Identifying rare genetic diseases in the first days of life, before symptoms appear, and enabling more timely access to targeted care and clinical pathways: this is the perspective at the heart of the study conducted by the Medical Genetics group at the University of Trieste, led by Paolo Gasparini, Professor of Medical Genetics at UniTS and Director of the Medical Genetics Unit at the IRCCS Burlo Garofolo.

The work, carried out in collaboration with Stefania Zampieri, senior biologist in Medical Genetics at the IRCCS Burlo Garofolo, assessed the clinical and economic impact of integrating genomics into newborn screening programmes. The study takes Friuli Venezia Giulia as a model and compares the traditional approach with a “genomic-first” scenario based on whole-exome sequencing (WES) as the first-line investigation.

Newborn screening is now one of the most effective tools for prevention: it enables the early identification of a number of treatable conditions and allows interventions to take place before they can lead to severe complications, disability or irreversible damage. The traditional model, however, is largely based on the analysis of biochemical markers and can therefore detect only those diseases for which known and measurable signals are already available.

“Newborn screening is highly effective today, but it can identify only conditions associated with specific biomarkers,” explains Paolo Gasparini. “With a genomic approach, we can detect genetic diseases at their root, even in the absence of clear early signals.”

The difference concerns not only the technology used, but the entire diagnostic pathway. In the traditional model, screening begins with a biochemical test, followed, in the event of a positive result, by further genetic investigations where appropriate. In the genomic model, by contrast, whole-exome sequencing becomes the first step of the investigation, followed where necessary by targeted biochemical tests or additional diagnostic confirmation. In this way, genomics broadens the scope of screening to include conditions that are not currently covered by traditional panels.

The study examined the 2023 newborn cohort in Friuli Venezia Giulia, comprising 7,543 children. In that year, screening identified one case of spinal muscular atrophy, one case of cystic fibrosis and eleven cases of metabolic diseases. Applying the comparison between the two models to this cohort, the analysis estimates a direct cost of €131 per newborn for traditional screening and €183 per newborn for genomic screening, an increase of €51 per newborn.

Against this initial increase, however, the genomic model shows a positive cost-effectiveness profile. According to the estimates, in Friuli Venezia Giulia the “genomic-first” approach could generate overall savings of around €2.2 million, taking into account the economic benefits associated with earlier diagnosis, fewer complications and the reduction of longer and more complex care pathways. Genomic screening could also make it possible to identify a further 7–8 cases of rare diseases each year that cannot be diagnosed through traditional biochemical tests.

“Investing in early diagnosis means making the system more sustainable in the medium to long term,” adds Gasparini. “It is an approach to healthcare that is oriented towards prevention.”

The value of genomics applied to newborn screening is therefore measured not only by the number of conditions that can be identified, but also by its potential to reduce the so-called “diagnostic odyssey” that many families face before receiving a diagnosis. Earlier diagnosis can support timely access to more effective therapies, improve clinical and functional outcomes, reduce the care burden and contain the social impact of disability.

The study also underlines the need to define carefully which conditions should be included in any newborn genomic screening programme. The main criteria include the availability of a therapeutic intervention, the clinical validity of the test, age of disease onset, severity of the clinical presentation, penetrance and the technical feasibility of genetic analysis. The perspective, therefore, is not the indiscriminate use of genomics, but an application guided by clinical, scientific and ethical criteria.

Another central issue is the relationship between genomic screening and metabolic screening. The two approaches should not be regarded as alternatives, but as complementary. Genomics makes it possible to identify genetic variants associated with disease; metabolic screening can help validate their functional effect, distinguishing between pathogenic variants, findings of uncertain significance and different clinical forms, including late-onset forms.

The decreasing cost of sequencing, the growth of gene and cell therapies and the identification of new therapeutic targets are making genomics an increasingly important tool for preventive and personalised medicine. Key issues remain open, from the management of variants of uncertain significance to the protection of newborns’ genomic data, as well as the need for adequate bioinformatics infrastructure and pilot studies shared across laboratories and health systems.