Abstract
Importance Genetic disorders, including congenital anomalies, are a leading cause of morbidity and mortality in infants, especially in neonatal and pediatric intensive care units (NICU and PICU). While genomic sequencing is useful for diagnosis of genetic diseases, results are usually reported too late to guide inpatient management.
Objective To test the hypothesis that rapid whole genome sequencing (rWGS) increases the proportion of infants in NICUs and PICUs receiving a genetic diagnosis within 28 days.
Design An investigator-initiated, partially blinded, pragmatic, randomized controlled study with enrollment from October 2014 - June 2016, and follow up until December 2016.
Setting A regional neonatal and pediatric intensive care unit in a tertiary referral childrens hospital.
Participants Sixty five of 129 screened families with infants aged less than four months, in neonatal and pediatric intensive care units, and with illnesses of unknown etiology, completed the study.
Intervention Parent and infant trio rWGS.
Main Outcome and Measure The hypothesis and end-points were formulated a priori. The primary end-point was rate of genetic diagnosis within 28 days of enrollment or first standard test order.
Results Twenty six female proband infants, 37 male infants, and two infants of undetermined sex were randomized to receive rWGS plus standard tests (n=32, cases) or standard tests alone (n=33, controls). The study was terminated early due to loss of equipoise: 63% (21) controls received genomic sequencing as standard tests. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days to be higher in cases (31%, ten of 32) than controls (3%, one of 33; difference, 28% [95% CI, 10% to 46%]; p=0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, seven of 22) than controls (0%, zero of 23; difference, 32% [95% CI, 11% to 53%]; p=0.004). Age at diagnosis (median in cases 25 days, range 14-90 days vs median in controls 130 days, range 37-451) and time to diagnosis (median in cases thirteen days, range 1-84 days vs median in controls 107 days, range 21-429 days) were significantly less in cases than controls (p=0.04).
CONCLUSIONS rWGS increased the proportion of infants in a regional NICU and PICU who received a timely diagnosis of a genetic disease. Additional, adequately powered studies are needed to determine whether accelerated diagnosis is associated with improved outcomes in this setting. ClinicalTrials.gov Identifier: NCT02225522.
