title: Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing.
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.
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Coll
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain.
authors.forename: Catarina
authors.initials: C
authors.lastname: Allegue
authors.affiliation: Institute of Public Health, Section of Legal Medicine, Catholic University, Largo F. Vito 1, 00168, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Partemi
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Mates
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain.
authors.forename: Bernat
authors.initials: B
authors.lastname: Del Olmo
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain.|Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Campuzano
authors.affiliation: Institute of Public Health, Section of Legal Medicine, Catholic University, Largo F. Vito 1, 00168, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pascali
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Pediatric Neurology and Neuromuscular Diseases Unit, Department of Neurosciences, Instituto G. Gaslini, University of Genova, Genoa, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.affiliation: Institute of Public Health, Section of Legal Medicine, Catholic University, Largo F. Vito 1, 00168, Rome, Italy. antonio.oliva@rm.unicatt.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliva
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain. ramon@brugada.org.|Department of Medical Sciences, School of Medicine, University of Girona, Girona, Spain. ramon@brugada.org.|Cardiac Genetics Unit, Cardiology Service, Hospital Josep Trueta, Girona, Spain. ramon@brugada.org.
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002135:Calcium-Binding Proteins / Q000235:genetics; D003645:Death, Sudden / Q000209:etiology*; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D000071838:Fibrillin-1 / Q000235:genetics; D053803:Forensic Genetics; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008297:Male; D008875:Middle Aged; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics; D055815:Young Adult; D054392:Adipokines
chemical_list: D002135:Calcium-Binding Proteins; D000071838:Fibrillin-1; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D051657:KCNQ1 Potassium Channel; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062553:NAV1.4 Voltage-Gated Sodium Channel; D015221:Potassium Channels; C489648:EFHC1 protein, human; C000605722:FBN1 protein, human; D054392:Adipokines; C578665:HCN1 protein, human; C496909:KCNQ1 protein, human; C568242:SCN1A protein, human; C106251:SCN4A protein, human
keywords: Epilepsy; Next-generation sequencing; SUDEP; Sudden cardiac death