2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families

Stiles, Martin K.; Wilde, Arthur A.M.; Abrams, Dominic J.; Ackerman, Michael J.; Albert, Christine M.; Behr, Elijah R.; Chugh, Sumeet S.; Cornel, Martina C.; Gardner, Karen; Ingles, Jodie; James, Cynthia A.; Juang, Jyh Ming Jimmy; Kääb, Stefan; Kaufman, Elizabeth S.; Krahn, Andrew D.; Lubitz, Steven A.; MacLeod, Heather; Morillo, Carlos A.; Nademanee, Koonlawee; Probst, Vincent; Saarel, Elizabeth V.; Sacilotto, Luciana; Semsarian, Christopher; Sheppard, Mary N.; Shimizu, Wataru; Skinner, Jonathan R.; Tfelt-Hansen, Jacob; Wang, Dao Wu

doi:10.1002/joa3.12449

Cited by 26 publications

(18 citation statements)

References 369 publications

(714 reference statements)

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“…Despite the relatively small number of clinically actionable gene variants, our findings are consistent with current guidelines 47 which support the use of genetic testing in young SCA victims. Cascade genetic testing facilitates recognition of family members that are at an increased risk of SCD and may therefore benefit from preventive interventions.…”

Section: Discussionsupporting

confidence: 88%

Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

Holmström

Chaudhary

Nakamura

et al. 2022

Preprint

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Background: Sudden cardiac arrest (SCA) is a rare and tragic event among the young and often caused by inherited cardiac disease. Previous studies have investigated referral cohorts, but the prevalence of disease-associated variants is unclear at the community level. We investigated the prevalence of genetic variants among community-based cases of SCA aged <21 years. Methods: The study sample is obtained from two prospective, community-based studies of out-of-hospital SCA ongoing in the Portland, OR metro area (population ~1 million) and Ventura County CA (population ~850,000). We performed next-generation whole genome sequencing and then rare variant analysis of candidate genes associated with arrhythmic syndromes and cardiomyopathy in ClinGen. Results: The mean age of the study subjects was 11.3 years (SD 8.0 years, 30% non-white, 45% female). We found that 36 of 52 young SCA victims (69%) harbored uncertain, likely pathogenic (LP), or pathogenic (P) variants. Eight subjects (15%) carried 9 LP/P variants. Patients with clinical histories suggesting primary arrhythmic syndromes or hypertrophic cardiomyopathy were more likely to harbor clinically actionable variants or variants of unknown significance (VUS), than subjects with myocarditis, sudden infant death syndrome, or sudden arrhythmic death. Variants were more likely to be classified as LP/P among Whites (8/9, 88.9%) as compared to non-Whites (1/9, 11.1%, p = 0.036). Conclusions: A notable proportion of young SCA victims in the community harbor rare, potentially disease-associated gene variants, and further studies are needed to understand variants of unknown significance. We identified differences by phenotype groups and race that have potential implications for genetic testing.

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Section: Discussionsupporting

confidence: 88%

Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

Holmström

Chaudhary

Nakamura

et al. 2022

Preprint

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“…Despite the clear recommendation to screen FDRs of SUD victims, we found that only 9.4% were screened in the current study [ 12 ]. The fact that 40% of SUD-FDR families have more than one SUD case highlight the lost opportunity of potentially preventing subsequent cases had a proper evaluation been performed after the first SUD case.…”

Section: Discussionmentioning

confidence: 62%

Prevalence and characteristics of family history of sudden unexplained death and predictors of negative attitude of family members toward medical autopsy and family screening in Saudi Arabia: A cross-sectional study

Alqarawi

Muammar²,

Alajlan³

et al. 2022

PLoS ONE

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Introduction Little is known about sudden unexplained death (SUD) in Saudi Arabia. Moreover, family screening and medical autopsy are not routinely performed due to perceived religious and cultural resistance. However, this has never been systematically examined. We sought to describe the prevalence and characteristics of family history of SUD and the attitude of family members toward medical autopsy and family screening. Methods This was a cross-sectional study utilizing an online survey distributed though social media platforms from August 15 to September 15, 2021. Participants’ characteristics, details about SUD cases, and the attitude toward medical autopsy and family screening were collected. Multivariable logistic regression was used to identify independent predictors of negative attitude toward medical autopsy. Results A total of 11374 were included in the final analysis after excluding children. The prevalence of FHx of at least one first degree relative (FDR) with SUD was found to be 9.4% [95% CI (8.9% - 10%)]. Among participants with any FHx of SUD, 1346/3489 (38.6%) had ≥ 2 family members affected. Only 183 participants with a FHx of SUD visited a physician for the purpose of family screening (183/3489, 5.3%). The total number of SUD cases reported was 5474. Of those, 22% were 35-year-old or younger. Only 22% of participants (2458/11374) had a negative attitude towards medical autopsy, and the most common reason was the perceived lack of benefit. Older age (> 35 years), family history of SUD, female gender, and lack of knowledge about the yield of medical autopsy were associated with negative attitude in the adjusted analysis. Conclusion SUD occurred at young age and affected multiple family members in a significant proportion of families. Despite that, family screening was seldom performed. There is an urgent need to improve the care of SUD by incorporating medical autopsy and developing clinical pathways to screen family members.

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“…Clinical assessment of family members should be also performed, including physical examination, ECGs, cardiac imaging, ambulatory monitoring, and provocative testing with multidisciplinary team supervision. Follow-up and periodic re-evaluation are important and are directed by initial findings 47 .…”

Section: Recommendationsmentioning

confidence: 99%

Molecular autopsy in sudden cardiac death

Campuzano

Sarquella‐Brugada

2023

gcsp

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A post-mortem genetic analysis in the process of investigating a sudden death episode is known as ‘molecular autopsy’. It is usually performed in cases without a conclusive cause of death and after a comprehensive medico-legal autopsy. In these sudden unexplained death cases, an underlying inherited arrhythmogenic cardiac disease is the main suspected cause of death. The objective is to unravel a genetic diagnosis of the victim, but it also enables cascade genetic screening of the victim’s relatives. Early identification of a deleterious genetic alteration associated with an inherited arrhythmogenic disease may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death. It is important to remark that the first symptom of an inherited arrhythmogenic cardiac disease may the malignant arrhythmia and even sudden death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis. Close interaction between the forensic scientist, pathologist, cardiologist, pediatric cardiologist and geneticist has allowed a progressive increase of genetic yield in recent years, identifying the pathogenic genetic alteration. However, large numbers of rare genetic alterations remain classified as having an ambiguous role, impeding a proper genetic interpretation and useful translation into both forensic and cardiological arena.

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2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families

Cited by 26 publications

References 369 publications

Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

Prevalence and characteristics of family history of sudden unexplained death and predictors of negative attitude of family members toward medical autopsy and family screening in Saudi Arabia: A cross-sectional study

Molecular autopsy in sudden cardiac death

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