Department of Neurosurgery, Massachusetts General Hospital, Boston.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
JAMA Netw Open. 2023 Nov 1;6(11):e2343384. doi: 10.1001/jamanetworkopen.2023.43384.
Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay and autism spectrum disorder; however, current recommendations are not specific to or inclusive of congenital hydrocephalus (CH).
To determine the diagnostic yield of ES in CH and whether ES should be considered as a first line diagnostic test for CH.
PubMed, Cochrane Library, and Google Scholar were used to identify studies published in English between January 1, 2010, and April 10, 2023. The following search terms were used to identify studies: congenital hydrocephalus, ventriculomegaly, cerebral ventriculomegaly, primary ventriculomegaly, fetal ventriculomegaly, prenatal ventriculomegaly, molecular analysis, genetic cause, genetic etiology, genetic testing, exome sequencing, whole exome sequencing, genome sequencing, microarray, microarray analysis, and copy number variants.
Eligible studies included those with at least 10 probands with the defining feature of CH and/or severe cerebral ventriculomegaly that had undergone ES. Studies with fewer than 10 probands, studies of mild or moderate ventriculomegaly, and studies using genetic tests other than ES were excluded. A full-text review of 68 studies was conducted by 2 reviewers. Discrepancies were resolved by consensus.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology guidelines were used by 2 reviewers to extract data. Data were synthesized using a random-effects model of single proportions. Data analysis occurred in April 2023.
The primary outcome was pooled diagnostic yield. Additional diagnostic yields were estimated for specific subgroups on the basis of clinical features, syndromic presentation, and parental consanguinity. For each outcome, a 95% CI and estimate of interstudy heterogeneity (I2 statistic) was reported.
From 498 deduplicated and screened records, 9 studies with a total of 538 CH probands were selected for final inclusion. The overall diagnostic yield was 37.9% (95% CI, 20.0%-57.4%; I2 = 90.1). The yield was lower for isolated and/or nonsyndromic cases (21.3%; 95% CI, 12.8%-31.0%; I2 = 55.7). The yield was higher for probands with reported consanguinity (76.3%; 95% CI, 65.1%-86.1%; I2 = 0) than those without (16.2%; 95% CI, 12.2%-20.5%; I2 = 0).
In this systematic review and meta-analysis of the diagnostic yield of ES in CH, the diagnostic yield was concordant with that of previous recommendations for other neurodevelopmental disorders, suggesting that ES should also be recommended as a routine diagnostic adjunct for patients with CH.
外显子组测序（ES）已被确立为某些神经发育障碍（如全面发育迟缓、自闭症谱系障碍）首选的一线诊断检测方法；然而，目前的建议并非专门针对或包含先天性脑积水（CH）。
确定 ES 在 CH 中的诊断效果，以及 ES 是否应被视为 CH 的一线诊断测试。
使用 PubMed、Cochrane 图书馆和 Google Scholar 从 2010 年 1 月 1 日至 2023 年 4 月 10 日发表的英文文章中确定研究。使用以下搜索词来识别研究：先天性脑积水、脑室扩大、脑室内扩大、原发性脑室扩大、胎儿脑室扩大、产前脑室扩大、分子分析、遗传原因、遗传病因、基因检测、外显子组测序、全外显子组测序、基因组测序、微阵列、微阵列分析和拷贝数变异。
符合条件的研究包括至少有 10 名以 CH 和/或严重脑室内扩大为特征的先证者并接受 ES 的研究。排除了先证者少于 10 名、脑室扩大程度较轻或中度以及使用除 ES 以外的基因检测的研究。两名评审员对 68 篇研究的全文进行了审查。分歧通过共识解决。
两名评审员使用系统评价和荟萃分析的首选报告项目和观察性研究荟萃分析的流行病学指南提取数据。使用单比例的随机效应模型综合数据。数据分析于 2023 年 4 月进行。
主要结果是汇总诊断效果。根据临床特征、综合征表现和父母近亲结婚情况，对特定亚组进行了额外的诊断效果估计。对于每个结果，报告了 95%CI 和研究间异质性（I2 统计量）的估计值。
从 498 篇去重和筛选的记录中，选择了 9 项共涉及 538 名 CH 先证者的研究进行最终纳入。总体诊断效果为 37.9%（95%CI，20.0%-57.4%；I2=90.1）。孤立性和/或非综合征病例的效果较低（21.3%；95%CI，12.8%-31.0%；I2=55.7）。有报道近亲结婚的先证者的效果（76.3%；95%CI，65.1%-86.1%；I2=0）高于无近亲结婚的先证者（16.2%；95%CI，12.2%-20.5%；I2=0）。
在这项对 ES 在 CH 中的诊断效果的系统评价和荟萃分析中，诊断效果与其他神经发育障碍的先前建议一致，表明 ES 也应被推荐作为 CH 患者的常规诊断辅助手段。
