Prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test

PurposeTo evaluate the diagnostic yield and clinical utility of clinical genome sequencing (cWGS) as a first genetic test for patients with suspected monogenic disorders. MethodsWe conducted a prospective randomized study with pediatric and adult patients recruited from genetics clinics at Massachusetts General Hospital who were undergoing planned genetic testing. Participants were randomized into two groups: standard-of-care genetic testing (SOC) only or SOC and cWGS. Results204 participants were enrolled and 99 received cWGS. cWGS returned 23 molecular diagnoses in 20 individuals: A diagnostic yield of 20% (20/99, 95%CI 12.3-28.1%)), which was not significantly different from SOC (17%, 95%CI 9.7%-24.6%, P=0.584). 19/23 cWGS diagnoses provided an explanation for clinical features or were considered worthy of additional workup by referring providers. While cWGS detected all variants reported by SOC, SOC failed to capture 9/23 cWGS diagnoses; primarily due to genes not included in SOC tests. Turnaround time was significantly shorter for SOC compared to cWGS (33.9 days vs 87.2 days, P<0.05). ConclusionscWGS is technically suitable as a first genetic test and identified clinically relevant variants not captured by SOC. However, further studies addressing other variant types and implementation challenges are needed to support feasibility of its broad-scale adoption.