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. Electronic supplementary material The online version of this article (10.1007/s00134-019-05552-x) contains supplementary material, which is available to authorized users.

Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability

“…We focused our analysis on studies of patients who present with CA early in life, at a time when a diagnosis made by ES/GS may have the greatest impact for the patient by ending the diagnostic odyssey and for family by providing opportunities for reproductive options in subsequent pregnancies. 7,8,14,31 However, patients who present after 1 year of age may also derive benefit from a diagnosis made through ES/GS.…”

“…Nine studies reported a withdrawal of care or start of palliative care for patients after ES/GS results. 8,11,14,20,22,23,[45][46][47] In a case series of patients with CA/DD/ID, care was withdrawn at the family's request for a patient after GS resulted in a diagnosis of infantile mitochondrial cardiomyopathy with lactic acidosis. 45 Among a series of 66 neonatal patients with CA/DD/ID, dysmorphic features, and other clinical symptoms from a clinical laboratory, rapid ES identified a pathogenic variant in SOX10, which is associated with peripheral demyelinating neuropathy, central dysmyelination, or Waardenburg syndrome with or without Hirschsprung disease.…”

“…We identified an impact of ES/GS on outcomes related to reproductive planning for families of patients in 20 studies, including the decisions to become pregnant, terminate a pregnancy, use assisted reproductive technologies, use preimplantation genetic diagnosis, use donor sperm/egg, and undergo previously unplanned additional prenatal testing such as chorionic villus sampling (CVS) or amniocentesis. 7,8,11,14,16,22,26,28,31,32,[35][36][37][40][41][42][43][44]46,48 ES and GS influenced the decision about having additional children in two studies. 37,46 In a case series from the United Kingdom, 1 of 40 parents were considering not having additional children after the patient underwent ES; 37 while in a case series from the Netherlands, 9% (2/23) families changed their minds about not having additional children, after learning about the availability of prenatal genetic testing.…”

Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data

“…GS was performed on 73 samples with digital PCR results, 45 samples with MLPA results, and 12,747 population samples from the 1000 Genomes Project 29 (1109 of which have MLPA calls), the National Institute for Health Research (NIHR) BioResource Rare Diseases project and the Next Generation Children (NGC) project. 31 The sequencing and processing of this data was done using a variety of sample preparation methods, Illumina sequencers, and read aligners. A full description of this data can be found in the Supplementary Methods.…”

Exome Sequencing in Gastrointestinal Food Allergy Induced by Multiple Food Protein

“…Furthermore, it has been reported that the difference in the diagnostic utility of WGS over WES is not significant yet [38,39], since most of WGS studies are limited to coding variants (or non-coding but previously reported) due to the challenges of analysing non-coding regions. Additionally, due to the large amount of data produced by WGS experiments, turnaround times take longer than for exome and panel experiments (although recent studies have demonstrated the possibility of rapid turnaround of WGS of ∼2 weeks [40,41]). This is especially relevant in a clinical context rather in a research setting, where performing fast clinical diagnoses in as many individuals as possible is a priority.…”