A team of researchers have developed a non-invasive genetic test that can screen the blood of pregnant women to survey all genes for foetal DNA sequence variants.

The team of investigators from Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH) and the Broad Institute of MIT and Harvard evaluated the test by examining blood samples from 51 pregnant women and found the test was able to capture variants that were inherited from the mother as well as new variants that were not present in the mother and associated with prenatal diagnoses.

Results from their proof-of-principle analysis are published in the New England Journal of Medicine.

“Our study suggests that it is feasible to screen most genes across the foetal genome using a blood test rather than requiring an invasive procedure such as amniocentesis,” senior author Michael E. Talkowski, 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 explained.

Non-invasive prenatal testing (NIPT), also known as prenatal-cell-free DNA-screening, allows pregnant women to receive a blood test that screens for very large changes in foetal chromosomes such as an extra copy of chromosome 21, known as Down syndrome (trisomy 21); the gain or loss of entire copies of other chromosomes; the presence and number of X and Y sex chromosomes (indicating the sex of the foetus), and, more recently, for a small number of variants that are relevant for some foetal conditions.

However, for many prenatal genetic diagnoses, it is necessary to determine individual nucleotide changes across the protein coding sequence of the genome, known as the ‘exome.’

Exome screening currently requires genetic testing with an invasive medical procedure such as amniocentesis that involves significant cost and carries some inherent risks to the mother and foetus.

The newly developed test could offer the capacity to discover and interpret variants across the foetal exome from DNA circulating in the mother’s blood. The method is referred to by the team as non-invasive foetal sequencing (NIFS).

This NIFS approach enabled the research team to survey the exome, discover sequence changes and distinguish potentially pathogenic variants from likely benign variants inherited from the mother.

Researchers tested their NIFS approach on 51 pregnancies that spanned all three trimesters and were representative of the pregnant population receiving care at Massachusetts General Hospital and Brigham and Women’s Hospital.

According to the study, the NIFS screening method used a maternal blood draw without the need for a separate genetic test on the mother or father. The research team found that the method was highly sensitive for discovering single-base DNA changes and small insertions and deletions that were present in the foetal genome but not in the maternal genome, irrespective of the amount of foetal DNA detected.

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

In 14 pregnancies referred for the current standard-of-care genetic testing that were also evaluated with the NIFS approach, NIFS detected all of the clinically relevant variants that were reported from invasive testing in the same individuals.

The authors conducted this initial test on 51 pregnancies, but the findings, they say, suggest the test could potentially be done on many samples.

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

Talkowski, the director of MGH’s Center for Genomic Medicine, added: “It has long been known that foetal sequence variants can be obtained from cell-free foetal DNA, and exome sequencing is already part of the standard-of-care, but it currently requires an invasive procedure.

“These results suggest that non-invasive sequencing can likely capture the same genetic information from the foetal 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 and to further develop the methods.

Co-lead author Christopher Whelan, a computational scientist at the Broad Institute, said: “Our benchmarking suggests there is more room for optimisation and that most variants currently captured in a standard exome test may be accessible to NIFS with further methods development.”

The team emphasised that this is not currently a clinical test and that these early studies will need to be replicated in much larger samples.