Purpose: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. Methods: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. Results: 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P < .001). Yield was greater for GS vs. TGPs in Hispanic/Latino(a) (17.2% vs. 9.5%, P < .001) and White/European American (19.8% vs. 7.9%, P < .001), but not in Black/African American (11.5% vs. 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs. White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. Conclusion: GS may yield up to twice as many diagnoses in pediatric patients compared to TGP testing, but not yet across all population groups.

Dr. Abul-Husn is an employee and equity holder of 23andMe; serves as a scientific advisory board member for Allelica; received personal fees from Genentech, Allelica, and 23andMe; received research funding from Akcea; and was previously employed by Regeneron Pharmaceuticals. Dr. Kenny received personal fees from Illumina, 23andMe, Allelica, and Regeneron Pharmaceuticals, received research funding from Allelica, and serves as a scientific advisory board member for Encompass Bio, Foresite Labs, and Galateo Bio. All other authors declare they have no disclosures to report.

NCT03738098

The NYCKidSeq Program (U01HG0096108; Principal Investigators Kenny, Wasserstein, Gelb and Horowitz) is supported by the Clinical Sequencing Evidence-Generating Research (CSER) consortium, which is funded by the National Institutes of Health (NIH) National Human Genome Research Institute, National Institute for Minority Heath and Health Disparities of the National Institutes of Health and the National Cancer Institute. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Icahn School of Medicine at Mount Sinai and the Albert Einstein College of Medicine Institutional Review Boards. All probands or parents/legal guardians provided written informed consent.

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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De-identified data for this study will be shared in secure, access-restricted scientific research databases called NHGRI Analysis Visualization and Informatics Lab-space (AnVIL) and the Database of Genes and Phenotypes (dbGaP) at the National Institutes of Health (dbGaP accession number phs002337.v1.p1). Interpretations of the clinical significance of variants from genetic testing have been submitted to the ClinVar database at the National Institutes of Health under the study name NYCKidSeq.