Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Sep 1;109(9):1605-1619.
doi: 10.1016/j.ajhg.2022.08.003. Epub 2022 Aug 24.

A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases

Stephen F Kingsmore  1 , Laurie D Smith  2 , Chris M Kunard  3 , Matthew Bainbridge  4 , Sergey Batalov  4 , Wendy Benson  4 , Eric Blincow  4 , Sara Caylor  4 , Christina Chambers  5 , Guillermo Del Angel  6 , David P Dimmock  4 , Yan Ding  4 , Katarzyna Ellsworth  4 , Annette Feigenbaum  7 , Erwin Frise  8 , Robert C Green  9 , Lucia Guidugli  4 , Kevin P Hall  3 , Christian Hansen  4 , Charlotte A Hobbs  4 , Scott D Kahn  10 , Mark Kiel  11 , Lucita Van Der Kraan  4 , Chad Krilow  12 , Yong H Kwon  4 , Lakshminarasimha Madhavrao  4 , Jennie Le  4 , Sebastien Lefebvre  6 , Rebecca Mardach  7 , William R Mowrey  6 , Danny Oh  4 , Mallory J Owen  4 , George Powley  12 , Gunter Scharer  2 , Seth Shelnutt  12 , Mari Tokita  4 , Shyamal S Mehtalia  3 , Albert Oriol  4 , Stavros Papadopoulos  12 , James Perry  13 , Edwin Rosales  4 , Erica Sanford  2 , Steve Schwartz  11 , Duke Tran  3 , Martin G Reese  8 , Meredith Wright  4 , Narayanan Veeraraghavan  4 , Kristen Wigby  7 , Mary J Willis  2 , Aaron R Wolen  12 , Thomas Defay  6
Affiliations
Review

A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases

Stephen F Kingsmore et al. Am J Hum Genet. .

Abstract

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

Keywords: UK Biobank; clinical decision support; clinical utility; diagnosis; diagnostic odyssey; gene therapy; genetic disease; newborn screening; orphan drug; rapid whole-genome sequencing; sensitivity; specificity; virtual management guidance.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests K.P.H., C.M.K., S.S.M., and D.T. are employees and shareholders of Illumina, Inc. G.D,A., B.M., S.L., and T.D. are employees and shareholders of Alexion Pharmaceuticals. E.F. and M.G.R. are employees and shareholders of Fabric Genomics, Inc. M.K. and S.S. are employees and shareholders of Genomenon, Inc. C.K., G.P., S.S., S.P., and A.R.W. are employees and shareholders of TileDB, Inc. S.K. is an employee and shareholder of Luna PBC, Inc. S.K. has filed a patent related to this work.

Figures

None
Graphical abstract
Figure 1
Figure 1
Flowchart of the modified Delphi technique for ongoing selection of disorders for NBS-rWGS after they have been included in the Genome-to-Treatment virtual management guidance system (GTRx) Abbreviations: ICU, intensive care unit; rWGS, rapid whole-genome sequencing.
Figure 2
Figure 2
Workflow diagrams of diagnostic rWGS and newborn screening by rWGS Shown are comparisons of the workflow for Dx-rWGS (A) with that for NBS-rWGS (B) and for a secondary use of data generated by NBS-rWGS (C). The interpretation burden of NBS-rWGS is approximately 1,000-fold less than that of Dx-rWGS. The light blue shading indicates the activities occurring in places of care for newborns or older children, while the darker blue shading indicates activities occurring in clinical laboratories. The dashed green arrows ① and ② in NBS-rWGS indicate feedback loops. Abbreviations: dB, database; EDTA, ethylene diamine tetra-acetic acid; ICU, intensive care unit; EHR, electronic health record; CLIA, clinical laboratory improvements act; GEM AI, a genome interpretation tool that employs artificial intelligence; GTRx, Genome-to-Treatment virtual management guidance system.
Figure 3
Figure 3
Funnel plots demonstrating the use of step-wise root cause analysis to improve the specificity and sensitivity of newborn screening by genomic sequencing Funnel plots showing reduction in 2,982 positive individuals in 73 positive NBS-rWGS genes among 454,707 UK Biobank participants by root cause analysis (A) and increase in retrospective NBS-rWGS positives among 4,376 children and their parents (B). Variant identifiers are from ClinVar. Abbreviations: LB, likely benign; B, benign; AR, autosomal recessive; AD, autosomal dominant; ICD, International Statistical Classification of Diseases and Related Health Problems; dB, database; UKBB, United Kingdom Biobank.
See this image and copyright information in PMC

Comment in

  • Progress in expanding newborn screening in the United States.
    Grosse SD, Cuthbert C, Gaffney M, Gaviglio A, Hinton CF, Kellar-Guenther Y, Kemper AR, McKasson S, Ojodu J, Riley C, Singh S, Sontag MK, Shapira SK. Grosse SD, et al. Am J Hum Genet. 2023 Jun 1;110(6):1015-1016. doi: 10.1016/j.ajhg.2023.05.002. Am J Hum Genet. 2023. PMID: 37267896 Free PMC article. No abstract available.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Therrell B.L., Padilla C.D., Loeber J.G., Kneisser I., Saadallah A., Borrajo G.J.C., Adams J. Current status of newborn screening worldwide. Semin. Perinatol. 2015;39:171–187. - PubMed
    1. American Academy of Pediatrics Newborn Screening Task Force Newborn screening: a blueprint for the future. Pediatrics. 2000;106(Suppl. 2):383–427. - PubMed
    1. Kayki-Mutlu G., Aksoyalp Z.S., Wojnowski L., Michel M.C. A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2022;395:867–885. - PMC - PubMed
    1. Sontag M.K., Yusuf C., Grosse S.D., Edelman S., Miller J.I., McKasson S., Kellar-Guenther Y., Gaffney M., Hinton C.F., Cuthbert C., et al. Infants with Congenital Disorders Identified Through Newborn Screening — United States, 2015–2017. MMWR Morb. Mortal. Wkly. Rep. 2020;69:1265–1268. - PMC - PubMed
    1. Centers for Disease Control and Prevention CDC Impact of expanded newborn screening—United States, 2006. MMWR Morb. Mortal. Wkly. Rep. 2008;57:1012–1015. - PubMed

Publication types