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Whole Genome Sequence Analysis of Intensively Ill Children: A Prospective Study of Parent-Child Trios in the UK

29 Pages Posted: 8 Oct 2018

See all articles by Courtney E French

Courtney E French

University of Cambridge

Isabelle Delon

NHS Foundation Trust - Cambridge University Hospitals

Alba Sanchis-Juan

University of Cambridge

Stephen Abbs

NHS Foundation Trust - Cambridge University Hospitals

Topun Austin

NHS Foundation Trust - Cambridge University Hospitals

Sarah Bowdin

NHS Foundation Trust - Cambridge University Hospitals

Ricardo G Branco

University of Cambridge

Helen Firth

NHS Foundation Trust - Cambridge University Hospitals

NIHR BioResource – Rare Disease

Next Generation Children Project

David H. Rowitch

University of California, San Francisco (UCSF) - Department of Pediatrics

F. Lucy Raymond

University of Cambridge - Department of Medical Genetics

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Abstract

Background: Each year 95,000 neonates are admitted to intensive care units (ICU) in the UK. With growing evidence that Mendelian diseases present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist with acute care decisions and long-term planning within a national health care system.

Methods: We performed trio whole genome sequence analysis (WGS) on a prospective cohort of 159 families recruited from neonatal and paediatric intensive care units (NICU and PICU) in the UK over a period of 18 months. We developed a research pipeline in collaboration with the National Health Service (NHS) to deliver validated pertinent pathogenic findings from WGS within 2-3 weeks of recruitment.

Findings: 48% of families approached consented to the study and 87% of those recruited provided parental samples for trio analysis. Overall, ~20% received a molecular genetic diagnosis. The phenotypic description of the child was a poor predictor of the gene identified in 87% of cases. The diagnosis affected clinical management in >75% of cases including modification of treatments, initiating new specialist care pathways and/or informing palliative care decisions. A 2-3 week turnaround was sufficient for clinical decision making.

Interpretation: The use of WGS in intensively ill children is acceptable to parents and trio analysis facilitates diagnoses. A trio gene agnostic analysis was highly effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. Scale up of this process will support NHS commissioning of WGS for first line management of intensively ill children.

Funding Statement: The study was supported by the Rosetrees Trust, Cambridge Biomedical Research Centre (FLR and DHR) and the National Institute for Health Research (NIHR) for the NIHR BioResource (grant number RG65966).

Declaration of Interests: The authors state: "none declared."

Ethics Approval Statement: Participants for this study were recruited through NHS Cambridge University Hospitals Foundation Trust under NRES Cambridge South Research Ethics Committee approval 13/EE/0325.

Suggested Citation

French, Courtney E and Delon, Isabelle and Sanchis-Juan, Alba and Abbs, Stephen and Austin, Topun and Bowdin, Sarah and Branco, Ricardo G and Firth, Helen and Disease, NIHR BioResource – Rare and Project, Next Generation Children and Rowitch, David H. and Raymond, F. Lucy, Whole Genome Sequence Analysis of Intensively Ill Children: A Prospective Study of Parent-Child Trios in the UK (September 28, 2018). Available at SSRN: https://ssrn.com/abstract=3258666

Courtney E French

University of Cambridge

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Isabelle Delon

NHS Foundation Trust - Cambridge University Hospitals

Hills Road
Cambridge, CB2 0QQ
United Kingdom

Alba Sanchis-Juan

University of Cambridge

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Stephen Abbs

NHS Foundation Trust - Cambridge University Hospitals

Hills Road
Cambridge, CB2 0QQ
United Kingdom

Topun Austin

NHS Foundation Trust - Cambridge University Hospitals

Hills Road
Cambridge, CB2 0QQ
United Kingdom

Sarah Bowdin

NHS Foundation Trust - Cambridge University Hospitals

Hills Road
Cambridge, CB2 0QQ
United Kingdom

Ricardo G Branco

University of Cambridge

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Helen Firth

NHS Foundation Trust - Cambridge University Hospitals

Hills Road
Cambridge, CB2 0QQ
United Kingdom

David H. Rowitch

University of California, San Francisco (UCSF) - Department of Pediatrics

550 16th Street, Box 0110
San Francisco, CA 94143
United States

F. Lucy Raymond (Contact Author)

University of Cambridge - Department of Medical Genetics ( email )

Cambridge, CB2 0XY
United Kingdom

No contact information is available for NIHR BioResource – Rare Disease
No contact information is available for Next Generation Children Project

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