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Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project

Genetics in Medicine (2021)Cite this article

Abstract

Purpose

Newborn screening (NBS) is performed to identify neonates at risk for actionable, severe, early-onset disorders, many of which are genetic. The BabySeq Project randomized neonates to receive conventional NBS or NBS plus exome sequencing (ES) capable of detecting sequence variants that may also diagnose monogenic disease or indicate genetic disease risk. We therefore evaluated how ES and conventional NBS results differ in this population.

Methods

We compared results of NBS (including hearing screens) and ES for 159 infants in the BabySeq Project. Infants were considered “NBS positive” if any abnormal result was found indicating disease risk and “ES positive” if ES identified a monogenic disease risk or a genetic diagnosis.

Results

Most infants (132/159, 84%) were NBS and ES negative. Only one infant was positive for the same disorder by both modalities. Nine infants were NBS positive/ES negative, though seven of these were subsequently determined to be false positives. Fifteen infants were ES positive/NBS negative, all of which represented risk of genetic conditions that are not included in NBS programs. No genetic explanation was identified for eight infants referred on the hearing screen.

Conclusion

These differences highlight the complementarity of information that may be gleaned from NBS and ES in the newborn period.

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Fig. 1: Comparison of conventional newborn screening (NBS) using dried blood spot versus exome sequencing (ES) results.

Data availability

The genomic data/analyses reported in this paper have been deposited in the NBSTRN LPDR (https://nbstrn.org/tools/lpdr) under accession identifier nbs000002.v1.p1. Data access is restricted; for information on how to request access, please contact corresponding author Monica Wojcik at monica.wojcik@childrens.harvard.edu or Pankaj Agrawal at pagrawal@enders.tch.harvard.edu.

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Acknowledgements

M.H.W. is supported by K23 HD102589–01. Research reported in this publication was supported by the National Institutes of Health under award numbers R01HG009922, R01HL143295, U01TR003201, and U19HD077671. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Affiliations

  1. Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Monica H. Wojcik, Tian Zhang, Casie A. Genetti, Timothy W. Yu, Ingrid A. Holm, Alan H. Beggs, Pankaj B. Agrawal, Pankaj B. Agrawal, Alan H. Beggs, Casie A. Genetti, Ingrid A. Holm, Harvey L. Levy, Amy Roberts, Talia S. Schwartz, Tina K. Truong, Grace E. VanNoy, Susan E. Waisbren & Timothy W. Yu

  2. Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Monica H. Wojcik, Pankaj B. Agrawal & Pankaj B. Agrawal

  3. Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Monica H. Wojcik, Heidi L. Rehm, Robert C. Green, Pankaj B. Agrawal, Pankaj B. Agrawal, Robert C. Green, Maegan Harden & Heidi L. Rehm

  4. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Ozge Ceyhan-Birsoy & Ozge Ceyhan-Birsoy

  5. Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, USA

    Matthew S. Lebo, Heidi L. Rehm, Chet Graham, Matthew S. Lebo, Kalotina Machini, Jaclyn B. Murry & Heidi L. Rehm

  6. Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Matthew S. Lebo, Heidi L. Rehm, Matthew S. Lebo & Heidi L. Rehm

  7. Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Richard B. Parad & Richard B. Parad

  8. Department of Medicine (Genetics), Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Robert C. Green, Wendi N. Betting, Kurt D. Christensen, Shawn Fayer, Robert C. Green, Joel B. Krier & Tiffany T. Nguyen

  9. Ariadne Labs, Boston, MA, USA

    Robert C. Green & Robert C. Green

  10. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

    Dmitry Dukhovny

  11. University of Houston, Department of Psychological, Health and Learning Sciences, Houston, TX, USA

    Leslie A. Frankel

  12. Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX, USA

    Amanda M. Guiterrez, Xingquan Lu, Amy L. McGuire, Medha Naik, Hayley A. Peoples, Stacey Pereira, Devan Petersen, Uma Ramamurthy, Vivek Ramanathan & Jill O. Robinson

  13. Division of Neonatology and Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Serguei Roumiantsev

Authors
  1. Monica H. Wojcik
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  2. Tian Zhang
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  3. Ozge Ceyhan-Birsoy
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  4. Casie A. Genetti
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  12. Pankaj B. Agrawal
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Consortia

BabySeq Project Team

Contributions

Conceptualization: P.B.A., M.H.W. Data curation: M.H.W., T.Z., O.Z.B., C.G. Formal analysis: M.H.W., O.Z.B.,M.L. Project administration: C.G. Supervision: R.C.G., A.H.B., I.A.H., R.B.P., H.L.R. Writing—original draft: M.H.W., T.Z; Writing—review & editing: all authors.

Corresponding authors

Correspondence to Monica H. Wojcik or Pankaj B. Agrawal.

Ethics declarations

Ethics declaration

The BCH’s Institutional Review Board (IRB) and the Partners Human Research Committee (the IRB for BWH) approved this study and informed consent was obtained from all participants as required by the IRB.

Competing interests

R.C.G. has received compensation for advising the following companies: AIA, Grail, Humanity, Kneed Media, Plumcare, UnitedHealth, Verily, VibrentHealth, Wamberg; and is co-founder of Genome Medical, Inc. P.B.A. is on the Clinical Advisory Board of Illumina Inc. and GeneDx. H.L.R. is a compensated scientific advisory board member of Genome Medical. The other authors declare no competing interests.

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Wojcik, M.H., Zhang, T., Ceyhan-Birsoy, O. et al. Discordant results between conventional newborn screening and genomic sequencing in the BabySeq Project. Genet Med (2021). https://doi.org/10.1038/s41436-021-01146-5

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