Genet Med. 2018 Feb;20(2):275-281. doi: 10.1038/gim.2017.100. Epub 2017 Sep 28.
PurposeAs part of the Epilepsy Genetics Initiative, we re-evaluated clinically generated exome sequence data from 54 epilepsy patients and their unaffected parents to identify molecular diagnoses not provided in the initial diagnostic interpretation.MethodsWe compiled and analyzed exome sequence data from 54 genetically undiagnosed trios using a validated analysis pipeline. We evaluated the significance of the genetic findings by reanalyzing sequence data generated at Ambry Genetics, and from a number of additional case and control cohorts.ResultsIn 54 previously undiagnosed trios, we identified two de novo missense variants in SCN8A in the highly expressed alternative exon 5 A-an exon only recently added to the Consensus Coding Sequence database. One additional undiagnosed epilepsy patient harboring a de novo variant in exon 5 A was found in the Ambry Genetics cohort. Missense variants in SCN8A exon 5 A are extremely rare in the population, further supporting the pathogenicity of the de novo alterations identified.ConclusionThese results expand the range of SCN8A variants in epileptic encephalopathy patients and illustrate the necessity of ongoing reanalysis of negative exome sequences, as advances in the knowledge of disease genes and their annotations will permit new diagnoses to be made.
目的
作为癫痫遗传学计划的一部分，我们重新评估了 54 名癫痫患者及其未受影响父母的临床生成外显子组序列数据，以确定初始诊断解释中未提供的分子诊断。
方法
我们使用经过验证的分析管道，编译和分析了 54 个遗传上未诊断的三体型的外显子组序列数据。我们通过重新分析在安布里遗传学（Ambry Genetics）生成的序列数据以及许多其他病例和对照队列中的数据来评估遗传发现的意义。
结果
在 54 个先前未诊断的三体型中，我们在高度表达的替代外显子 5A 中发现了 SCN8A 中的两个从头错义变异 - 该外显子最近才被添加到共识编码序列数据库中。在安布里遗传学队列中还发现了另一个患有 SCN8A 外显子 5A 中从头变异的未诊断癫痫患者。SCN8A 外显子 5A 中的错义变异在人群中极为罕见，进一步支持了鉴定的从头改变的致病性。
结论
这些结果扩展了癫痫性脑病患者 SCN8A 变异的范围，并说明了持续重新分析阴性外显子序列的必要性，因为疾病基因及其注释知识的进步将允许做出新的诊断。
