Coll Monica, Allegue Catarina, Partemi Sara, Mates Jesus, Del Olmo Bernat, Campuzano Oscar, Pascali Vincenzo, Iglesias Anna, Striano Pasquale, Oliva Antonio, Brugada Ramon
Cardiovascular Genetics Center, University of Girona-IDIBGI, 17003, Girona, Spain.
Institute of Public Health, Section of Legal Medicine, Catholic University, Largo F. Vito 1, 00168, Rome, Italy.
Int J Legal Med. 2016 Mar;130(2):331-9. doi: 10.1007/s00414-015-1269-0. Epub 2015 Sep 30.
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.
癫痫猝死（SUDEP）被定义为在良性情况下，癫痫患者突然发生的、无创伤性的、有目击者或无目击者的死亡，无论是否有癫痫发作证据，且排除记录在案的癫痫持续状态（发作持续时间≥30分钟或发作后未恢复），尸检未发现死因。尽管SUDEP背后的生理病理机制仍有待阐明，但遗传背景已被描述为在这种疾病中起作用。与癫痫相关且编码心脏离子通道的基因中的致病变异可能解释SUDEP的表型。为了验证这一点，我们使用下一代测序技术对一组SUDEP病例进行测序，并将其应用于临床和法医领域。使用靶向重测序面板研究了14例SUDEP病例，其中包括2例尸检病例和12例在世患者病例。对已经与SUDEP相关的基因以及候选基因进行了研究。总体而言，在13例SUDEP病例中鉴定出24个罕见的遗传变异。4例病例在SCN1A、FBN1、HCN1、SCN4A和EFHC1基因中显示出罕见变异且完全分离，1例在KCNQ1基因中有罕见变异的病例显示出不完全的遗传模式。在4例病例中，在CACNA1A、SCN11A、SCN10A和KCNQ1基因中检测到罕见变异，但由于缺乏亲属的DNA，无法进行家族分离分析。最后，在其余4例病例中，罕见变异在家族中未分离。这项研究证实了癫痫、猝死和心脏病之间的联系。此外，我们确定了SUDEP的新潜在候选基因：FBN1、HCN1、SCN4A、EFHC1、CACNA1A、SCN11A和SCN10A。特别是如果将SUDEP的基因筛查应用于法医学和临床医学，有必要在更大的队列中进行进一步验证。然而，这项研究支持了遗传决定的心脑通道病这一新兴概念。
