Whole-Genome Sequencing Applied to Acutely Ill Infants

Genetic disorders are a leading cause of ICU admission, and recent studies have used comprehensive genomic testing in populations of acutely ill infants, using either whole-exome sequencing, which surveys approximately 2% of the genome that codes for proteins, or whole-genome sequencing (WGS), which evaluates approximately 95% of nuclear and mitochondrial DNA.

Medical Scientist at six children’s hospital (NICU-Seq trial) collaborated with the sequencing company Illumina and conducted a randomized time-delayed clinical trial, with a diverse population of 354 infants to receive Whole-Genome Sequencing (WGS) either 15 days or 60 days after enrollment. Infants' mean age was 15 days in the full 354-member sample. About 57% were boys, 71% were white, and 23% were Hispanic (either white or Black).

Clinical whole genome testing was performed by the Illumina Clinical Services Laboratory (ICSL, San Diego CA USA). Whole genome sequencing was performed on extracted DNA using sequencing-by-synthesis (SBS) next generation sequencing (NGS). The data were aligned and reported using build 37.1 of the Human Reference Genome. The genome was sequenced to an average of 38.9 fold coverage (IQR 37.3-39.77) and an average of 97.9% of the genome was callable (IQR 97.5-98.1).

The team reported that the largest number of diagnoses were in infants with multiple congenital anomalies (63/191; 33%), and the highest proportion were those with a single major clinical feature (19/35; 54%) Some 15% had a neurological disorder, and 11% had just a single major feature prompting the desire for testing. Infants with an isolated major congenital anomaly were the least likely to receive a positive finding from sequencing.

In addition to the primary outcome assessment at day 60, The scientists were able to follow almost all the sample out to day 90, by which point the control group had also undergone sequencing. At that point, another four infants in the original intervention group had a change in management; in the control group, meanwhile, another 28 infants had a new care plan, presumably based on the sequencing results for most of them.

One positive finding the authors called "unexpected" was that, among 32 extremely and very premature infants, whole genome sequencing identified a likely cause of their illness in nine (28.1%), suggesting that sequencing may have broad applicability in premature neonates.

The authors concluded that they found that two-thirds of patients received a change of management (COM) regardless of the testing modality, suggesting that the 2-fold higher diagnostic efficacy of systematically applied first-line WGS in acute infant care could reduce health care disparities. The study was published on September 27, 2021 in the JAMA Pediatrics.

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Illumina Clinical Services Laboratory