Diagnostic Yield of Exome Sequencing in Prenatal Agenesis of Corpus Callosum: A Systematic Review and Meta‐analysis

To determine the incremental increase in diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in prenatally diagnosed ACC and to classify associated genes and variants.A systematic search was performed to identify relevant studies published until June 2022 using four databases including PubMed, Scopus, Web of Science, and 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 of which two provided their extended cohorts. The incremental increase in diagnostic yield with ES was assessed for pathogenic/likely pathogenic in: (1) all cases of ACC; (2) isolated ACC; (3) ACC with other cranial anomalies; and (4) non-isolated ACC (ACC with extracranial anomalies). To be able to identify all reported genetic variants, the systematic review portion included all ACC cases, however, for the meta-analysis portion, we included studies with ≥ 3 ACC cases. 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.Twenty-eight studies encompassing 285 prenatal ACC cases that underwent ES following a negative CMA met the inclusion criteria for the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC along with full phenotypic description. Studies reporting on ≥3 ACC cases were total of 15 studies encompassing 267 cases. Of all the included cases, 43% had positive P/LP ES. The highest yield was for ACC with extracranial anomalies 55% (95% CI 35, 73), then ACC with other cranial anomalies 43% (95% CI 30, 57), followed by isolated ACC 32% (95% CI 18, 51).There is an apparent incremental increase in diagnostic yield of ES following negative CMA in prenatally diagnosed ACC. While the greatest yield is in ACC with extracranial anomalies and ACC with other CNS anomalies, consideration should also be given to performing ES in the presence of isolated ACC as the only brain anomaly on prenatal imaging. This article is protected by copyright. All rights reserved.