Abstract：
To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify the associated genes and variants.
A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta-analysis, only studies with ≥ three ACC cases were included. Meta-analysis of proportions was employed using a random-effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria.
A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta-analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35-73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30-57%)) and isolated ACC (32% (95% CI, 18-51%)).
ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta-analysis, only studies with ≥ three ACC cases were included. Meta-analysis of proportions was employed using a random-effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria.
A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta-analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35-73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30-57%)) and isolated ACC (32% (95% CI, 18-51%)).
ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
摘要：
目的：确定在产前诊断的ACC中，阴性染色体微阵列分析（CMA）后，外显子组测序（ES）的诊断率增加，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,科克伦图书馆包括有关产前诊断为部分或完全ACC的CMA阴性后ES诊断率的英文报告研究。与队列研究的作者联系，以获取单个参与者的数据，其中两个提供了他们的扩展队列。评估了ES诊断率的递增增加的致病性/可能致病性：（1）所有ACC病例；（2）孤立的ACC；（3）伴有其他颅骨异常的ACC；（4）非孤立的ACC（伴有颅外异常的ACC）。为了能够识别所有报告的遗传变异，系统审查部分包括所有ACC案例，然而,对于荟萃分析部分，我们纳入了≥3例ACC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项研究包括285例产前ACC病例，在CMA阴性后接受ES，符合系统评价的纳入标准。我们对与产前ACC相关的83个基因中的116个遗传变异进行了分类，并进行了完整的表型描述。报告≥3例ACC病例的研究共15项研究，涵盖267例病例。在所有包括的案件中，43%P/LPES阳性。最高产量是颅外异常的ACC55%(95%CI35，73)，然后ACC伴有其他颅骨异常43%(95%CI30，57)，其次是分离的ACC32%（95%CI18，51）。
结论：产前诊断为ACC的CMA阴性后，ES的诊断率明显增加。虽然最大的产量是颅外异常的ACC和其他中枢神经系统异常的ACC，还应考虑在孤立的ACC存在的情况下进行ES作为产前成像中唯一的大脑异常。本文受版权保护。保留所有权利。
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,科克伦图书馆包括有关产前诊断为部分或完全ACC的CMA阴性后ES诊断率的英文报告研究。与队列研究的作者联系，以获取单个参与者的数据，其中两个提供了他们的扩展队列。评估了ES诊断率的递增增加的致病性/可能致病性：（1）所有ACC病例；（2）孤立的ACC；（3）伴有其他颅骨异常的ACC；（4）非孤立的ACC（伴有颅外异常的ACC）。为了能够识别所有报告的遗传变异，系统审查部分包括所有ACC案例，然而,对于荟萃分析部分，我们纳入了≥3例ACC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项研究包括285例产前ACC病例，在CMA阴性后接受ES，符合系统评价的纳入标准。我们对与产前ACC相关的83个基因中的116个遗传变异进行了分类，并进行了完整的表型描述。报告≥3例ACC病例的研究共15项研究，涵盖267例病例。在所有包括的案件中，43%P/LPES阳性。最高产量是颅外异常的ACC55%(95%CI35，73)，然后ACC伴有其他颅骨异常43%(95%CI30，57)，其次是分离的ACC32%（95%CI18，51）。
结论：产前诊断为ACC的CMA阴性后，ES的诊断率明显增加。虽然最大的产量是颅外异常的ACC和其他中枢神经系统异常的ACC，还应考虑在孤立的ACC存在的情况下进行ES作为产前成像中唯一的大脑异常。本文受版权保护。保留所有权利。
