目的:确定产前诊断为双侧重度脑室增宽(SVM)或脑积水的染色体微阵列分析(CMA)阴性后的产前外显子组测序(ES)的诊断产量,并对相关基因和变异进行分类。
方法:使用包括PubMed在内的四个数据库进行了系统搜索,以确定直到2022年6月发表的相关研究。Scopus,WebofScience,科克伦图书馆
方法:研究报告了产前诊断的双侧SVM中CMA阴性后ES的诊断率。
方法:联系了队列研究的作者,以获取个体参与者的数据,其中2项研究提供了他们的扩展队列。在以下情况下评估了ES的致病性/可能致病性的增量诊断率:(1)所有SVM病例;(2)孤立的SVM(SVM是唯一的颅骨异常),和(3)具有其他颅骨异常的SVM;和(4)非孤立的(具有颅外异常的SVM)。为了能够识别所有报告的遗传关联,系统评价部分不限于任何最小的SVM病例数,然而,对于综合荟萃分析,我们纳入了≥3例SVM病例的研究.使用随机效应模型对比例进行Meta分析。使用改良的诊断准确性标准报告标准对纳入研究进行质量评估。
结果:28项研究在1988年对各种产前表型的CMA阴性后进行了产前ES研究,其中138例具有产前双侧SVM。我们对与产前SVM相关的47个基因中的59个遗传变异及其完整的表型描述进行了分类。报告≥3例SVM病例的研究共有13例,包括117例SVM病例,包括在综合分析中。在所有包括的案件中,45%(95%CI30,60)P/LPES阳性。非孤立病例(存在颅外异常)的产量最高,为54%(95%CI38,69),然后SVM与其他颅骨异常38%(95%CI22,57),其次是分离的SVM35%(95%CI18,58)。
结论:双侧SVM中CMA阴性后,产前ES的诊断率明显增加。虽然最大的产量是非孤立的SVM,还应考虑在存在孤立的SVM的情况下进行ES,这是产前成像中唯一的大脑异常。
This study aimed to determine the incremental diagnostic yield of prenatal exome sequencing after negative chromosomal
microarray analysis results in prenatally diagnosed bilateral severe ventriculomegaly or hydrocephalus; another objective was to categorize the associated genes and variants.
A systematic search was performed to identify relevant studies published until June 2022 using 4 databases (Cochrane Library, Web of Science, Scopus, and MEDLINE).
Studies in English reporting on the diagnostic yield of exome sequencing following negative chromosomal
microarray analysis results in cases of prenatally diagnosed bilateral severe ventriculomegaly were included.
Authors of cohort studies were contacted for individual participant data, and 2 studies provided their extended cohort data. The incremental diagnostic yield of exome sequencing was assessed for pathogenic/likely pathogenic findings in cases of: (1) all severe ventriculomegaly; (2) isolated severe ventriculomegaly (as the only cranial anomaly); (3) severe ventriculomegaly with other cranial anomalies; and (4) nonisolated severe ventriculomegaly (with extracranial anomalies). To be able to identify all reported genetic associations, the systematic
review portion was not limited to any minimal severe ventriculomegaly case numbers; however, for the synthetic meta-analysis, we included studies with ≥3 severe ventriculomegaly cases. Meta-analysis of proportions was done using a random-effects model. Quality assessment of the included studies was performed using the modified STARD (Standards for Reporting of Diagnostic Accuracy Studies) criteria.
A total of 28 studies had 1988 prenatal exome sequencing analyses performed following negative chromosomal
microarray analysis results for various prenatal phenotypes; this included 138 cases with prenatal bilateral severe ventriculomegaly. We categorized 59 genetic variants in 47 genes associated with prenatal severe ventriculomegaly along with their full phenotypic description. There were 13 studies reporting on ≥3 severe ventriculomegaly cases, encompassing 117 severe ventriculomegaly cases that were included in the synthetic analysis. Of all the included cases, 45% (95% confidence interval, 30-60) had positive pathogenic/likely pathogenic exome sequencing results. The highest yield was for nonisolated cases (presence of extracranial anomalies; 54%; 95% confidence interval, 38-69), followed by severe ventriculomegaly with other cranial anomalies (38%; 95% confidence interval, 22-57) and isolated severe ventriculomegaly (35%; 95% confidence interval, 18-58).
There is an apparent incremental diagnostic yield of prenatal exome sequencing following negative chromosomal
microarray analysis results in bilateral severe ventriculomegaly. Although the greatest yield was found in cases of nonisolated severe ventriculomegaly, consideration should also be given to performing exome sequencing in cases of isolated severe ventriculomegaly as the only brain anomaly identified on prenatal imaging.