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Baylor NIPT for Dominant Single-Gene Disorders May Expand Existing Prenatal Screening

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This article has been updated with a comment from Natera.

NEW YORK (GenomeWeb) – Two years after Baylor Genetics launched PreSeek, its noninvasive prenatal single-gene screening test for dominant disorders, the assay is gaining traction while researchers collect data on its use.

Baylor released the test, which analyzes a panel of 30 genes by next-generation sequencing in cell-free DNA from maternal plasma, in early 2017. It also runs the test for Natera, which was involved in its development and markets it under the name Vistara.

In a clinical study published in Nature Medicine this week, Baylor researchers and their collaborators at Natera and elsewhere demonstrated that in a cohort of 422 pregnancies from clinics around the world, about half of which were at increased risk for fetal disorders, the test identified all positives and provided no false-positive or false-negative results for those cases where follow-up information was available.

Christine Eng, chief medical officer at Baylor Genetics and the senior author of the publication, said that PreSeek is currently the only prenatal genetic screening test for dominant monogenic disorders available in the US, though at least two other labs in Europe also offer single-gene NIPT. The test looks for de novo or paternally-inherited disease-causing variants in 30 genes that are associated with fairly common diseases that have a combined prevalence of about 1 in 600. "This is the need that this test is filling," she said.

PreSeek can be performed as early as nine weeks into pregnancy, requires samples from both parents, and has a turnaround time of two weeks. Pricing information for the test was unavailable. PreSeek has seen a steady uptake over the last two years, Eng said, but is currently mainly ordered by maternal-fetal medicine specialists, often for pregnancies with an abnormal ultrasound, advanced paternal age, or a family history of genetic disease, which all increase the risk for dominant single-gene disorders. She cautioned, however, that PreSeek should not be used when a specific diagnosis is suspected, for example from an abnormal ultrasound, in which case invasive testing is recommended.

According to Sheetal Parmar, senior director of clinical genetic services at Natera, the Vistara test is a complement to the company's Panorama NIPT for chromosomal aneuploidies, identifying risk for conditions that may have otherwise gone undetected until after birth or into childhood. Natera currently sells the test for a number of indications, including pregnancies with advanced paternal age, an abnormal ultrasound, and as an adjunct to an invasive diagnostic test. In addition, the company says the test is indicated for "parents who want to know as much as possible about their pregnancies."

The Baylor researchers hope PreSeek might eventually be useful for the general population, complementing widely used prenatal genetic screening tests, such as NIPT for aneuploidies and microdeletions/microduplications and carrier screening tests for recessive disorders. "We want to use it as a screening test in the future to discover things that cannot be found by current screening tests," said Jinglan Zhang, an assistant professor of molecular and human genetics at Baylor College of Medicine and the lead author of the publication.

Organizations other than Natera – which has a non-exclusive arrangement with Baylor for Vistara – have already expressed an interest in the test, Eng said, though she did not name any potential partners, which she said are located both in the US and abroad.

"I do believe that monogenic diseases is the next frontier in NIPS," said Rossa Chiu, professor of chemical pathology at the Chinese University of Hong Kong, whose group developed a different approach for single-gene NIPT that relies on parental haplotyping. "However, for such tests to be generally applicable in pregnancy, the approaches would need to be able to also determine the fetal inheritance of maternally transmitted mutations," she said, which the Baylor test currently does not.

As a next step, the Baylor researchers plan to conduct additional studies in average-risk pregnancies. "We have to follow up with more cases in the average [risk] world to see the clinical utility for those pregnancies without an indication or with no family history," Zhang said. For example, they want to determine the overall positive rate in the general population, and how it correlates with paternal and maternal age, which would be important to calculate the cost-effectiveness of the test as a screening tool.

Such studies will also precede any changes to the test, such as the addition of more genes for disorders that are not covered by the current panel. "We want to work very closely with our maternal-fetal medicine and Ob/Gyn partners to determine what the need is and how best to fill that need by improving our test in future iterations," Eng said.

For their clinical study, the Baylor researchers collected samples from 458 women from 131 clinics in the US, Europe, and Asia, of which 422 met their acceptance criteria, such as minimum fetal DNA fraction or sequence coverage. More than a third of the women tested had abnormal prenatal ultrasound findings, and about 10 percent had a family history of genetic disease. Also, almost 60 percent of the women were of advanced maternal age and almost half the fathers were of advanced paternal age.

The researchers had outcome information available for 233 or almost half of 498 cases, which also included 76 cases from a validation study. These confirmed all 20 of the positive results PreSeek had delivered as well as 127 negative results. In addition, there were no false-positive or false-negative results reported.

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