NEW YORK – After undertaking a successful pilot study, researchers in Greece will next year embark on the larger, second phase of a newborn sequencing project that could see as many as 100,000 babies sequenced in coming years.
One of the aims of this effort, called FirstSteps, is to create a population-specific dataset that could better inform state health authorities about the incidence of various genetic conditions in the Greek population. But participants are also collecting data on how whole-genome sequencing might complement conventional screening methods.
Should the results be favorable, it could lay the foundation for whole-genome sequencing to be the standard of care for newborn screening in Greece, according to Petros Tsipouras, an adjunct professor at Yale School of Medicine who is also the scientific director of FirstSteps.
Tsipouras last year provided an overview of the first phase of FirstSteps at the International Conference on Newborn Sequencing in London. The first phase saw a thousand newborns screened with whole-genome sequencing for 385 genes and 510 associated conditions. Screening was carried out in cooperation with three university hospitals in Greece in Thessaloniki, Larissa, and Athens. Enrollment has since been completed while sequencing and analysis are still underway. Tsipouras said that so far, the screen positive rate has been about 4 percent.
"This was purely a feasibility study," Tsipouras said of the first phase, in which researchers also spoke with prospective parents who needed to consent to have their newborns sequenced. "We got an overwhelming response, close to 90 percent wanted their babies tested," he said. Another aspect made clear was that reports would be targeted to return information only for conditions for which a therapeutic intervention exists.
FirstSteps is now ramping up to embark on its second, larger phase. Tsipouras underscored that FirstSteps remains a research project and is being carried out with the partnership and blessing of Greece's Ministry of Health. Another partner in the project is PlumCare RWE, a Woodbridge, Connecticut-based company that Tsipouras cofounded and leads as CEO. While the second phase of FirstSteps is being funded through private philanthropy, Tsipouras said PlumCare will "ensure that [First Steps] secures the funding it needs to run smoothly."
Last year, PlumCare partnered with Fabric Genomics, an Oakland, California-based genomics software company, to use its Fabric AI platform for clinical genomic variant interpretation for the sequencing data collected in the FirstSteps project. Tsipouras said this partnership continues.
According to Tsipouras, FirstSteps builds on newborn biochemical screening services that have been in place in Greece since 1974. Relying on blood samples obtained from newborn heel pricks, biochemical screening in Greece originally targeted four diseases but now covers 33 and is carried out using gas chromatography-mass spectrometry. Every Greek newborn is screened in the program. Tsipouras described the existing service as "very successful and well run" but said that newborn screening with whole-genome sequencing could expand the breadth of diseases detected. He likened Greece's program to similar projects that are underway in the US, UK, Europe, and Australia.
In its second phase, FirstSteps will first look to sequence 20,000 newborns, beginning in the spring of 2025. Samples will be obtained for standard screening through Greece's central biochemical laboratory, pseudonymized, and then dispatched to a to-be-built sequencing lab for screening. The samples will be barcoded, and any results of interest will be reported to the central lab.
"We will not report directly to families, and we will relay data to the central biochemical lab," Tsipouras stressed. He added that the lab has the statutory authority to contact families about results and to suggest intervention. "We will be at arm's length from the families," he said.
Should sequencing-based newborn screening one day be fully implemented, a different kind of process would have to be put in place, he acknowledged. "That field is being actively debated," he remarked. "I'm not a policymaker," said Tsipouras. "When newborn genomic screening is offered as a universal mandate, I assume there will be an opt-out provision," he said.
According to Tsipouras, the second phase of FirstSteps has multiple goals. One is to create a Southern European dataset that is representative of the Greek population. "We have a different gene pool than Northern Europeans," he said. This dataset will be diverse and inclusive, as it will cover all babies screened in the country of 10.4 million, where there are about 70,000 births annually. It will also provide regional granularity, showing diversity within the Greek population.
"This is a massive population health experiment," Tsipouras remarked. By the end of 2026, FirstSteps aims to have about 100,000 babies sequenced. He said that a technology partner for the study has not been selected, though the project is in discussions with potential vendors.
With that genetic snapshot of the Greek population in place, FirstSteps will have a better idea of what disease-causing variants are prevalent in the Greek population. This will at the very least allow the Ministry of Health to shape its screening coverage. But with a health-cost analysis, FirstSteps could also make the case that whole-genome sequencing should be a new standard.
"We'll be able to say what are the top 50 genetic diseases in Greece," Tsipouras said, "and how much it would cost to have the prevention machinery in place." Based on those findings, the Greek government will be able to decide if it wants to adopt sequencing.
In general, Tsipouras said Greek society has similar concerns to other European countries with regards to data privacy. While Greeks are socially more conservative than Northern Europeans, they are health conscious and family oriented, which makes them supportive of such a program.
"When it comes to preventative care, particularly with babies, Greeks are very positive," he said.