Non-invasive Genetic Prenatal Screening (NGPS)
Research type
Research Study
Full title
Non-invasive genetic prenatal screening of fetal abnormalities diagnosed at ultrasound.
IRAS ID
243759
Contact name
Baskaran Thilaganathan
Contact email
Sponsor organisation
St George's University Hospitals NHS Foundation Trust & St George's University of London
Duration of Study in the UK
1 years, 0 months, 0 days
Research summary
Summary of Research
Currently, if a baby has a genetic abnormality suspected on ultrasound, an invasive procedure (such as amniocentesis) needs to be performed to obtain material for genetic testing. However, this procedure is associated with an increased risk of miscarriage of about 1%. During pregnancy, maternal blood normally contains fragments of the baby's DNA, known as cell-free fetal DNA (cfDNA), which originates from the placenta. We can currently use cfDNA to assess the risk of Down's syndrome, thereby avoiding the risk of miscarriage associated with invasive testing. Using the same principle, we will look at cfDNA in maternal blood to develop a screening test to look for wider genetic changes that can cause fetal abnormalities.
Summary of Results
Fetal anomalies are detected in ~3% of pregnancies and are responsible for ~20% of perinatal deaths. Approximately two-thirds of single gene causes of fetal anomalies are de novo mutations (DNMs). Advances in genomic technology have led to rapid adoption of non-invasive prenatal testing for aneuploidy, but tools to support non-invasive diagnosis of single gene disorders are limited.
Our objective was to develop a comprehensive assay and analytical pipeline to pair with a clinical decision support platform, to enable non-invasive detection of de novo mutations associated with fetal anomalies.
Maternal, paternal and fetal gDNA and maternal cfDNA from the same pregnancy was collected from families with ultrasound detected fetal structural anomaly and absence of chromosomal abnormality. Putative de novo (novel) variants in cfDNA, were identified by a custom pipeline including incorporation of fetal fraction, quality metrics and a dynamic error calling algorithm.
Cases from 73 quads with gestation range 10+6 to 36+4 weeks were assessed and in total, 17 de novo DNA variants were identified - 6 of these variants were confirmed to be pathogenic. All 6 (100%) were correctly identified in the non-invasive cfDNA sample.
Our non-invasive approach correctly identified all pathogenic de novo variants, in RAF1, SOS1, FGFR3, COL1A1 and NRAS genes.
REC name
Wales REC 5
REC reference
18/WA/0221
Date of REC Opinion
26 Jun 2018
REC opinion
Favourable Opinion