To evaluate the diagnostic yield and clinical relevance of clinical genome sequencing (cGS) as a first genetic test for patients with suspected monogenic disorders.
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.
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.
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.
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Variants reported by cGS have been submitted to ClinVar. De-identified genomic and phenotype data will be made available on the National Human Genome Research Institute (NHGRI) AnVIL platform (pending approval of our application by AnVIL). Data access requests can be made per instructions here https://anvilproject.org/learn/accessing-data/requesting-data-access#accessing-controlled-access-data. For additional information, contact C.A.A-T. (email@example.com).
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This study was funded by the Department of Medicine at Massachusetts General Hospital. Illumina supplied a portion of the sequencing reagents to enable this study. M.U. was supported in part by NIDDK K23DK114551. We thank the patients and families for participating in this study. We are grateful to Stephanie Harris, Lauren O’Grady, Marcie Steeves, Jin Yun Helen Chen, Megan Hawley, Erica Blouch, Linda Rodgers, Kristen Shannon, David Sweetser, Paula Goldenberg, Frances High, Amel Karaa, Angela Lin, Stephanie Santoro, Steven Lubitz, Christopher Newton-Cheh, and Jeremy Schmahmann for referring patients to the study. We also thank Edyta Malolepsza, Harrison Brand, and members of Michael Talkowski’s laboratory for their assistance with SV calling and analysis.
All study participants provided written consent or assent. This study was completed as a demonstration project in the MGH Center for Genomic Medicine and was approved by the Massachusetts General Brigham Institutional Review Board. Additional information about the study can be found on Clinicaltrials.gov (NCT03829176).
The authors declare no competing interests.
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Brockman, D.G., Austin-Tse, C.A., Pelletier, R.C. et al. Randomized prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test. Genet Med 23, 1689–1696 (2021). https://doi.org/10.1038/s41436-021-01193-y