Approximately 11 000 individuals younger than 45 years in the United States die suddenly and unexpectedly each year from conditions including sudden infant death, pulmonary embolism, ruptured aortic aneurysm, and sudden cardiac death (SCD). Sometimes the cause of death is not determined, even after a clinical autopsy, leaving living relatives with an inaccurate or ambiguous family health history. Moreover, the rate of clinical autopsy has declined from approximately 50% fifty years ago to less than 10% in 2008, contributing further to uncertain family health histories.1 This uncertainty may be partially resolved with postmortem genetic testing (“molecular autopsy”).2 Initial studies, limited to cardiac channelopathy and epilepsy genes, have yielded molecular diagnoses in approximately 25% of cases.3,4 A more comprehensive molecular autopsy program, expanded beyond SCD, has the potential to provide more accurate family health information to a wider spectrum of afflicted families. Here we report preliminary results from a systematic, prospective, family-based, molecular autopsy study.
Exome sequencing was performed on blood or tissue samples collected from deceased persons aged 45 years or younger, with sudden unexpected death, sequentially referred to Scripps Translational Science Institute by the medical examiner between October 2014 and November 2015. Deaths from an external cause or in persons with known comorbid conditions were excluded. Exome sequencing of saliva samples from parents, when available, was also performed. Full details of the genome sequencing, analysis, and interpretation methodology have been previously described.5 Mutations were categorized as likely cause of death (mutation previously reported or expected in an SCD-related gene); plausible cause of death (mutation of unknown significance in an SCD gene); or speculative cause of death (mutation previously reported in other disorders). Reported allele frequencies are the highest population-specific frequencies observed in the Exome Aggregation Consortium Browser. The study was approved by the Scripps institutional review board. Written informed consent was obtained from all participants and from next of kin for deceased individuals.
Twenty-five cases (80% male) were sequenced, with 9 including both parents of the deceased. Clinical autopsies discovered the likely cause of death in 5 cases. A likely cause of death was identified by molecular autopsy in 4 cases (16%), a plausible cause in 6 (24%), and a speculative cause in 7 (28%); no mutations were identified in 8 (32%) (Table). The likely genetic cause of death was corroborated with clinical autopsy findings in 2 of 5 cases. All other clinical autopsy findings (3 cases) could be linked to a plausible or speculative genetic cause. Seventy percent (7/10 cases) of likely and plausible pathogenic mutations were inherited from relatives who did not die suddenly, as determined either by direct observation of the variant in a family member4 or inference based on previous observation in reference populations.3
Molecular autopsy was able to uncover a likely or plausible cause of death in 40% of cases (10/25). Many of the findings were variants of unknown significance inherited from relatives not affected by sudden death and present at population frequencies incompatible with full disease penetrance. Although this study is limited by its small sample size and potentially by selection bias, the observation of likely and plausible pathogenic variants in unaffected relatives is consistent with recent large-scale studies that identified clinically relevant variants in living relatives of SCD cases.4,6 Our study suggests similar findings may be observed in non-SCD sudden death. It should be noted that these speculative and plausible findings cannot definitively be linked to sudden death.
The ambiguity associated with some of these genetic findings should be balanced against the potential for clinical follow-up, active surveillance, or preventive interventions in living relatives. Although molecular autopsies may help identify genetic causes of sudden unexpected death, a comprehensive and systematic effort to collect and share genetic and phenotypic data is needed to more precisely define pathogenic variants and provide quantifiable risks to living relatives.
Corresponding Author: Ali Torkamani, PhD, 3344 N Torrey Pines Court, Ste 300, La Jolla, CA 92037 (firstname.lastname@example.org).
Author Contributions: Dr Torkamani had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Torkamani, Muse, Spencer, Wagner, Topol.
Acquisition, analysis, or interpretation of data: All Authors.
Drafting of the manuscript: Torkamani, Muse, Wagner.
Critical revision of the manuscript for important intellectual content: All Authors.
Statistical analysis: Torkamani, Rueda.
Obtaining funding: Torkamani, Topol.
Administrative, technical, or material support: Torkamani, Spencer, Rueda, Wagner, Lucas.
Study supervision: Torkamani, Muse, Topol.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Dr Torkamani reports grants from the National Institutes of Health, National Center for Advancing Translational Sciences, National Human Genome Research Institute, and other funding from Cypher Genomics. Dr Topol reports personal fees from Illumina and nonfinancial support from Genapys and Edico Genome. No other disclosures were reported.
Funding/Support: This work is supported by a National Institutes of Health and National Center for Advancing Translational Sciences clinical and translational science award (5-UL1-RR025774) and grants U01HG006476 and U54GM114833 from Scripps Genomic Medicine.
Role of the Funders/Sponsors: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the deceased patients’ families for their cooperation. We also thank Galina Erikson, BS (Scripps Genomic Medicine), for her work on the pilot program and Dov Fox, JD (San Diego State University), for his input. These persons received no compensation for their contributions.
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