Prenatal Blood Test Accurately Gauges SMA Risk

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by Steve Bryson PhD |

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UNITY Screen, a noninvasive prenatal blood test, can provide an accurate personalized risk assessment for hereditary diseases such as spinal muscular atrophy (SMA) in fetuses, according to a recent study.

Offered by BillionToOne in the U.S., the single-gene noninvasive prenatal test (sgNIPT) included in UNITY Screen requires only a small sample of the mother’s blood to determine whether the fetus has an elevated risk for developing SMA or other conditions after birth.

UNITY was more accurate than traditional screening methods that require samples from both parents, including paternal samples that are not available in some cases.

The test also applies to other single-gene conditions, including cystic fibrosis (CF) and the blood disorders sickle cell disease (SCD) and thalassemia, and to diseases caused by changes in chromosomal numbers.

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“These results indicate that the real-world sensitivity of UNITY Screen is estimated to be more than [two times] higher compared to traditional carrier screening,” Oguzhan Atay, PhD, BillionToOne’s CEO, said in a company press release. “We believe that UNITY Screen will lead to more equitable care for pregnant individuals across the United States.”

The UNITY Screen’s clinical performance was published in the journal Genetics in Medicine, in the study, “Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions.”

SMA is a recessive genetic disorder, meaning that for children to develop the disease, they must inherit a copy of a defective gene from both parents. A carrier is an individual who has only one mutated copy of a particular gene but doesn’t show symptoms.

Due to the condition’s progressive nature, early diagnosis and treatment are critical, especially in the more severe, earlier-onset forms of SMA.

“Identification of high-risk pregnancies through prenatal carrier screening is critical to provide appropriate counseling for prenatal diagnostic testing, pregnancy care, and neonatal management,” the researchers wrote.

However, more than half of fetuses at risk of developing inherited conditions like SMA are not identified in prenatal screening tests because traditional screening methods rely on knowing whether both parents carry recessive genes. In many cases, paternal samples are not available.

A single blood sample

Screening with sgNIPS provides an alternative way to address these deficiencies by assessing the mother’s carrier status and fetal risk from a single blood sample, without the need for paternal screening.

The UNITY Screen test uses BillionToOne’s proprietary molecular counting technology, or Quantitative Counting Templates, which analyzes cell-free DNA (cfDNA) fragments found at very low levels in the bloodstream and detects changes associated with inherited diseases.

“We’re excited to see our revolutionary Quantitative Counting Templates (QCT) setting the stage for better assessment of fetal risk for these important genetic conditions,” Atay said.

Researchers at BillionToOne, in collaboration with a team at the University of North Carolina School of Medicine, evaluated the clinical performance of UNITY Screen recently shared the results. They particularly determined the test’s accuracy at identifying fetuses at risk for SMA, CF, SCD, and thalassemia, compared with traditional prenatal diagnostic testing and actual newborn outcomes.

The sgNIPS results included a numerical fetal risk score and category: high risk, increased risk, decreased risk, or low risk.

The team examined blood samples from a group of 9,151 pregnant individuals from the U.S. Of them, 1,669 (18.2%) were identified as carriers for one or more disease-causing genetic variants.

These samples were forwarded (reflexed) to sgNIPS. Out of 1,833 sgNIPS tests, 2.26% carried an SMA variant, 4.47% carried a CF variant, 4.64% carried variants related to SCD, and 8.65% were carriers for variants underlying thalassemia.

Comparing test results

Researchers then compared sgNIPS results with newborn outcomes obtained from parent surveys or care providers for 201 pregnancies. sgNIPS identified 14 out of 15 affected fetuses as being at high risk for one of the conditions, resulting in a sensitivity of 93.3% — the test’s ability to identify fetuses at risk correctly.

Among the 162 low-risk results, 161 were unaffected, leading to a negative predictive value of 99.4%, which is the likelihood an individual with a negative test is truly unaffected.

Of the 29 high-risk results, 14 newborns were affected, resulting in a positive predictive value (PPV) — the likelihood that a person with a positive test does have the disease — of 48.3%. This PPV value is “higher than the best-case 25% PPV that traditional carrier screening can achieve during a pregnancy with complete paternal follow-up,” the team noted.

Among the 41 pregnant women who were carriers of an SMA variant, all 27 fetuses identified as low risk were unaffected. In addition, 14 fetuses were classified as high-risk, and five of those were affected.

A final sensitivity analysis compared sgNIPS to traditional carrier screening. The sensitivity to identify a high-risk couple with traditional screening was 93%, given a hypothetical scenario with 100% paternal samples available and no “misattributed paternity.” That means the presumed father is likely not the biological father.

In a real world scenario, however, in which paternity may be misattributed in up to 10% of cases, and paternal screening may not be performed in up to 58% of cases, the sensitivity dropped to 35%.

“Because carrier screening with reflex sgNIPS does not rely on paternal screening, its sensitivity is not affected by misattributed paternity or paternal screening uptake,” the researchers noted.

In fact, the sensitivity of sgNIPS in a real-world scenario was 90%, which is “higher than that of traditional screening in the real-world scenario … and similar to the hypothetical scenario,” they added.

The test “provides a sgNIPS fetal risk tailored to the pregnancy, facilitating appropriate counseling for diagnostic testing and follow-up,” the researchers concluded.

The UNITY test also is available in Germany, Austria, Switzerland, and the Netherlands, where it is commercialized by Eluthia.

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