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Whole genome sequencing reveals that genetic conditions are frequent in intensively ill childrenOpen access

Courtney E. French| Isabelle Delon| Helen Dolling| Alba Sanchis-Juan| Olga Shamardina| Karyn Mégy| Stephen Abbs| Topun Austin| Sarah Bowdin| Ricardo G. Branco| Helen Firth| David H. Rowitch| F. Lucy Raymond
Original
Online First ™ - March , 2019

Pages 1 - 10

Abstract

Purpose

With growing evidence that rare single gene disorders present in the neonatal period, there is a need for rapid, systematic, and comprehensive genomic diagnoses in ICUs to assist acute and long-term clinical decisions. This study aimed to identify genetic conditions in neonatal (NICU) and paediatric (PICU) intensive care populations.

Methods

We performed trio whole genome sequence (WGS) analysis on a prospective cohort of families recruited in NICU and PICU at a single site in the UK. We developed a research pipeline in collaboration with the National Health Service to deliver validated pertinent pathogenic findings within 2–3 weeks of recruitment.

Results

A total of 195 families had whole genome analysis performed (567 samples) and 21% received a molecular diagnosis for the underlying genetic condition in the child. The phenotypic description of the child was a poor predictor of the gene identified in 90% of cases, arguing for gene agnostic testing in NICU/PICU. The diagnosis affected clinical management in more than 65% of cases (83% in neonates) including modification of treatments and care pathways and/or informing palliative care decisions. A 2–3 week turnaround was sufficient to impact most clinical decision-making.

Conclusions

The use of WGS in intensively ill children is acceptable and trio analysis facilitates diagnoses. A gene agnostic approach was effective in identifying an underlying genetic condition, with phenotypes and symptomatology being primarily used for data interpretation rather than gene selection. WGS analysis has the potential to be a first-line diagnostic tool for a subset of intensively ill children.

Keywords

References

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