Utility and limitations of exome sequencing as a genetic diagnostic tool for conditions associated with pediatric sudden cardiac arrest/sudden cardiac death.

BACKGROUND: Conditions associated with sudden cardiac arrest/death (SCA/D) in youth often have a genetic etiology. While SCA/D is uncommon, a pro-active family screening approach may identify these inherited structural and electrical abnormalities prior to symptomatic events and allow appropriate surveillance and treatment. This study investigated the diagnostic utility of exome sequencing (ES) by evaluating the capture and coverage of genes related to SCA/D. METHODS: Samples from 102 individuals (13 with known molecular etiologies for SCA/D, 30 individuals without known molecular etiologies for SCA/D and 59 with other conditions) were analyzed following exome capture and sequencing at an average read depth of 100X. Reads were mapped to human genome GRCh37 using Novoalign, and post-processing and analysis was done using Picard and GATK. A total of 103 genes (2,190 exons) related to SCA/D were used as a primary filter. An additional 100 random variants within the targeted genes associated with SCA/D were also selected and evaluated for depth of sequencing and coverage. Although the primary objective was to evaluate the adequacy of depth of sequencing and coverage of targeted SCA/D genes and not for primary diagnosis, all patients who had SCA/D (known or unknown molecular etiologies) were evaluated with the project's variant analysis pipeline to determine if the molecular etiologies could be successfully identified. RESULTS: The majority of exons (97.6 %) were captured and fully covered on average at minimum of 20x sequencing depth. The proportion of unique genomic positions reported within poorly covered exons remained small (4 %). Exonic regions with less coverage reflect the need to enrich these areas to improve coverage. Despite limitations in coverage, we identified 100 % of cases with a prior known molecular etiology for SCA/D, and analysis of an additional 30 individuals with SCA/D but no known molecular etiology revealed a diagnostic answer in 5/30 (17 %). We also demonstrated 95 % of 100 randomly selected reported variants within our targeted genes would have been picked up on ES based on our coverage analysis. CONCLUSIONS: ES is a helpful clinical diagnostic tool for SCA/D given its potential to successfully identify a molecular diagnosis, but clinicians should be aware of limitations of available platforms from technical and diagnostic perspectives.

Cardiovascular deaths in children: general overview from the National Center for the Review and Prevention of Child Deaths.

BACKGROUND: Cardiovascular conditions rank sixth in causes of death in 1- to 19-year-olds. Our study is the first analysis of the cardiovascular death data set from the National Center for the Review and Prevention of Child Deaths, which provides the only systematic collection of cardiovascular deaths in children. METHODS: We developed an analytical data set from the National Center for the Review and Prevention of Child Deaths database for cardiovascular deaths in children 0 to 21 years old, reviewing 1,098 cases from 2005 to 2009 in 16 states who agreed to participate. RESULTS: Cardiovascular cases were aged 4.8 ± 6.6 years; 55.3%, ≤1 year; 24.6%, ≥10 years; male, 58%; white, 70.5%; black, 22.3%; Hispanic, 19.5%. Prior conditions were present in 48.5%: congenital heart disease, 23%; cardiomyopathies, 4.6%; arrhythmia, 1.7%; and congestive heart failure, 1.6%. Deaths occurred most frequently in urban settings, 49.2%; and in the hospital, 40.4%; home, 26.1%; or at school/work/sports, 4.8%. Emergency medical services were not evenly distributed with differences by age, race, ethnicity, and area. Autopsies (40.4%) occurred more often in those >10 years old (odds ratio [OR] 2.9), blacks (OR 1.6), or in those who died at school/work/sports (OR 3.9). The most common cardiovascular causes of death included congenital heart disease, 40.8%; arrhythmias, 27.1%; cardiomyopathy, 11.8%; myocarditis, 4.6%; congestive heart failure, 3.6%; and coronary artery anomalies, 2.2%. CONCLUSIONS: Our study identified differences in causes and frequencies of cardiovascular deaths by age, race, and ethnicity. Prevention of death may be impacted by knowledge of prior conditions, emergency plans, automated external defibrillator programs, bystander cardiopulmonary resuscitation education, and by a registry for all cardiovascular deaths in children.

Development of a data set of national cardiovascular deaths in the young.

BACKGROUND: The only systematic collection of cardiovascular (CV) deaths in children resides in the database derived from the Case Reporting System of the National Center for the Review and Prevention of Child Deaths (NCRPCD). We describe the process used to develop an analytical data set to inform our understanding of CV deaths in children from this database. METHODS: Twenty-five states reporting natural CV deaths during 2005 to 2009 were contacted. Sixteen states agreed to participate. Cases experienced a natural CV death and were 0 to 21 years. Challenges to building a final analytical data set were identified and included reclassification, recategorization, and the development of new variables from existing data, including an algorithm to identify sudden cardiac deaths. RESULTS: The final data set included 1,098 cases. Missing data comprised a mean of 41.7% for most key variables. Cardiovascular cases were aged 4.8 ± 6.6 years; 55.3%, ≤1 year, 24.6%, ≥10 years; male, 58%; white, 70.5%; black, 22.3%; and Hispanic, 19.5%. CONCLUSIONS: This manuscript provides the first description of the natural CV death data set from the NCRPCD. We identify potential beneficial changes in the NCRPCD Case Reporting System and review process. Analysis of these data will help determine characteristics of CV deaths and allow the assessment of risk factors that can be used to prevent CV death in the young. The rate of CV death can be lowered using knowledge of associations that can be gleaned from this robust database. Best practices for prevention hold promise for a future with fewer deaths that will need to be reviewed.

