The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants

Genetic disorders are a leading cause of morbidity and mortality in infants in neonatal and pediatric intensive care units (NICU/PICU). While genomic sequencing is useful for genetic disease diagnosis, results are usually reported too late to guide inpatient management. We performed an investigator-initiated, partially blinded, pragmatic, randomized, controlled trial to test the hypothesis that rapid whole-genome sequencing (rWGS) increased the proportion of NICU/PICU infants receiving a genetic diagnosis within 28 days. The participants were families with infants aged <4 months in a regional NICU and PICU, with illnesses of unknown etiology. The intervention was trio rWGS. Enrollment from October 2014 to June 2016, and follow-up until November 2016. Of all, 26 female infants, 37 male infants, and 2 infants of undetermined sex were randomized to receive rWGS plus standard genetic tests (n = 32, cases) or standard genetic tests alone (n = 33, controls). The study was terminated early due to loss of equipoise: 73% (24) controls received genomic sequencing as standard tests, and 15% (five) controls underwent compassionate cross-over to receive rWGS. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days of enrollment (the primary end-point) to be higher in cases (31%, 10 of 32) than controls (3%, 1 of 33; difference, 28% [95% CI, 10–46%]; p = 0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, 7 of 22) than controls (0%, 0 of 23; difference, 32% [95% CI, 11–53%];p = 0.004). Median age at diagnosis (25 days [range 14–90] in cases vs. 130 days [range 37–451] in controls) and median time to diagnosis (13 days [range 1–84] in cases, vs. 107 days [range 21–429] in controls) were significantly less in cases than controls (p = 0.04). In conclusion, rWGS increased the proportion of NICU/PICU infants who received timely diagnoses of genetic diseases. Genetic disorders in critically ill infants can be diagnosed in as little as 26 h by rapid whole genome sequencing (rWGS). A study led by Stephen F. Kingsmore at the Rady Children’s Institute for Genomic Medicine in San Diego and Children’s Mercy Hospital in Kansas City compared the time to genetic diagnosis in 65 infants with inherited diseases of unknown cause using rWGS, clinical confirmatory testing and standard genetic tests or standard genetic tests alone. They found that the addition of rWGS including confirmatory testing significantly decreased the time to diagnosis, which in newborns can mean the difference between life and death. Because of the increasing accessibility and decreasing costs of the technology and the critical need for timely and effective intervention in infants with suspected genetic diseases, the authors advocate the use of rWGS as a first-line diagnostic test.