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

Abstract

Purpose: To evaluate the diagnostic yield and clinical relevance of clinical genome sequencing (cGS) as a first genetic test for patients with suspected monogenic disorders.

Methods: We 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 cGS.

Results: Two hundred four participants were enrolled, 202 were randomized to one of the intervention arms, and 99 received cGS. In total, cGS returned 16 molecular diagnoses that fully or partially explained the indication for testing in 16 individuals (16.2% of the cohort, 95% confidence interval [CI] 8.9-23.4%), which was not significantly different from SOC (18.2%, 95% CI 10.6-25.8%, P = 0.71). An additional eight molecular diagnoses reported by cGS had uncertain relevance to the participant's phenotype. Nevertheless, referring providers considered 20/24 total cGS molecular diagnoses (83%) to be explanatory for clinical features or worthy of additional workup.

Conclusion: cGS is technically suitable as a first genetic test. In our cohort, diagnostic yield was not significantly different from SOC. Further studies addressing other variant types and implementation challenges are needed to support feasibility and utility of broad-scale cGS adoption.

Fig. 1. Proband participant enrollment flowchart.

Two additional clinical genome sequencing (cGS) reports were produced for parents enrolled in a trio, but were not included in this diagram. SOC standard-of-care.

Fig. 2. Molecular diagnoses (probands only) made by clinical genome sequencing (cGS) and standard-of-care (SOC).

*A participant with multiple diagnoses is represented by more than one column. P/LP pathogenic/likely pathogenic, VUS variant of uncertain significance.

Fig. 3. Clinical relevance of clinical genome sequencing (cGS) molecular diagnoses and suspicious variant of uncertain significance (VUS) results. Each variant identified by cGS was reviewed for clinical relevance by the research team and referring clinical provider.

Column 1 is the number of individuals with a pathogenic/ likely pathogenic variant(s) or variant(s) of uncertain significance. Column 2 is the number of molecular diagnoses. Column 3 is an assessment of the degree to which the variant(s) identified explains patient features. Column 4 is an assessment of additional clinical workup needed to assess the significance of the variant(s) identified. Column 5 is the case identification number and corresponding gene of interest.