A discussion of electrocardiographic screening and sudden cardiac death prevention: evidence and consensus.

PURPOSE OF REVIEW: Frequent media reports of sudden cardiac arrest or death (SCA/SCD) keep alive a debate as to how best to prevent these tragedies. Several new studies in the past 2 years serve as an impetus to reframe the debate into a reasonable discussion that seeks to obtain more evidence wherever needed and to develop a consensus wherever possible. RECENT FINDINGS: Since the report from Italy of the 89% decrease in SCD over 25 years of an ECG-based cardiovascular screening program, proponents and opponents of ECG screening have been busily debating. Multiple studies on screening have shown that adding an ECG to a history and physical examination is more sensitive than history and physical examination alone in identifying those potentially at risk. A major gap exists regarding managing these new 'patients' as their clinical course is not known. Reports, without data, have warned of unintended or harmful consequences of ECG screening. Economic models have shown cost-effectiveness of ECG screening to be variable. SUMMARY: Studies suggest that adding an ECG to the screening is a very reasonable effort that will identify at-risk youth and prevent SCD, but more information is needed. If data support the addition of an ECG, efforts should be made to make this opportunity available.

A pilot study of the feasibility of heart screening for sudden cardiac arrest in healthy children.

BACKGROUND: In children, sudden cardiac arrest (SCA) is associated with structural and electrical cardiac abnormalities. No studies have systematically screened healthy school children in the United States for conditions leading to SCA to identify those at risk. METHODS: From June 2006 to June 2007, we screened 400 healthy 5- to 19-year-olds (11.8 ± 3.9 years) in clinical offices at The Children's Hospital of Philadelphia using a medical and family history questionnaire, weight, height, blood pressure, heart rate, cardiac examination, electrocardiogram (ECG), and echocardiogram (ECHO). Our goals were to determine the feasibility of adding an ECG to history and physical examination and to identify a methodology to be used in a larger multicenter study. A secondary objective was to compare identification of cardiovascular abnormalities by history and physical examination, ECG, and ECHO. RESULTS: Previously undiagnosed cardiac abnormalities were found in 23 subjects (5.8%); an additional 20 (5%) had hypertension. Potentially serious cardiac conditions were identified in 10 subjects (2.5%); 7 were suspected or identified by ECG and 3 more only by ECHO. Only 1 of the 10 had symptoms (previously dismissed); none had a positive family history. CONCLUSIONS: It is feasible to screen for conditions associated with SCA in healthy children by adding ECG to history and physical examination. In this nongeneralizable sample, ECG identified more cases compared to history and physical examination alone, with further augmentation from ECHOs. Improvements in ECG and echocardiographic normative standards, representing age, gender, race, and ethnicity, are needed to increase the efficacy of screening in a young population.

Innovative cardiopulmonary resuscitation and automated external defibrillator programs in schools: Results from the Student Program for Olympic Resuscitation Training in Schools (SPORTS) study.

BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) rates are low. Our study objective was to encourage Philadelphia high school students to develop CPR/AED (automated external defibrillator) training programs and to assess their efficacy. The focus was on developing innovative ways to learn the skills of CPR/AED use, increasing willingness to respond in an emergency, and retention of effective psychomotor resuscitation skills. METHODS AND RESULTS: Health education classes in 15 Philadelphia School District high schools were selected, with one Control and one Study Class per school. Both completed CPR/AED pre- and post-tests to assess cognitive knowledge and psychomotor skills. After pre-tests, both were taught CPR skills and AED use by their health teacher. Study Classes developed innovative programs to learn, teach, and retain CPR/AED skills. The study culminated with Study Classes competing in multiple CPR/AED skills events at the CPR/AED Olympic event. Outcomes included post-tests, Mock Code, and presentation scores. All students' cognitive and psychomotor skills improved with standard classroom education (p<0.001). Competition with other schools at the CPR/AED Olympics and the development of their own student-directed education programs resulted in remarkable retention of psychomotor skill scores in the Study Class (88%) vs the Control Class (79%) (p<0.001). Olympic participants averaged 93.1% on the Mock Code with 10 of 12 schools ≥94%. CONCLUSION: Students who developed creative and novel methods of teaching and learning resuscitation skills showed outstanding application of these skills in a Mock Code with remarkable psychomotor skill retention, potentially empowering a new generation of effectively trained CPR bystanders.