Hesse Andrew N, Bevilacqua Jennifer, Shankar Kritika, Reddi Honey V
Transgenomic Inc, 5 Science Park, New Haven, CT, 06511, USA.
Transgenomic Inc, 5 Science Park, New Haven, CT, 06511, USA.
Epilepsy Res. 2018 Aug;144:53-61. doi: 10.1016/j.eplepsyres.2018.05.004. Epub 2018 May 16.
Epilepsy is a diverse neurological condition with extreme genetic and phenotypic heterogeneity. The introduction of next-generation sequencing into the clinical laboratory has made it possible to investigate hundreds of associated genes simultaneously for a patient, even in the absence of a clearly defined syndrome. This has resulted in the detection of rare and novel mutations at a rate well beyond our ability to characterize their effects. This retrospective study reviews genotype data in the context of available phenotypic information on 305 patients spanning the epileptic spectrum to identify established and novel patterns of correlation.
Our epilepsy panel comprising 377 genes was used to sequence 305 patients referred for genetic testing. Qualifying variants were annotated with phenotypic data obtained from either the test requisition form or supporting clinical documentation. Observed phenotypes were compared with established phenotypes in OMIM, published literature and the ILAEs 2010 report on genetic testing to assess congruity with known gene aberrations.
We identified a number of novel and recognized genetic variants consistent with established epileptic phenotypes. Forty-one pathogenic or predicted deleterious variants were detected in 39 patients with accompanying clinical documentation. Twenty-five of these variants across 15 genes were novel. Furthermore, evaluation of phenotype data for 194 patients with variants of unknown significance in genes with autosomal dominant and X-linked disease inheritance elucidated potentially disease-causing variants that were not currently characterized in the literature.
Assessment of key genotype-phenotype correlations from our cohort provide insight into variant classification, as well as the importance of including ILAE recommended genes as part of minimum panel content for comprehensive epilepsy tests. Many of the reported VUSs are likely genuine pathogenic variants driving the observed phenotypes, but not enough evidence is available for assertive classifications. Similar studies will provide more utility via mounting independent genotype-phenotype data from unrelated patients. The possible outcome would be a better molecular diagnostic product, with fewer indeterminate reports containing only VUSs.
癫痫是一种具有高度遗传和表型异质性的复杂神经系统疾病。将下一代测序技术引入临床实验室后，即使在没有明确综合征的情况下，也能够同时对患者的数百个相关基因进行研究。这使得罕见和新突变的检测率远超我们对其影响进行特征描述的能力。这项回顾性研究在305例涵盖癫痫谱系的患者的可用表型信息背景下，对基因型数据进行回顾，以识别已确立和新的关联模式。
我们使用包含377个基因的癫痫检测板对305例转诊进行基因检测的患者进行测序。合格变异用从检测申请表或支持性临床文档中获得的表型数据进行注释。将观察到的表型与OMIM、已发表文献以及国际抗癫痫联盟（ILAE）2010年基因检测报告中的既定表型进行比较，以评估与已知基因异常的一致性。
我们鉴定出一些与既定癫痫表型一致的新的和已知遗传变异。在39例伴有临床文档的患者中检测到41个致病或预测有害变异。其中跨越15个基因的25个变异是新的。此外，对194例具有常染色体显性和X连锁疾病遗传基因中意义未明变异的患者的表型数据进行评估，阐明了目前文献中未描述的潜在致病变异。
对我们队列中关键基因型-表型相关性的评估为变异分类提供了见解，也说明了将ILAE推荐基因纳入全面癫痫检测最小检测板内容的重要性。许多报告的意义未明变异（VUS）可能是驱动观察到的表型的真正致病变异，但尚无足够证据进行确定性分类。类似研究将通过收集来自无关患者的越来越多的独立基因型-表型数据提供更多实用价值。可能的结果将是一种更好的分子诊断产品，包含仅VUS的不确定报告更少。
