Diagnostic yield of exome sequencing in fetuses with skeletal dysplasia: systematic review and meta-analysis

Abstract Objective To determine the diagnostic yield of exome sequencing (ES) above that of chromosomal microarray analysis (CMA) or karyotyping in fetuses with skeletal dysplasia (SD) from various perspectives. Methods This systematic review was conducted in accordance with PRISMA criteria. Searching PubMed, EMBASE, Scopus, and Cochrane Library, we identified studies describing ES, next-generation sequencing, and/or genes panel in fetuses with SD. Inclusion criteria were: (i) fetuses diagnosed with suspected SD by prenatal ultrasound; (ii) more than 5 fetuses included; (iii) normal karyotype and CMA results. Two reviewers completed the data of Prenatal (Ultrasound) phenotype and genotype information collection independently and merged it. Results We identified 18 studies with data on ES diagnostic yield including 599 individuals with SD. Overall, a pathogenic or likely pathogenic variant was found in 306 fetuses, resulting in a 60% (95% CI, 48–72%) diagnostic yield. The number of gene mutations detected was 346, involving 74 genes related to SD and 23.7% of novel variants. The targeted skeletal gene panel showed a diagnostic yield of 76% (95% CI, 62–89%). Conclusions The application of ES in fetuses with SD and normal karyotype or CMA can provide a considerable diagnostic yield. The benefits of using ES in selected groups will be more obvious.