main causes of SCD are structural abnormalities, including HCM and ARVC. It is likely that the relatively low number of structural heart disorders in our cohort is partly explained by the fact that our institution is a tertiary referral center and that the patients and families were mostly referred when autopsy, conducted by the referring physician, had not revealed structural abnormalities. Moreover, the young age of SCD in our cohort may have played a role. Structural heart diseases, such as HCM and ARVC, usually do not develop sufficiently rapidly over time for life-threatening arrhythmias to appear at this young age. Both children in this study in whom HCM was diagnosed carried compound heterozygote mutations to explain the severe clinical phenotype. Disease manifestations of HCM, in particular, are usually rare in young children,14 but a malignant outcome is frequently observed in patients with homozygous or compound heterozygous mutations.15–17 Conversely, it is well established that children with LQTS and CPVT mutations are at higher risk of serious and life-threatening arrhythmias. Swimming has been identified as a specific trigger in LQTS type 118 and CPVT,19 diagnoses that were also obtained in our patients. Accordingly, a diagnosis was made in a particularly high proportion (7 of 9) of (aborted) SCD cases related to swimming. In both remaining cases, no DNA of the SCD victim was available. Because of this, identification of (de novo) LQTS (KCNQ1) or CPVT (RYR2)–associated DNA variants was not possible.

Although SCD of a child has a profound psychological impact, there were fewer surviving relatives available for cardiologic or genetic investigation than in similar studies in adult SCD victims.12 This discrepancy may be explained by the fact that family screening starts preferably with first-degree relatives. Children have, on average, fewer first-degree relatives than adults: they do not have children by themselves and probably also fewer siblings, because the family might not be completed yet. Yet, the proportion of families in whom a diagnosis was found was similar, if not higher, than in studies on adult SCD victims. Of interest, the diagnostic yield through investigation of relatives of a deceased child seems to be comparable with the yield of diagnosis in the probands with aborted SCD themselves. The high proportion of families in whom a diagnosis could be established warrants thorough investigation of relatives of a deceased child. This is particularly relevant, because this may reveal which relatives may be disease carriers, and, consequently, also at risk of serious arrhythmias and SCD. This analysis is particularly facilitated if a disease-causing mutation has been identified, because this allows for DNA testing for carriership. Therefore, we advise general practitioners and pediatricians to refer parents (and other first-degree relatives) of a child who died suddenly and unexpectedly to a cardiogenetics department for cardiologic investigation, genetic counseling, and DNA analysis.3


   STUDY LIMITATIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 STUDY LIMITATIONS
CONCLUSIONS
 REFERENCES
 
Autopsies were not performed in all cases (because this is not mandatory in the Netherlands), nor did we revise all of the autopsies conducted elsewhere. Of 25 SCD victims, autopsies were conducted or revised in 20 and yielded 3 diagnoses (HCM: n = 2; myocarditis [after revision]: n = 1). In 8 of the remaining 17 SCD cases with available pathology specimens, a primary electrical disease was identified as the most likely cause of SCD after cardiologic workup in surviving relatives. Of the other 9 autopsies, a complete revision was attempted in 1; however, we could not recover sufficient material (notably, ARVC could not be diagnosed or excluded because the right ventricular tissue had not been stored). It is conceivable that a full revision of these autopsies may have revealed a higher proportion of structural heart diseases, more comparable with earlier studies. Still, we have now established that a proportion of SCD cases in children may be explained by primary electrical diseases. Of note, these potential causes were not analyzed in previous studies in which only autopsy studies were performed. These electrical diseases can only be diagnosed in survivors of aborted SCD or relatives. Overall, it is likely that the primary electrical diseases identified here may increase the overall proportion of SCD in children with a causal diagnosis.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 STUDY LIMITATIONS
 CONCLUSIONS
REFERENCES
 
In the children aged 1 to 18 years that we studied, SCD is, in part, caused by inherited heart disease, both structural (HCM and ARVC) and primary electrical (LQTS and CPVT). These familial diseases can be identified in high proportion even after the SCD victim has died, that is, by postmortem analysis or cardiologic and genetic investigation of surviving relatives. Referral to a cardiogenetics department is encouraged, because such departments offer not only cardiologic investigation and DNA analysis but also specialized genetic counseling, including psychosocial support.


   FOOTNOTES
 
Accepted Mar 14, 2007.

Address correspondence to Arthur A. M. Wilde, MD, PhD, Department of Cardiology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, Netherlands. E-mail: a.a.wilde{at}amc.uva.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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