Campuzano Oscar, Sanchez-Molero Olallo, Mademont-Soler Irene, Coll Monica, Allegue Catarina, Ferrer-Costa Carles, Mates Jesus, Perez-Serra Alexandra, Del Olmo Bernat, Iglesias Anna, Sarquella-Brugada Georgia, Brugada Josep, Borondo Juan Carlos, Castella Josep, Medallo Jordi, Brugada Ramon
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain.
Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
Forensic Sci Int. 2017 Feb;271:120-125. doi: 10.1016/j.forsciint.2016.12.035. Epub 2017 Jan 3.
Sudden cardiac arrest is a leading cause of death worldwide. Most cardiac arrests happen in patients who have previously suffered a myocardial infarct. The risk of sudden death after infarction may increase in people who carry a pathogenic genetic alteration in cardiac ion channels. We hypothesized that micro-ischemia could trigger lethal arrhythmogenesis, thus we sought to identify genetic alterations in cardiac ion channels in patients with micro-ischemic disease. We studied a cohort of 56 post-mortem samples. Autopsy studies identified myocardial infarction as the cause of death in each case. We used both Sanger sequencing and next-generation sequencing to screen candidate genes associated with sudden cardiac death. We identified six rare missense genetic variations in five unrelated patients. Two variants have been previously reported; one is associated with atrial fibrillation (SCN5A_p.H445D), and the other is predicted to be benign (ANK2_p.T2059M). The novel variants were predicted in silico as benign, except for one (RyR2_p.M4019T), which was classified as deleterious. Our post-mortem, micro-infarction cohort displayed a rate of nearly 10% non-common genetic variants. However, the clinical significance of most of the identified variants remains unknown due to lack of family assessment. Further analyses should be performed in large cohorts to clarify the role of ion-channel gene analysis in samples showing microscopic ischemic alterations.
心脏骤停是全球主要的死亡原因之一。大多数心脏骤停发生在既往有心肌梗死的患者中。携带心脏离子通道致病性基因改变的人在心肌梗死后猝死的风险可能会增加。我们推测微缺血可能触发致命性心律失常的发生，因此我们试图确定微缺血性疾病患者心脏离子通道的基因改变。我们研究了一组56份尸检样本。尸检研究确定每例患者的死亡原因均为心肌梗死。我们使用桑格测序和下一代测序来筛选与心脏性猝死相关的候选基因。我们在5名无亲缘关系的患者中鉴定出6种罕见的错义基因变异。其中两种变异此前已有报道；一种与心房颤动相关（SCN5A_p.H445D），另一种预计为良性（ANK2_p.T2059M）。除一种（RyR2_p.M4019T）被分类为有害变异外，新发现的变异经计算机模拟预测为良性。我们的尸检微梗死队列显示非常见基因变异率近10%。然而，由于缺乏家系评估，大多数已鉴定变异的临床意义仍不明确。应在大型队列中进行进一步分析，以阐明离子通道基因分析在显示微观缺血改变的样本中的作用。
