Importance: Clinical genetic sequencing is frequently utilized to diagnose individuals with neurodevelopmental disorders (NDDs). Several reviews have been published regarding clinical genetic testing in various NDD subtypes. However, there is no systematic review and meta-analysis - in accordance with the PRISMA guidelines - which compares the genetic testing yield across neurodevelopmental disorder subtypes and sequencing technology. Objective: To perform a meta-analysis and systematic review of the success rate (diagnostic yield) of clinical sequencing through NGS across NDDs. Data Sources: Systematic review of the literature from PubMed until July 2019 for clinical sequencing studies that utilized NGS in individuals with epilepsy, autism spectrum disorder (ASD), or intellectual disability (ID). Study Selection: Data were taken from clinical sequencing studies that screened more than five genes and performed variant classification in at least 20 individuals with epilepsy, ASD, or ID. 5.6% of identified studies met the selection criteria. Data Extraction and Synthesis: Data were extracted, reviewed, and categorized according to PRISMA guidelines. Clinical evaluation and grouping were performed by two investigators following the ILAE guidelines. Pooled rates of the diagnostic yield and 95% confidence intervals were estimated with a random-effects model and adjusted for publication bias by the Duval and Tweedie procedure. Main Outcomes and Measures: Diagnostic yield, defined as the proportion of individuals in a cohort who received a diagnosis based on a positive genetic test with variants identified as pathogenic or likely pathogenic. Results: We identified 79 studies (epilepsy, n = 54; ASD, n = 13; ID, n = 17) across 29,301 individuals. Targeted gene panel sequencing was used in 53 cohorts and exome sequencing (ES) in 27 cohorts. The diagnostic yield was 16.7% for epilepsy, 20.2% for ASD, 24.8% for ID, and 16.6% overall. The diagnostic yield was significantly higher for exome sequencing compared to panels (33.9% vs. 16.2%, P = 1.38x10^-5). We observed that the number of clinical sequencing studies increased annually, particularly studies from Asia (0- 2 per year between 2012 and 2017, up to 10 in 2018). No studies from Africa, India, or Latin America were identified. We also found that recent studies are more likely to report variants of uncertain significance and few studies reported benign variants. Conclusions and Relevance: This meta-analysis and systematic review provides a comprehensive overview of clinical sequencing studies of NDDs, which will help guide policymaking and steer decision-making in patient management.

中文翻译：

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癫痫，自闭症谱系障碍和智力障碍的临床测序结果：系统评价和荟萃分析

重要性：临床遗传测序常用于诊断患有神经发育障碍（NDD）的个体。关于各种NDD亚型的临床基因检测，已经发表了一些评论。但是，根据PRISMA指南，没有系统的综述和荟萃分析可比较神经发育障碍亚型和测序技术的基因测试产率。目的：对跨NDD的NGS进行临床测序的成功率（诊断结果）进行荟萃分析和系统评价。数据来源：PubMed直至2019年7月的文献的系统评价，涉及临床测序研究，该研究在癫痫，自闭症谱系障碍（ASD）或智力障碍（ID）的个体中使用NGS。研究选择：数据来自临床测序研究，该研究筛选了五个以上的基因，并对至少20名患有癫痫，ASD或ID的个体进行了变异分类。5.6％的已鉴定研究符合选择标准。数据提取和综合：根据PRISMA准则提取，审查和分类数据。由两名研究人员按照ILAE指南进行临床评估和分组。使用随机效应模型估算诊断率和95％置信区间的合并率，并通过Duval和Tweedie程序对发布偏倚进行调整。主要结果和衡量指标：诊断结果，定义为队列中根据阳性基因测试接受诊断的个体所占的比例，其变异被确定为致病或可能致病。结果：我们在29,301名个体中鉴定出79项研究（癫痫症，n = 54； ASD，n = 13； ID，n = 17）。靶向基因组测序用于53个队列，外显子组测序（ES）用于27个队列。癫痫的诊断产率为16.7％，ASD的诊断率为20.2％，ID的诊断率为24.8％，总体诊断率为16.6％。与面板相比，外显子组测序的诊断产率显着更高（33.9％对16.2％，P = 1.38x10^-5）。我们观察到，临床测序研究的数量每年都在增加，特别是来自亚洲的研究（2012年至2017年每年为0-2，2018年最多为10）。没有发现来自非洲，印度或拉丁美洲的研究。我们还发现，最近的研究更有可能报告不确定意义的变体，很少有研究报道良性变体。结论与相关性：这项荟萃分析和系统综述对NDD的临床测序研究进行了全面概述，这将有助于指导患者管理中的决策制定和决策制定。