Diagnostic yield of exome sequencing in fetuses with multisystem malformations: systematic review and meta‐analysis

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Abstract
Objective To determine the diagnostic yield of exome sequencing (ES) above chromosomal microarray analysis (CMA) or karyotype in fetuses with multiple multisystem structural anomalies (at least two major anomalies from different anatomical systems). Method This is a systematic review conducted in accordance with PRISMA criteria. All studies identified in PubMed, Ovid Medline and Web of Science, describing ES, whole genome and next-generation sequencing in fetuses with multisystem malformation. Selected studies included those with: a) five cases or more; b) only fetuses with at least two major anomalies from different anatomical systems; and c) only positive variants classified as IV or V (likely pathogenic or pathogenic) determined to be causative of the fetal phenotype were considered. A negative CMA or karyotype result was treated as the reference standard. Incidence was used as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance), along with the Clopper–Pearson exact method for calculation of confidence intervals. The solo (the fetus alone was sequenced) was compared with the trio approach (the fetus and both parents were sequenced). Results Seventeen articles with data on ES diagnostic yield including 694 individuals with multisystem malformation were identified. Overall, a pathogenic or likely pathogenic variant was found in 213 fetuses, resulting in a 33%; (95%CI: 27% to 40%) incremental performance pool of ES. A stratified analysis showed similar diagnostic yields of ES using the solo approach {33% (95%CI: 27 to 40)} as compared to the trio approach {34% (95%CI: 27 to 42)}. Conclusion ES applied in fetuses with multiple multisystem structural anomalies is able to find the causative gene in a third of the cases. No differences were observed between the solo and trio approach for ES.

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