Non- invasive Prenatal Genetic Testing

A group of researchers from Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH), and the Broad Institute of MIT and Harvard have created a non-invasive genetic test. This test can analyze the blood of pregnant individuals to examine all genes for fetal DNA sequence variations.

The team analyzed the test by studying blood samples from 51 pregnant individuals. They discovered that the test could detect inherited variants from the mother as well as new variants not found in the mother, which were linked to prenatal diagnoses. The findings from their initial analysis have been published in the New England Journal of Medicine.

“Our study suggests that it is feasible to screen most genes across the fetal genome using a blood test rather than requiring an invasive procedure such as amniocentesis,” explains senior author Michael E. Talkowski, Ph.D., director of MGH’s Center for Genomic Medicine, an associate professor of Neurology at Harvard Medical School (HMS), and Institute Member of the Broad Institute.

Non-invasive prenatal testing (NIPT), also known as prenatal-cell-free DNA screening, enables pregnant individuals to undergo a blood test that screens for significant fetal chromosome changes, such as extra copies of chromosome 21 (Down syndrome), the gain or loss of entire copies of other chromosomes, and the presence and number of sex chromosomes.

Additionally, it can detect a small number of variants relevant to certain fetal conditions. However, for many prenatal genetic diagnoses, it is necessary to identify individual nucleotide changes across the protein-coding sequence of the genome, referred to as the “exome.” Currently, exome screening requires invasive genetic testing, which is costly and carries inherent risks.

A newly developed test, known as non-invasive fetal sequencing (NIFS), has the potential to discover and interpret variants across the fetal exome from DNA circulating in the mother’s blood. The high-resolution NIFS approach allowed the research team to survey the exome, identify sequence changes, and distinguish potentially pathogenic variants from likely benign variants inherited from the mother. The NIFS approach was tested on 51 pregnancies across all three trimesters, representing the pregnant population receiving care at Massachusetts General Hospital and Brigham and Women’s Hospital.

The NIFS screening method utilized a maternal blood draw without the need for a separate genetic test on the parents. The research team found that the method was highly sensitive in detecting single-base DNA changes and small insertions and deletions present in the fetal genome but not in the maternal genome, regardless of the amount of fetal DNA detected.

“In our retrospective analysis, we were able to accurately discover and predict fetal sequence variants from the NIFS approach with >99% sensitivity from the raw data and >90% sensitivity after filtering using our analysis methods,” said co-lead author Harrison Brand, Ph.D., an investigator in the department of Neurology at MGH and an assistant professor at HMS.

In a study of 14 pregnancies that underwent standard genetic testing and were also assessed using the NIFS method, NIFS identified all clinically significant variants that were detected through invasive testing in the same individuals. The initial test was carried out on 51 pregnancies, and the results indicate that the test may have the potential to be applied to numerous samples.

“The clinical implications of this research are potentially profound, particularly for pregnancies in which a fetal anomaly is suspected from ultrasound and an invasive test is indicated,” says co-senior author Kathryn Gray, MD, Ph.D., an obstetrician and clinical geneticist at Brigham and Women’s Hospital and assistant professor of Obstetrics and Gynecology at HMS at the time of the study.

“It has long been known that fetal sequence variants can be obtained from cell-free fetal DNA, and exome sequencing is already part of the standard-of-care, but it currently requires an invasive procedure,” adds Talkowski, who is also the Desmond and Ann Heathwood MGH Research Scholar 2015–2020.

“These results suggest that non-invasive sequencing can likely capture the same genetic information from the fetal exome that is already being obtained in the standard-of-care, but from a blood test alone without the invasive procedure.”

The team is currently working with other researchers to expand and validate these findings of prenatal genetic testing and to further develop the methods.

“Our benchmarking suggests there is more room for optimization and that most variants currently captured in a standard exome test may be accessible to NIFS with further methods development,” says co-lead author Christopher Whelan, Ph.D., a computational scientist at the Broad Institute and the Talkowski laboratory.

The team stresses that this is not presently a clinical trial and that these initial studies will have to be duplicated in significantly larger samples. As this research continues, Talkowski, Gray, and their team are already strategizing on the best ways to assist patients as they undergo testing options and receive test results while pregnant.

As Dr. Gray notes, “We understand the fear and uncertainty that patients experience during pregnancy. In instances where a current standard-of-care test identifies an abnormality during prenatal diagnostic testing, we ensure that patients have access to a multi-disciplinary team, including maternal-fetal medicine and pediatric specialists, genetic counselors, and social workers to help patients understand complicated test results. Non-invasive tests, including currently available NIPT screening methods, will require the same support network.”