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Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing

机译：使用靶向基因测序对难治性早发性癫痫进行分子诊断的有效策略

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We intended to evaluate diagnostic utility of a targeted gene sequencing by using next generation sequencing (NGS) panel in patients with intractable early-onset epilepsy (EOE) and find the efficient analytical step for increasing the diagnosis rate. We assessed 74 patients with EOE whose seizures started before 3?years of age using a customized NGS panel that included 172 genes. Single nucleotide variants (SNVs) and exonic and chromosomal copy number variations (CNVs) were intensively examined with our customized pipeline and crosschecked with commercial or pre-built software. Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Each case was further discussed in a monthly consensus meeting that included the participation of all laboratory personnel, bioinformaticians, geneticists, and clinicians. The NGS panel identified 28 patients (37.8%) with genetic abnormalities; 25 patients had pathogenic or likely pathogenic SNVs in 17 genes including SXTBP1 (n?=?3), CDKL5 (n?=?2), KCNQ2 (n?=?2), SCN1A (n?=?2), SYNGAP1 (n?=?2), GNAO1 (n?=?2), KCNT1 (n?=?2), BRAT1, WWOX, ZEB2, CHD2, PRICKLE2, COL4A1, DNM1, SCN8A, MECP2, SLC9A6 (n?=?1). The other 3 patients had pathogenic CNVs (2 duplications and 1 deletion) with varying sizes (from 2.5?Mb to 12?Mb). The overall diagnostic yield was 37.8% after following our step-by-step approach for clinical consensus. NGS is a useful diagnostic tool with great utility for patients with EOE. Diagnostic yields can be maximized with a standardized and team-based approach.
机译：我们打算通过使用下一代测序（NGS）面板评估难治性早发性癫痫（EOE）患者的靶向基因测序的诊断效用，并找到提高诊断率的有效分析步骤。我们使用包含172个基因的定制NGS评估小组评估了74例EOE患者，其癫痫发作在3岁之前开始。单核苷酸变体（SNV）以及外显子和染色体拷贝数变异（CNV）通过我们的定制管道进行了深入检查，并通过商业或预建软件进行了交叉检查。筛选变体并通过深入的临床审查确定优先顺序，最后根据美国医学遗传学和基因组学指南进行分类。在每月一次的共识会议上进一步讨论了每个案例，该会议包括所有实验室人员，生物信息学家，遗传学家和临床医生的参与。 NGS小组确定了28例遗传异常患者（37.8％）; 25个患者在17个基因中具有致病性或可能致病性SNV，包括SXTBP1（n == 3），CDKL5（n == 2），KCNQ2（n == 2），SCN1A（n == 2），SYNGAP1（ n = 2），GNAO1（n = 2），KCNT1（n = 2），BRAT1，WWOX，ZEB2，CHD2，PRICKLE2，COL4A1，DNM1，SCN8A，MECP2，SLC9A6（n = 1 ）。另外3例患者的病原性CNV（2个重复和1个缺失）大小不等（从2.5？Mb到12？Mb）。遵循我们的循序渐进方法进行临床共识后，总诊断率为37.8％。 NGS是一种有用的诊断工具，对EOE患者具有很大的实用性。使用标准化且基于团队的方法可以最大程度地提高诊断收益。

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