Newborn screening (NBS), including genomic screening, plays an important role in identifying rare diseases, but it cannot be assumed to be enough on its own to end the often lengthy diagnostic journey many patients still face.

Caroline Fiona Wright, PhD, professor of genomic medicine at the University of Exeter in Exeter, England, and colleagues wrote this in a commentary recently published in Nature Medicine, clarifying the role of neonatal screening without hiding its limitations and emphasizing the need for complementary approaches.

The average time to diagnosis is 5 years, and about 10% of patients have waited more than 20 years for a diagnosis of their condition, the authors wrote, noting that this difficult journey has not only medical and economic implications for patients and their families but also an enormous emotional burden stemming from the uncertainty caused by the lack of a diagnosis.

When NBS Becomes Genomic

In recent years, advances in technology have made whole-genome sequencing increasingly common, paving the way for a newer approach to NBS known as genomic NBS (gNBS). This testing, which sequences a newborn’s entire genome, is designed to identify DNA changes linked to rare diseases. In some cases, it has helped shorten the time to diagnosis, but it is not a complete solution to diagnostic delays and has limitations that cannot be ignored.

As Wright and colleagues pointed out, there are at least 7000 rare diseases, 80% of which have a genetic cause and approximately 70% of which manifest during childhood. It must be noted, however, that for the majority of rare diseases (90%-95%), no approved treatments are currently available; consequently, the number of patients who could truly benefit from gNBS from both a diagnostic and therapeutic standpoint is significantly reduced. Furthermore, we must not forget that for nearly half of all rare diseases, the molecular cause is unknown.

“In this context, NBS — including genomic screening — addresses only a small part of pediatric rare diseases,” Maria Rosaria Iascone, PhD, head of the Medical Genetics Laboratory at ASST Papa Giovanni XXIII in Bergamo, Italy, a reference center for this type of testing, told Univadis Italy, part of the Medscape Professional Network. “Screening is focused on diseases for which a treatment is available or for which early diagnosis can substantially alter the natural history of the disease,” she added.

The International Consortium on Newborn Sequencing is an international initiative established, as stated on its website, to “contribute to clinical and public health research and to the implementation of genomic screening in newborns through the harmonization and pooling of scientific evidence and resources.” Thanks in part to these initiatives, efforts are being made to standardize the selection of genes to be included in screening; however, contextualization for each individual country is still necessary. “It makes no sense to include a disease in a screening program for which no treatment is available in that country,” Iascone clarified.

NBS and Advanced Diagnostics

According to Iascone, who is also a member of the executive board of the Italian Society of Human Genetics (SIGU), there is currently no clarity regarding the difference between NBS and advanced diagnostics.

The laboratory Iascone directs was the first in Italy to introduce rapid exome analysis — the part of DNA that codes for proteins — and later urgent whole-genome analysis for newborns and even some adults admitted to intensive care. “The importance of rapid diagnosis in intensive care is well documented in the literature: In these critical situations, the results of genetic testing help guide the patient’s clinical management,” she told Univadis Italy.

This is a form of advanced diagnostics, but it does not always provide a useful answer for patients. In some cases, it may even help guide clinicians away from further futile medical treatment. Still, as the Nature Medicine commentary notes, for some well-characterized rare diseases, the best approach may be to quickly recognize the symptoms and move directly to targeted genetic or genomic testing — testing that should be available to everyone. “In Italy, even today, access to this type of diagnostic testing depends on where one lives, with enormous disparities between regions and even between different areas within the same region,” Iascone said.

NBS — whether genomic or not — takes a completely different approach and has a different significance; it plays an important role in early diagnosis, understood as the opportunity to intervene promptly by initiating targeted clinical management or specific therapy, which may include dietary changes, supplementation or, in some cases, even gene therapies.

“Screening cannot replace advanced diagnostics: It is a complementary tool that must be added to a whole series of investigations and considerations,” stated Iascone. In fact, screening results can generate new uncertainties, including false positives and false negatives, and — in the case of genomic screening — it is essential to take into account specific characteristics such as incomplete penetrance, pathogenic variants or variants of uncertain significance, and the quality of the available evidence.

Focus on Italy

With regard to expanded NBS, Italy ranks among the most advanced nations: the national program covers 50 conditions — while countries such as France and England cover fewer than 10 — and is supported by a well-established organization that, for the past 10 years, has ensured access to screening throughout the country, despite regional organizational differences.

In the areas of genetic diagnosis and research on rare diseases as well, the country possesses a high level of expertise and centers of excellence involved in European-level projects, although there remains a patchy distribution of resources and diagnostic capabilities, with regional differences in access to technologies such as genomic sequencing.

With no updates to national regulations, some regions — including Lombardy — have independently adopted routine exome and genome sequencing, while others have not, creating inequalities and gaps in access. To help manage the growing role of genomics in clinical practice, SIGU has created a Genomics Commission that will work on two fronts: developing guidelines and organizational models while engaging with institutions and promoting accurate information and outreach on genomics-related topics, including outreach to the general public.

“In this context, alongside technological innovation and greater integration between referral centers and the local community, communication plays a central role,” Iascone told Univadis Italy. Genetic information, in fact, must always be contextualized within a counseling and care pathway capable of supporting the patient and their family.

More broadly, scientific communication is becoming an increasingly important part of the care pathway and should include discussion among specialists, training for healthcare professionals, and ongoing dialogue with patients and the public. “In particular, family pediatricians, general practitioners, and other local specialists do not necessarily need specialized knowledge of individual rare diseases, but they must be able to recognize cases that need further evaluation and refer them promptly to referral centers, within networks that also allow for follow-up and continuity of care in the local community,” she concluded.

Iascone has disclosed no relevant financial relationship.

This story was translated from Univadis Italy.