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Post-mortem Whole Exome Sequencing with Gene-Specific Analysis for Autopsy-Negative Sudden Unexplained Death in the Young: A Case Series

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Abstract

Annually, thousands of sudden deaths in individuals under 35 years remain unexplained following comprehensive medico-legal autopsy. Previously, post-mortem genetic analysis by Sanger sequencing of four major cardiac channelopathy genes revealed that approximately one-fourth of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation. However, there are now over 100 sudden death-predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes. Here, we set out to determine whether post-mortem whole exome sequencing (WES) is an efficient strategy to detect ultra-rare, potentially pathogenic variants. We performed post-mortem WES and gene-specific analysis of 117 sudden death-susceptibility genes for 14 consecutively referred Caucasian SUDY victims (average age at death 17.4 ± 8.6 years) to identify putative SUDY-associated mutations. On average, each SUDY case had 12,758 ± 2,016 non-synonymous variants, of which 79 ± 15 localized to these 117 genes. Overall, eight ultra-rare variants (seven missense, one in-frame insertion) absent in three publically available exome databases were identified in six genes (three in TTN, and one each in CACNA1C, JPH2, MYH7, VCL, RYR2) in seven of 14 cases (50 %). Of the seven missense alterations, two (T171M-CACNA1C, I22160T-TTN) were predicted damaging by three independent in silico tools. Although WES and gene-specific surveillance is an efficient means to detect rare genetic variants that might underlie the pathogenic cause of death, accurate interpretation of each variant is challenging. Great restraint and caution must be exercised otherwise families may be informed prematurely and incorrectly that the root cause has been found.

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Acknowledgments

This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program, the Sheikh Zayed Saif Mohammed Al Nahyan Fund in Pediatric Cardiology Research, the Dr. Scholl Fund, and the Hannah M. Wernke Memorial Fund. This Project was also supported in part by funding from Mayo Clinic’s Center for Individualized Medicine (CIM).

Conflict of interest

DJT, MJA, and Mayo Clinic receive royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests.

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Authors and Affiliations

  1. Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    Nupoor Narula, David J. Tester, Joseph J. Maleszewski & Michael J. Ackerman

  2. Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN, USA

    David J. Tester, Anna Paulmichl & Michael J. Ackerman

  3. Divisions of Anatomic Pathology and Molecular Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Joseph J. Maleszewski

  4. Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

  5. Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

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  1. Nupoor Narula
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  2. David J. Tester
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  3. Anna Paulmichl
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  4. Joseph J. Maleszewski
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  5. Michael J. Ackerman
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Corresponding author

Correspondence to Michael J. Ackerman.

Additional information

Nupoor Narula and David J. Tester are co-equal first authors.

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Narula, N., Tester, D.J., Paulmichl, A. et al. Post-mortem Whole Exome Sequencing with Gene-Specific Analysis for Autopsy-Negative Sudden Unexplained Death in the Young: A Case Series. Pediatr Cardiol 36, 768–778 (2015). https://doi.org/10.1007/s00246-014-1082-4

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  • DOI: https://doi.org/10.1007/s00246-014-1082-4

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