Meta-analysis of genome and predicted exome sequencing diagnostic yield

Abstract This meta-analysis assesses the relative diagnostic yield of genome sequencing (GS) compared to the predicted exome sequencing (ES) yield in patients with suspected Mendelian disorders. Employing the PRISMA guidelines and PICO framework, we conducted a systematic review of studies that used GS in the context of rare disorders. We collected reported diagnostic findings and estimated the reliability of their detection via a comprehensive ES approach. A comparative analysis of 44 included studies (from an initially evaluated 72) involving 15,559 probands revealed a GS diagnostic yield of 25.8% and a predicted ES diagnostic yield of 24.3%. Variants which could not have been detected using ES were predominantly small or complex structural variants and intronic variants. This meta-analysis suggests a statistically significant but modest increase in diagnostic yield of GS over ES. Consequently, ES might be considered a suitable initial diagnostic approach for most patients with Mendelian disorders.