Combined newborn screening test spots 2 rare diseases

A combined newborn screening test for two rare diseases — spinal muscular atrophy (SMA) and severe combined immunodeficiency (SCID), a condition that leaves infants with little or no working immune systems — correctly identified every affected baby, with no missed or false diagnoses.

The five-year Italian pilot screened 32,289 newborns and found 10 affected babies, most of whom began treatment within weeks of birth and went on to have good outcomes.

“The study demonstrates that combined SMA and SCID newborn screening is feasible, reliable, and clinically impactful, supporting its integration into public health screening programs,” the authors said.

The study, “Five-year experience of a combined newborn screening for spinal muscular atrophy and severe combined immunodeficiency in Liguria, Italy,” was published in the European Journal of Human Genetics.

SMA is caused in nearly all cases by a loss of part of the SMN1 gene, which leads to the degeneration of nerve cells controlling muscle movement. Its severity depends partly on how many copies a person has of a backup gene, SMN2.

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SCID, often called bubble baby disease, is a group of inherited conditions. Without early intervention, SCID is typically fatal within the first year or two of life due to severe infections.

Both conditions now have effective treatments, but these work best when started before symptoms appear. Newborn screening (NBS) is a valuable tool for identifying babies with either condition as early as possible.

Researchers in the Liguria region of Italy investigated whether a single blood test could screen newborns for both conditions at once, rather than running separate tests. The team screened 32,289 newborns, collecting a single drop of blood from each baby two to three days after birth, reaching 99.8% of babies born in the region.

The blood spots were checked for an SMN1 deletion and for TREC and KREC, two immune system markers that reflect the development of T-cells and B-cells, two types of immune cells. Cutoff values were set from a reference group of 3,000 healthy newborns.

Of the babies screened, 654 (2%) had an initial positive result on the first test. Almost all of these were flagged for possible SCID, with five flagged for possible SMA.

After a second round of testing due to borderline or inconclusive results, 10 babies remained positive and were referred for full diagnostic testing. All 10 received an official diagnosis of the genuine condition, meaning the test’s positive predictive value was 100%. No healthy baby was wrongly referred, and no case was missed during follow-up.

Five babies were diagnosed with SMA, four of whom were treated before symptoms appeared. In one case, a newborn girl with SMA type 1 who showed reduced muscle tone, received gene therapy to replace the missing SMN1 gene. She reached normal developmental milestones and was walking independently by 17 months.

One boy and two girls, all without symptoms, began treatment with either Spinraza (nusinersen) or Evrysdi (risdiplam).

One baby, with the most severe form (SMA type 0), died within days of birth despite an early diagnosis. The authors noted that for this type of SMA, which develops before birth, “even the most rapid postnatal risk-stratification and intervention may be insufficient to alter the disease trajectory.”

Five babies were diagnosed with immune conditions. Two had ADA-SCID, a form of SCID caused by a missing enzyme; both were started on enzyme replacement therapy, with one going on to gene therapy.

The other three babies had related but less severe immune findings: low T-cells, DiGeorge syndrome (a condition linked to a small missing piece of chromosome 22), and a temporary drop in B-cells that resolved on its own by three months.

The authors described these three cases as “clinically significant secondary findings” rather than SCID itself. Since they didn’t meet strict SCID criteria, the babies still needed follow-up measures, such as avoiding certain vaccines.

Babies with positive results were typically called back for evaluation at a median age of 13 days, with timing ranging from 7-22 days. It took a median of 14 days (range: 12-26 days) for doctors to reach a final genetic diagnosis for the immune conditions.

The researchers estimated that in the Liguria region, SMA occurs in about one in 6,433 live births, and SCID-related conditions occur in about one in 16,084. The researchers describe those figures as consistent with other Italian and European studies.

“Our findings demonstrate that integrating molecular assays for these severe conditions into a regional NBS framework is feasible, accurate, and operationally sustainable,” the scientists wrote. “The program enabled early diagnosis and timely treatment in ten affected newborns, resulting in improved clinical outcomes.”