Abstract：
Many patients with epilepsy undergo exome or genome sequencing as part of a diagnostic workup; however, many remain genetically unsolved. There are various factors that account for negative results in exome/genome sequencing for patients with epilepsy: (1) the underlying cause is not genetic; (2) there is a complex polygenic explanation; (3) the illness is monogenic but the causative gene remains to be linked to a human disorder; (4) family segregation with reduced penetrance; (5) somatic mosaicism or the complexity of, for example, a structural rearrangement; or (6) limited knowledge or diagnostic tools that hinder the proper classification of a variant, resulting in its designation as a variant of unknown significance. The objective of this review is to outline some of the diagnostic options that lie beyond the exome/genome, and that might become clinically relevant within the foreseeable future. These options include: (1) re-analysis of older exome/genome data as knowledge increases or symptoms change; (2) looking for somatic mosaicism or long-read sequencing to detect low-complexity repeat variants or specific structural variants missed by traditional exome/genome sequencing; (3) exploration of the non-coding genome including disruption of topologically associated domains, long range non-coding RNA, or other regulatory elements; and finally (4) transcriptomics, DNA methylation signatures, and metabolomics as complementary diagnostic methods that may be used in the assessment of variants of unknown significance. Some of these tools are currently not integrated into standard diagnostic workup. However, it is reasonable to expect that they will become increasingly available and improve current diagnostic capabilities, thereby enabling precision diagnosis in patients who are currently undiagnosed.
摘要：
许多癫痫患者接受外显子组或基因组测序作为诊断工作的一部分，然而,许多基因仍未解决。在癫痫患者的外显子组/基因组测序中，有多种因素导致阴性结果；1）根本原因不是遗传，2)有复杂的多基因解释，3）疾病是单基因的，但致病基因仍然与人类疾病有关，4)减少外显率的家庭隔离，5)体细胞镶嵌或eg的复杂性。结构重组，或6)有限的知识或诊断工具阻碍了变体的正确分类，导致其指定为未知意义的变体。这篇综述的目的是概述一些超越外显子组/基因组的诊断选择，在可预见的将来，这可能会成为临床相关的。这些选择包括：1）随着知识的增加或症状的改变，重新分析较旧的外显子组/基因组数据，2）寻找体细胞镶嵌或长读测序，以检测传统外显子组/基因组测序遗漏的低复杂度重复变异或特定结构变异，3）非编码基因组的探索，包括拓扑相关域的破坏，长范围非编码RNA或其他调控元件，最后是4）转录组学，DNA甲基化特征和代谢组学作为补充诊断方法，可用于评估未知意义的变体。其中一些工具目前尚未集成到标准诊断工作中。然而,可以合理地预期它们将变得越来越可用并提高当前的诊断能力，从而能够对当前未诊断的患者进行精确诊断。
