To determine the diagnostic yield of exome sequencing (ES), a microarray analysis was carried out of fetuses with recurrent fetal structural anomalies (with similar anomalies in consecutive pregnancies). This is a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The selected studies describing ES in fetuses with recurrent fetal malformation were assessed using the Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria for risk of bias. Incidence was used as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance). We identified nine studies on ES diagnostic yield that included 140 fetuses with recurrent structural anomalies. A pathogenic or likely pathogenic variant was found in 57 fetuses, resulting in a 40% (95%CI: 26% to 54%) incremental performance pool of ES. As expected, the vast majority (86%: 36/42) of the newly identified diseases had a recessive inheritance pattern, and among these, 42% (15/36) of variants were found in homozygosity. Meckel syndrome was the monogenic disease most frequently found, although the genes involved were diverse. The ES diagnostic yield in pregnancies with recurrent fetal structural anomalies was 40% (57/140). Homozygous disease-causing variants were found in 36% (15/57) of the newly identified monogenic disorders.
Keywords: diagnostic yield; exome sequencing; fetal structural anomalies; prenatal diagnosis; recurrent anomalies.