Whole Genome Sequencing in Babies Proves Mettle

About one in five extremely ill infants lacking a clear diagnosis benefited from whole genome sequencing, researchers found in a randomized trial.

Clinical management shifted for 34 of 161 evaluable patients whose full genomic sequences were obtained (20.1%), compared with 17 of 165 (10.3%) in an unsequenced control group 60 days after enrollment, according to Ryan Taft, PhD, of the sequencing company Illumina, and colleagues.

In addition, twice as many infants undergoing sequencing received a molecular diagnosis compared with controls (31% vs 15%), the researchers reported in JAMA Pediatrics.

But the benefit was limited: neither ICU stays nor overall survival differed significantly in the so-called NICU-Seq trial, although follow-up was short. About 90% of both groups were still alive 120 days after enrollment, and approximately half of the infants in each group were discharged by day 30, with similar proportions still hospitalized at day 120.

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.”

Taft and colleagues had little to say, however, about the biggest question on whole genome sequencing as a clinical tool: whether it can be done cheaply enough to warrant its routine use.

When the first genome sequence was finished in 2000, the National Human Genome Research Institute had spent something like $3 billion to get there. The institute now estimates that, with the technology then in hand, sequencing one person’s genome in 2001 cost $100 million; it has since fallen to about $1,000, although the figure hasn’t changed much over the past 5 years.

The NICU-Seq investigators didn’t give cost figures for their sequencing. But if the $1,000 figure is a reasonable approximation, $488,000 was spent to change treatment plans for 34 infants — including the sequencing performed in family members — or about $14,400 per patient. That’s almost pocket change for infants whose average stay in intensive care is 1 month. Yet in the last line of their paper, Taft and colleagues suggested that would still be much too expensive as an everyday tool.

“The cost of [whole genome sequencing] may be a barrier to implementation in some environments, but this may be ameliorated by 2030 if recent projections of a $20 [sequence] are correct,” they wrote.

Study Details

NICU-Seq was a collaboration between Illumina and five children’s hospitals in Philadelphia; St. Louis; Omaha, Nebraska; Memphis, Tennessee; and Orange, California. Infants were enrolled from 2017 to 2019. They were considered for the study if they were 0 to 120 days old without a clear diagnosis, but with symptoms and lab findings suggestive of a genetic disorder. Those whose conditions could be fully explained as consequences of prematurity were excluded.

A total of 354 infants were enrolled and randomized. Sequencing was performed 15 days (intervention group, n=176) or 60 days (control, n=178) after enrollment. Twenty-four infants died and three others were unavailable for assessment by day 60 after enrollment, the time frame for the primary evaluation. This design, with sequencing performed in controls after outcomes were assessed, thus guaranteed that all participants would eventually receive the intervention. Family members (most often parents but also siblings in some cases) were sequenced as well.

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).

Just under 60% had multiple congenital anomalies as the indication for genetic testing. 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, Taft and colleagues 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.

The most common type of management change was subspecialty referral. Others included new or withdrawn medications, invasive procedures, and altered supportive care.