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

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: Critically ill children; Genetics; Genomics; NICU; PICU; Whole genome sequencing.

Fig. 1

Recruitment summary of cohort. Families were recruited from the neonatal intensive care unit (NICU), paediatric intensive care unit (PICU) and paediatric neurology or clinical genetics department (N/G)

Fig. 2

Impact of diagnosis on each case. Cases are ordered by increasing age. Green, specialist care. Blue, modification of treatment. Yellow, recurrence risk. Red, deceased and/or lethal condition. EIEE early infantile epileptic encephalopathy, Mito. mitochondrial, EI early infantile, NDD neurodevelopmental disorder, ND neurodegeneration

Fig. 3

Bar chart showing where the diagnosed gene ranked in phenotype similarity score to the proband, compared to all 3926 HPO-typed genes in OMIM. The white bar indicates that the diagnosed gene was only recently reported and not yet HPO-typed. An asterisk (*) indicates that the gene only partially explained the phenotype. Families 111 and 170 are not included because both are large deletions where a specific gene has not been implicated. Red, under 1 month old at recruitment. Purple, 1 month–1 year old at recruitment. Blue, over 1 year old at recruitment