Noninvasive prenatal screening for single-gene disorders


A study in the journal Ultrasound in Obstetrics & Gynecology1 has found that noninvasive prenatal testing (NIPT) can help in the early detection of a set of single gene disorders (SGDs), especially in the presence of either abnormal ultrasound findings or a family history.

Peter Benn, PhD

Peter Benn, PhD

While NIPT through the analysis of maternal plasma cell-free DNA is well established for fetal aneuploidy and microdeletion syndromes, “the technology has not yet been widely applied to clinically significant SGDs, a proportion of which are attributable to a set of common de novo, or paternally inherited, dominant gene variants,” said senior author Peter Benn, PhD, professor emeritus from the Department of Genetics and Genome Sciences at the University of Connecticut Health Center in Farmington.

Potential use of NIPT for 25 SGDs, with a combined incidence of 1 in 600 births, was initially presented in a proof-of-principle study published in Nature Medicine in 2019.2

“Some of these conditions may not be recognized by a prenatal ultrasound examination, but are associated with physical or cognitive disability,” Benn told Contemporary OB/GYNÒ.

In the new study, testing was available to 2,284 women with singleton pregnancies at 9 weeks gestational age or later. Cell-free fetal DNA isolated from maternal plasma was analyzed by next-generation sequencing to look for pathogenic or likely pathogenic variants implicated in the 25 disease conditions. Testing of maternal and paternal genomic DNA assisted in interpretation. A minimum 4.5% fetal fraction was required.

Results were provided to 97% of the eligible women, of whom 5.7% tested positive. “We were surprised how many cases were test-positive,” Benn said. “We thought it would be much lower.”

Particularly elevated test-positive rates were seen when the primary indication for testing involved the sonographic detection of a fetal long bone abnormality (33.7% positivity), craniofacial abnormality (28.6%), lymphatic abnormality (13.3%), major cardiac defect (12.9%) or a family history of a disorder on the panel (15.2%).

For paternal age equal to or greater than 40 years as a sole risk factor, the test positive rate was 0.2%. Among cases with abnormal ultrasound findings, 18% had a paternal age greater than 40 years, suggesting a paternal age effect.

Of the 125 positive cases, follow-up information was available for 52%, with none classified as false-positive; neither were any false-negative cases identified.

When care providers were asked whether a NIPT-SGD positive result precipitated pregnancy management changes, 60.5% (26 of 43 respondents) said yes.

“Until now, the prenatal detection and diagnosis of SGDs has largely been limited to those situations where there was a known family history or ultrasound evidence for fetal anatomic abnormality,” Benn said. “Definitive diagnosis has required chorionic villus sampling or amniocentesis, usually with exome sequencing. In most instances, a complete diagnosis has not been possible until late in pregnancy.”

The study demonstrates that a proportion of SGDs could be detected by a noninvasive test that can be offered before there is abnormality detectable by ultrasound, according to Benn. “The incidence of de novo autosomal variants is also thought to increase with paternal age and therefore this testing might be more strongly indicated for older fathers,” he said.

Benn noted that NIPT for SGDs offers a safe and timely prenatal screening option. “In addition, the NIPT gene panel can be expanded to include variants in additional genes that recently have been discovered through exome sequencing as pathogenic and recurrent,” he said. “The testing could also eventually be developed to detect maternally inherited variants and autosomal recessive conditions.”

However, optimal delivery requires strong partnerships between obstetricians, maternal-fetal medicine specialists, geneticists, counselors and the NIPT laboratories, according to Benn.



Benn is a consultant and has stock options in Natera.


  1. Mohan P, Lemoine J, Trotter C, et al. Clinical experience with non-invasive prenatal screening for single-gene disorders (NIPT-SGD). Ultrasound Obstet Gynecol. Published online August 6, 2021. doi:10.1002/uog.23756
  2. Zhang J, Li J, Saucier JB, et al. Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA. Nat Med. 2019;25(3):439-447. doi:org/10.1038/s41591-018-0334-x
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