Comparing the diagnostic and clinical utility of WGS and WES with standard genetic testing (SGT) in children with suspected genetic diseases: A systematic review and meta-analysis

3.0ImportanceRare genetic diseases are one of the leading causes of infant mortality worldwide. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) are relatively new techniques for diagnosing genetic diseases, that classic newborn screening (NBS) fails to detect. ObjectiveTo systematically assess the diagnostic and clinical utility of WGS and WES, compared to standard genetic testing (SGT), in children with suspected genetic diseases, and discuss its impact on the expansion of NBS. Data SourcesEMBASE, MEDLINE, PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, and references of included full-text articles were searched until 21st October 2021. Study SelectionStudies reporting the diagnostic yield or rate of change of management for WGS and/or WES were included. The meta-analysis included 43 of the original 1768 identified articles (2%). Data Extraction and SynthesisData extraction followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. The quality of included papers was assessed using QUADAS-2, and a meta-analysis was performed using a random-effects model to create pooled proportions and a pooled odds ratio. Main Outcome(s) and Measure(s)Diagnostic utility, as determined by the diagnostic yield, which is defined as P/LP variants with strong or moderate associations with the presenting clinical phenotype of the affected patient, and that were reported to the patients clinician. Clinical utility as defined by any change in clinical management (medically or surgically), determined through clinician questionnaires or Electronic Health Record reviews. ResultsA total of 43 studies were included, comprising 6168 children. The pooled diagnostic utility of WES (0.40, 95% CI 0.34-0.45, I2=90%), was qualitatively greater than WGS (0.34, 95% CI 0.29-0.39, I2=79%), and SGT (0.19, 95% CI 0.13-0.25, I2=64%). The pooled clinical utility of WGS (0.74, 95% CI 0.56-0.89, I2=93%), was qualitatively greater than WES (0.72, 95% CI 0.61-0.81, I2=86%), while both were qualitatively greater than SGT (0.69, 95% CI 0.38-0.94). Conclusions and RelevanceOur evidence suggests that WGS/WES should be considered the first-line test for genetic diseases. There is reason to believe that WGS and WES should be included as part of NBS, however, more studies are required to assess the cost-effectiveness of this approach.