Genomic Autopsy of Sudden Deaths in Young Individuals.

Importance: Postmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information. Objective: To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families. Design, Setting, and Participants: Pathological and whole-genome sequence analysis was conducted in a cohort referred from a national network of medical examiners. Cases were accrued prospectively from May 2015 to March 2019 across 24 US states. Analysis began September 2016 and ended November 2020. Exposures: Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation. Results: A total of 103 decedents (mean [SD] age at death, 23.7 [11.9] years; age range, 1-44 years), their surviving family members, and 140 sex- and genetic ancestry-matched controls were analyzed. Among 103 decedents, autopsy and clinical data review categorized 36 decedents with postmortem diagnoses, 23 decedents with findings of uncertain significance, and 44 with sudden unexplained death. Pathogenic/likely pathogenic (P/LP) genetic variants in arrhythmia or cardiomyopathy genes were identified in 13 decedents (12.6%). A multivariable analysis including decedent phenotype, ancestry, and sex demonstrated that younger decedents had a higher burden of P/LP variants and select variants of uncertain significance (effect size, -1.64; P = .001). These select, curated variants of uncertain significance in cardiac genes were more common in decedents than controls (83 of 103 decedents [86%] vs 100 of 140 controls [71%]; P = .005), and decedents harbored more rare cardiac variants than controls (2.3 variants per individual vs 1.8 in controls; P = .006). Genetic testing of 31 parent-decedent trios and 14 parent-decedent dyads revealed 8 transmitted P/LP variants and 1 de novo P/LP variant. Incomplete penetrance was present in 6 of 8 parents who transmitted a P/LP variant. Conclusions and Relevance: Whole-genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes. Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort.

Surveillance Cultures and Infection in 230 Pacemaker and Defibrillator Generator Changes in Pediatric and Adult Congenital Patients.

BACKGROUND: Postoperative infections can occur during surgical replacement of pulse generators for pacemakers and implantable cardioverter-defibrillators. The incidence of infection is poorly documented in children and patients with adult congenital heart disease. The utility of surveillance cultures obtained from device pocket swabs is unknown in this group. METHODS: We reviewed surgical replacements of cardiovascular implantable pulse generators from 2010 to 2017. Two cohorts were defined. In a surveillance cohort (123 patients), aerobic and anaerobic culture swabs of the device pocket were obtained at the time of generator change. In a nonsurveillance cohort (107 patients), generator change occurred without obtaining cultures. RESULTS: During 230 generator changes (mean patient age 19 years; 77% with structural congenital heart disease), two clinical infections occurred at the surgical site (0.9% incidence). Neither infection occurred in the surveillance cohort. Cultures were positive in 12 (9.8%) of 123 patients in the surveillance cohort, but 11 of 12 were likely contaminants and none were subsequently associated with clinical disease. There was no association between clinical infection or positive surveillance cultures and the location of pulse generator, the presence of other concurrent surgeries, or a history of prior pocket infection. CONCLUSIONS: Clinical infection was rare after pulse generator change in children and young adults. No cases required reintervention on the pocket. Surveillance cultures did not improve clinical care. These data extend current recommendations that surveillance cultures are not required during generator change to the pediatric and young adult population.

Changes in genetic variant results over time in pediatric cardiomyopathy and electrophysiology.

Genetic testing for cardiac disorders continues to change. Our objective was to assess trends in variant classification in pediatric arrhythmia and cardiomyopathy. We conducted a retrospective review of patients tested for genetic arrhythmia and cardiomyopathy disorders from 2006-2017. Variants were classified by CLIA laboratories. Trends were assessed by the Spearman correlation. There were 914 variants in 583 patients from 337 families. The total number of tests ordered increased over time, accelerating after 2012. There was a strong positive correlation between the average number of genes tested per panel and year of testing (r = .97, p < .001) and a weak correlation between the year and a decrease in the percentage of clinically actionable variants (r = -.20, p = .005). By 2011, VUS represented >50% of variants reported on panels. Over 12 years, 203 genes were interrogated; one or more variants were reported in 91 of 203 genes (45%). 32% of patients had at least one clinically actionable variant; 28% had at least one VUS. Reclassification is an important long-term issue, with 21.5% variants changing clinical interpretation. We observed an increase over time in three areas: total number of tests ordered, average number of genes/panel, and percentage of VUS. Providers may need to interpret results from 90 + genes, and ongoing education is critical. Due to their specific training in test result interpretation, we recommend the inclusion of a genetic counselor in pediatric electrophysiology and cardiomyopathy teams.

Prevalence of Abnormal Heart Weight After Sudden Death in People Younger than 40 Years of Age.

Background After sudden cardiac death in people aged <40 years, heart weight is a surrogate for cardiomegaly and a marker for cardiomyopathy. However, thresholds for cardiomegaly based on heart weight have not been validated in a cohort of cases of sudden cardiac death in young people. Methods and Results We surveyed medical examiner offices to determine which tools were used to assess heart weight norms. The survey determined that there was no gold standard for cardiomegaly (52 centers reported 22 different methods). We used a collection of heart weight data from sudden deaths in the Northwestern Sudden Death Collaboration (NSDC) to test the 22 methods. We found that the methods reported in our survey had little consistency: they classified between 18% and 81% of NSDC hearts with cardiomegaly. Therefore, we obtained biometric and postmortem data from a reference population of 3398 decedents aged <40 years. The reference population was ethnically diverse and had no known cardiac pathology on autopsy or histology. We derived and validated a multivariable regression model to predict normal heart weights and a threshold for cardiomegaly (upper 95% CI limit) in the young reference population (the Chicago model). Using the new model, the prevalence of cardiomegaly in hearts from the NSDC was 19%. Conclusions Medical examiner offices use a variety of tools to classify cardiomegaly. These approaches produce inconsistent results, and many overinterpret cardiomegaly. We recommend the model proposed to classify postmortem cardiomegaly in cases of sudden cardiac death in young people.

Cardiac Evaluation of Children With a Family History of Sudden Death.

BACKGROUND: After sudden death occurs in the young, first-degree family members should undergo clinical screening for occult cardiac disease, but the diagnostic yield from screening is not well-defined in the United States. OBJECTIVES: The purpose of this study was to determine the clinical predictors of cardiac diagnosis in children referred for evaluation following a sudden death in the family. METHODS: Patients referred for a family history of sudden death were evaluated in a retrospective review from a tertiary pediatric referral center. RESULTS: Among 419 pediatric relatives of 256 decedents, 27% of patients were diagnosed with a disease or had a clinical finding of uncertain significance. Patients were diagnosed with heritable cardiac disease in 39 cases (9.3%). Nonheritable cardiac disease was diagnosed in another 5.5% of patients. Clinical findings of uncertain significance were present in 52 patients (12.4%), including abnormal electrophysiological test results (41 of 52) or imaging test results (11 of 52). Among patients diagnosed with a heritable cardiac disease, the nearest affected relative was almost always a first-degree relative (37 of 39, 95%). The strongest predictors for a successful diagnosis in the patient were an abnormal electrocardiogram and a first-degree relationship to the nearest affected relative (odds ratios: 24.2 and 18.8, respectively). CONCLUSIONS: Children referred for a family history of sudden death receive cardiac disease diagnoses (14%), but clinical findings of uncertain significance increase the challenge of clinical management. The importance of a diagnosis in first-degree affected relatives supports the clinical practice of testing intervening family members first when patients are second- or higher-degree relatives to the decedent.