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

Abstract

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.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Summary of steps from patient nomination for STATseq to confirmatory result

STATseq=rapid whole-genome sequencing.

Figure 2. Flow diagram of the comparison of the diagnostic sensitivity and accuracy of STATseq with standard clinical genetic testing for infants in NICU

STATseq=rapid whole-genome sequencing. NICU=neonatal intensive care unit.

Figure 3. Characteristics of patients with STATseq diagnoses

(A) Time from enrolment to confirmed diagnosis with STATseq in 18 infants. Two infants who were diagnosed at days 167 and 912 are not shown. (B) Kaplan-Meier survival curves of infants in NICU and PICU who did (n=21) or did not (n=14) receive a diagnosis of a genetic disease. 12 infants diagnosed with genetic diseases died before day of life 120, whereas three infants without a genetic disease died. (C) Timecourse for development of acute liver failure, enrolment, STATseq diagnosis, and treatment in infant CMH487. (D) Time course for admission, enrolment, diagnosis, and treatment of infant CMH569 with hyperinsulinaemic hypoglycaemia. STATseq=rapid whole-genome sequencing. NICU=neonatal intensive care unit. PICU=paediatric intensive care unit.