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Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

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Abstract

Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy.

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Acknowledgments

This work was partly supported by “Fundació La Caixa.” We also thank the Genetic Commission of the Italian League Against Epilepsy for the collaboration.

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Authors and Affiliations

  1. Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain

    Monica Coll, Catarina Allegue, Jesus Mates, Bernat Del Olmo, Oscar Campuzano, Anna Iglesias & Ramon Brugada

  2. Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain

    Oscar Campuzano & Ramon Brugada

  3. Cardiac Genetics Unit, Cardiology Service, Hospital Josep Trueta, Girona, Spain

    Ramon Brugada

  4. Institute of Public Health, Section of Legal Medicine, Catholic University, Largo F. Vito 1, 00168, Rome, Italy

    Sara Partemi, Vincenzo Pascali & Antonio Oliva

  5. Pediatric Neurology and Neuromuscular Diseases Unit, Department of Neurosciences, Instituto G. Gaslini, University of Genova, Genoa, Italy

    Pasquale Striano

Authors
  1. Monica Coll
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  2. Catarina Allegue
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  3. Sara Partemi
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  4. Jesus Mates
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  5. Bernat Del Olmo
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  6. Oscar Campuzano
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  7. Vincenzo Pascali
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  8. Anna Iglesias
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  9. Pasquale Striano
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  10. Antonio Oliva
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  11. Ramon Brugada
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Corresponding authors

Correspondence to Antonio Oliva or Ramon Brugada.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Antonio Oliva and Ramon Brugada are co-senior authors.

Contributors

Carlo Minetti MD, PhD, Pediatric Neurology and Neuromuscular Diseases Unit, Department of Neurosciences; Institute G. Gaslini, University of Genova, Genoa, Italy

Susanna Casellato, Department of Child Neuropsychiatry, University of Sassari, Sassari, Italy

Federico Zara PhD, Laboratory of Neurogenetics, Department of Neurosciences; Institute G. Gaslini, Genoa, Italy

Amedeo Bianchi, MD, Department of Neurology and Epilepsy Centre, San Donato Hospital, Arezzo, Italy

Angela La Neve, Titti Francavilla, MD, Department of Neurological and Psychiatric Sciences, Section of 1st Neurologic Clinic, University of Bari, Bari, Italy

Carlo Alberto Tassinari MD, Department of Neurological Sciences, University of Bologna, Bologna, Italy

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Coll, M., Allegue, C., Partemi, S. et al. Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing. Int J Legal Med 130, 331–339 (2016). https://doi.org/10.1007/s00414-015-1269-0

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