Department of Pediatrics, Pediatric Neuroscience Center, Seoul National University Children's Hospital, Seoul National University Children's Hospital, Seoul, South Korea.
Rare Diseases Center, Seoul National University Hospital, Seoul, South Korea.
Clin Genet. 2021 Mar;99(3):418-424. doi: 10.1111/cge.13903. Epub 2021 Jan 3.
This study aimed to evaluate the clinical utility of whole-exome sequencing in a group of infantile-onset epilepsy patients who tested negative for epilepsy using a gene panel test. Whole-exome sequencing was performed on 59 patients who tested negative on customized epilepsy gene panel testing. We identified eight pathogenic or likely pathogenic sequence variants in eight different genes (FARS2, YWHAG, KCNC1, DYRK1A, SMC1A, PIGA, OGT, and FGF12), one pathogenic structural variant (8.6 Mb-sized deletion on chromosome X [140 994 419-149 630 805]), and three putative low-frequency mosaic variants from three different genes (GABBR2, MTOR, and CUX1). Subsequent whole-exome sequencing revealed an additional 8% of diagnostic yield with genetic confirmation of epilepsy in 55.4% (62/112) of our cohort. Three genes (YWHAG, KCNC1, and FGF12) were identified as epilepsy-causing genes after the original gene panel was designed. The others were initially linked with mitochondrial encephalopathy or different neurodevelopmental disorders, although an epilepsy phenotype was listed as one of the clinical features. Application of whole-exome sequencing following epilepsy gene panel testing provided 8% of additional diagnostic yield in an infantile-onset epilepsy cohort. Whole-exome sequencing could provide an opportunity to reanalyze newly recognized epilepsy-linked genes without updating the gene panel design.
本研究旨在评估全外显子组测序在一组经基因panel 检测为阴性的婴儿起病型癫痫患者中的临床应用价值。对 59 例经定制性癫痫基因panel 检测为阴性的患者进行了全外显子组测序。我们在 8 个不同基因（FARS2、YWHAG、KCNC1、DYRK1A、SMC1A、PIGA、OGT 和 FGF12）中发现了 8 个致病性或可能致病性的序列变异体，1 个致病性结构变异体（X 染色体上 8.6Mb 大小的缺失[140994419-149630805]）和 3 个来自 3 个不同基因的假定低频镶嵌变异体（GABBR2、MTOR 和 CUX1）。随后的全外显子组测序在我们的队列中，有 55.4%（62/112）的患者遗传上确认了癫痫，从而获得了额外 8%的诊断率。在最初的基因panel 设计后，有 3 个基因（YWHAG、KCNC1 和 FGF12）被确定为癫痫致病基因。其他基因最初与线粒体脑病或不同的神经发育障碍有关，尽管癫痫表型被列为其中一种临床特征。在癫痫基因panel 检测之后应用全外显子组测序为婴儿起病型癫痫队列提供了 8%的额外诊断率。全外显子组测序为重新分析新发现的与癫痫相关的基因提供了机会，而无需更新基因panel 设计。
