Whole genome sequencing in babies proves courage

By on September 27, 2021 0

About one in five extremely sick infants without a clear diagnosis have benefited from whole genome sequencing, researchers found in a randomized trial.

Clinical management changed for 34 of 161 evaluable patients whose complete genomic sequences were obtained (20.1%), compared to 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 his colleagues.

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

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

One positive result that the authors called “unexpected” was that, among 32 extremely and very premature infants, whole genome sequencing identified a probable cause of their disease in nine (28.1%), “suggesting that [sequencing] may have wide applicability in premature infants. “

Taft and his colleagues, however, had little to say on the bigger question of whole genome sequencing as a clinical tool: whether it could be done at a price low enough to justify its routine use.

When the first genome sequence was completed in 2000, the National Human Genome Research Institute had spent some $ 3 billion to make it happen. The institute now estimates that with the technology then in hand, sequencing a person’s genome in 2001 cost $ 100 million; he has since fell to around $ 1,000, although the figure has not changed much over the past 5 years.

NICU-Seq investigators did not give figures on the costs of their sequencing. But if the $ 1,000 figure is a reasonable approximation, $ 488,000 was spent to change treatment plans for 34 infants – including sequencing done in family members – or about $ 14,400 per patient. It’s almost pocket change for infants with an average ICU stay of 1 month. Yet in the last line of their article, Taft and his colleagues suggested that it would still be far too expensive as an everyday tool.

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

Study details

NICU-Seq was a collaboration between Illumina and five children’s hospitals in Philadelphia; Saint Louis; Omaha, Nebraska; Memphis, Tennessee; and Orange, California. Infants were recruited 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 results suggesting a genetic condition. Those whose conditions could be fully explained as consequences of prematurity were excluded.

A total of 354 infants were recruited 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 more were unavailable for assessment on day 60 after enrollment, the deadline for primary assessment. This design, with sequencing performed in controls after outcome evaluation, ensured that all participants would eventually receive the intervention. Family members (most often parents but also siblings in some cases) were also sequenced.

The average age of infants was 15 days in the full sample of 354 members. About 57% were boys, 71% were white, and 23% were Hispanic (white or black).

Just under 60% had multiple birth defects as an indication for genetic testing. About 15% suffered from a neurological disorder and 11% had only one major characteristic that prompted a desire to be tested. Infants with an isolated major birth defect were the least likely to receive a positive sequencing result.

In addition to evaluating the primary results on Day 60, Taft and his colleagues were able to follow almost the entire sample until Day 90, when the control group also underwent sequencing. At this point, four more infants from the original intervention group underwent a change in management; in the control group, meanwhile, another 28 infants had a new plan of care – presumably based on the sequencing results for most of them.

The most common type of management change was a referral to a subspecialty. Others included new or withdrawn drugs, invasive procedures and modified supportive care.

  • John Gever was editor from 2014 to 2021; he is now a regular contributor.


The study was funded by Illumina, whose products and services were used to perform the genomic analyzes and who commercialize them commercially, as well as internal funds and grants at individual study sites.

Many of the authors were employees of Illumina. Other authors have reported relationships with various business entities.

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