Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings

Abstract

Summary Background Genetic disorders and congenital anomalies are the leading causes of infant mortality. Diagnosis of most genetic diseases in neonatal and paediatric intensive care units (NICU and PICU) is not sufficiently timely to guide acute clinical management. We used rapid whole-genome sequencing (STATseq) in a level 4 NICU and PICU to assess the rate and types of molecular diagnoses, and the prevalence, types, and effect of diagnoses that are likely to change medical management in critically ill infants. Methods We did a retrospective comparison of STATseq and standard genetic testing in a case series from the NICU and PICU of a large children's hospital between Nov 11, 2011, and Oct 1, 2014. The participants were families with an infant younger than 4 months with an acute illness of suspected genetic cause. The intervention was STATseq of trios (both parents and their affected infant). The main measures were the diagnostic rate, time to diagnosis, and rate of change in management after standard genetic testing and STATseq. Findings 20 (57%) of 35 infants were diagnosed with a genetic disease by use of STATseq and three (9%) of 32 by use of standard genetic testing (p=0·0002). Median time to genome analysis was 5 days (range 3–153) and median time to STATseq report was 23 days (5–912). 13 (65%) of 20 STATseq diagnoses were associated with de-novo mutations. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a STATseq diagnosis, four (20%) had diagnoses with strongly favourable effects on management, and six (30%) were started on palliative care. 120-day mortality was 57% (12 of 21) in infants with a genetic diagnosis. Interpretation In selected acutely ill infants, STATseq had a high rate of diagnosis of genetic disorders. Most diagnoses altered the management of infants in the NICU or PICU. The very high infant mortality rate indicates a substantial need for rapid genomic diagnoses to be allied with a novel framework for precision medicine for infants in NICU and PICU who are diagnosed with genetic diseases to improve outcomes. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences.

Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit

“…15 In a study of wholegenome sequencing in children retrospectively identified after an inpa tient stay in either the neonatal or pediatric inten sive care unit, a diagnosis was achieved in 57% (20/35) of cases. 11 These wholegenome sequencing studies required highthroughput sequencers, bioinformatics support, automation and experts in the field of translational genomics, resources that are not readily available to most diagnostic laboratories at this time. Another option, wholeexome sequencing, focuses on the protein coding regions of the approximately 22 000 human genes.…”

Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature

“…3,[31][32][33][34][35][36][37][38][39][40][41][42] Seven studies presented data on the costs of WES or WGS testing pathways, [24][25][26][27][43][44][45] and eight studies presented data on clinically relevant outcome measures for these tests. 5,6,[8][9][10][46][47][48] Of the eight full economic evaluations, two were CUAs 22,23 and six were CEAs, published between 2014 and 2017 in Australia (2), the United States (1), the UK (1), the Netherlands (1), and Canada (1). [18][19][20][21][28][29][30] Of these publications, the study by Soden et al 29 did not directly report WES costs but estimated Population unclear 2 (6) No study population 6 (17) WES, whole-exome sequencing; WGS, whole-genome sequencing.…”

“…Seven of these studies investigated WES; 5,6,[8][9][10]46,47 the eighth evaluated WGS. 48 Four publications used the traditional care pathway in the investigated condition as a comparator. 6,10,46,48 Three publications were retrospective analyses 6,47,48 and three were diagnostic studies, estimating the diagnostic yield of WES in a variety of conditions.…”

“…48 Four publications used the traditional care pathway in the investigated condition as a comparator. 6,10,46,48 Three publications were retrospective analyses 6,47,48 and three were diagnostic studies, estimating the diagnostic yield of WES in a variety of conditions. 5,8,9 The final two studies were case studies on single probands and families.…”

Challenges of using next generation sequencing in newborn screening

“…BRCA-negative familial breast cancer), and even to screen healthy individuals for future planning and predictive outcomes. Though WES is not generally applied to newborns, in critically ill infants it has shown a high rate of diagnosis of genetic disorders that have a direct effect on management and outcome (Saunders et al, 2012;Willig et al, 2015).…”