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RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit—successes and challenges

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Abstract

Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women’s Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant’s phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.

Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed.

What is Known:

• Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation.

What is New:

• This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES).

• In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.

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Abbreviations

NICU:

Neonatal intensive care unit

GWS:

Genome-wide sequencing

ES:

Exome sequencing

WGS:

Whole genome sequencing

OMIM:

Online Mendelian Inheritance in Man

CMA:

Chromosomal microarray analysis

CMV:

Cytomegalovirus

TPN:

Total parenteral nutrition

VUS:

Variant of uncertain significance

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Acknowledgments

We thank the families who participated in this study, Jennifer Claydon, and clinical staff who assisted with coordination. We are grateful to Drs. Susan Albersheim, Michael Castaldo, Deepak Manhas, Julia Panczuk, Jonathan Wong, and Grace Yu from Neonatology who contributed to patient selection and follow-up. RAPIDOMICS study investigators include the following: Tara Candido, Jan Christilaw, Nick Dragojlovic, Christèle du Souich, Alison M. Elliott, Daniel M. Evans, Matthew J. Farrer, Jan M. Friedman, Ilaria Guella, Anna Lehman, Larry Lynd, Horacio Osiovich, and Leah Tooman.

Funding

This project was funded by the User Partnership Program (UPP): Genome British Columbia with co-funding from the Provincial Health Services Authority (PHSA). The Centre for Applied Neurogenetics was supported by the Canada Excellence Research Chairs program (MJF). Leading Edge Endowment Funds from the Province of British Columbia, LifeLabs, and Genome BC support the Dr. Donald Rix BC Leadership Chair (MJF). “Neuroseq” bioinformatics development is supported through the Canadian Consortium on Neurodegeneration in Aging and the Pacific Parkinson’s Research Institute.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, University of British Columbia, Vancouver, Canada

    Alison M. Elliott, Christèle du Souich, Anna Lehman, Linlea Armstrong, Lorne Clarke, William Gibson, Harinder Gill, Suzanne Lewis, Margaret L. McKinnon, Sarah M. Nikkel, Millan Patel, Margot van Allen & Jan M. Friedman

  2. Provincial Medical Genetics Program, BC Women’s Hospital and Health Centre, 4500 Oak Street, Vancouver, British Columbia, V6H 3N1, Canada

    Alison M. Elliott, Christèle du Souich, Anna Lehman, Linlea Armstrong, Lorne Clarke, William Gibson, Harinder Gill, Suzanne Lewis, Margaret L. McKinnon, Sarah M. Nikkel, Millan Patel, Margot van Allen & Jan M. Friedman

  3. Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada

    Ilaria Guella, Daniel M. Evans, Tara Candido, Leah Tooman & Matthew J. Farrer

  4. Division of Neonatology, Department of Paediatrics, University of British Columbia, Vancouver, Canada

    Pascal M. Lavoie, Alfonso Solimano, Anne Synnes, Joseph Ting & Horacio Osiovich

  5. Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, Canada

    Jan Christilaw

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  1. Alison M. Elliott
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  2. Christèle du Souich
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Contributions

Dr. Elliott conceptualized and designed the study; was involved in data acquisition, analysis, and interpretation; drafted the initial manuscript; and revised the manuscript.

Ms. du Souich, Dr. Lehman, and Dr. Horacio Osiovich conceptualized and designed the study, were involved in data acquisition and analysis and interpretation of the data, reviewed and revised the manuscript.

Dr. Friedman conceptualized and designed the study, was involved in analysis and interpretation of the data, and reviewed and critically revised the manuscript.

Dr. Guella, Mr. Evans, Ms. Candido, Ms. Tooman, and Dr. Farrer conceptualized and designed the study, were involved in data analysis and interpretation, and reviewed and revised the manuscript.

Drs. Armstrong, Clarke, Gibson, Gill, Lewis, McKinnon, Nikkel, Patel, and van Allen were involved in data collection and interpretation of the data and critically revised the manuscript.

Drs. Lavoie, Solimano, Synnes, and Ting were involved in data collection and interpretation and critically revised the manuscript.

Dr. Christilaw conceptualized and designed the study, facilitated data acquisition, and provided revision of the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Alison M. Elliott.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the University of British Columbia (UBC)/BC Children’s and Women’s Clinical Research Ethics Board (REB H15-02750).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Communicated by Patrick Van Reempts

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Revisions received: 4 May 2019 / 7 May 2019

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Elliott, A.M., du Souich, C., Lehman, A. et al. RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit—successes and challenges. Eur J Pediatr 178, 1207–1218 (2019). https://doi.org/10.1007/s00431-019-03399-4

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