Genetic diagnosis of infantile‐onset epilepsy in the clinic: Application of whole‐exome sequencing following epilepsy gene panel testing,Clinical Genetics

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Genetic diagnosis of infantile‐onset epilepsy in the clinic: Application of whole‐exome sequencing following epilepsy gene panel testing
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-12-21 , DOI: 10.1111/cge.13903
Soo Yeon Kim _{1,

2} , Se Song Jang ₁ , Hunmin Kim ₃ , Hee Hwang ₃ , Ji Eun Choi ₄ , Jong-Hee Chae _{1,

2,

5} , Ki Joong Kim _{1,

5} , Byung Chan Lim _{1,

2,

5}

Affiliation

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.

中文翻译：

婴幼儿癫痫的临床遗传诊断：全外显子组测序在癫痫基因panel检测后的应用

本研究旨在评估全外显子组测序在一组使用基因组测试检测为癫痫阴性的婴儿癫痫患者中的临床效用。对 59 名在定制癫痫基因面板测试中呈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）中鉴定了 8 个致病或可能致病的序列变异，一个致病结构变异（X 染色体上 8.6 Mb 大小的缺失 [140 994 419– 149 630 805]），以及来自三个不同基因的三个假定的低频镶嵌变异（GABBR2、MTOR和CUX1 )。随后的全外显子组测序显示，在我们队列中 55.4% (62/112) 的癫痫基因确诊率增加了 8%。三个基因（YWHAG、KCNC1和FGF12) 在最初的基因面板设计后被确定为导致癫痫的基因。其他的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临床特征之一。在癫痫基因组测试后应用全外显子组测序在婴儿发作的癫痫队列中提供了 8% 的额外诊断率。全外显子组测序可以为重新分析新识别的癫痫相关基因提供机会，而无需更新基因面板设计。

更新日期：2021-02-08

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