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November 12th, 2021

Cell-free fetal DNA (cffDNA) is made of short fragments of extracellular DNA originating from the fetus and can comprise up to 5-20% of the circulating cell-free DNA in the maternal plasma (Mellis, Chandler and Chitty, 2018). Its discovery, along with the advancement in next-generation sequencing (NGS) technology, has enabled the clinical implementation of non-invasive fetal aneuploidy screening and non-invasive prenatal diagnosis (NIPD) of monogenetic diseases. The use of such diagnostic tools offered safer and accurate non-invasive diagnostic possibilities in early pregnancy (as early as 7 weeks in some cases).


Alternatively, following a positive prenatal ultrasound scan for fetal abnormalities after 11 weeks of gestation, the option for invasive testing (e.g. chorionic villus sampling or amniocentesis) becomes available. In fetuses that exhibited multiple multisystem major structural and selected other abnormalities, NGS technology enabled the analysis of fetal genetic material obtained from the invasive procedure to allow for screening of multiple genes in one test (Mellis, Chandler and Chitty, 2018). Studies relating to the use of whole-genome sequencing (WGS) are still sparse, as whole-exome sequencing (WES), which captures only the ‘protein-encoding’ regions (exons) of the DNA, is still the method of choice (Lord et al., 2019). This offers broader possibilities to evaluate the fetus with structural anomalies, improving the delineation of the prognosis, yield and accuracy of diagnoses, providing better clinical utility and allowing better options for genetic counselling for parents (Kilby, 2021). In addition, it is also possible that the identification of prenatal pathological variants associated with structural anomalies might facilitate opportunities for antenatal therapies in some cases (e.g. mesenchymal stem cell transplantation).

Nina Fajs, Edinburgh Genetics


Kilby, M. D. (2021) ‘The role of next-generation sequencing in the investigation of ultrasound-identified fetal structural anomalies’, BJOG: An International Journal of Obstetrics and Gynaecology, 128(2), pp. 420–429. doi: 10.1111/1471-0528.16533.

Lord, J. et al. (2019) ‘Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study’, The Lancet, 393(10173), pp. 747–757. doi: 10.1016/S0140-6736(18)31940-8.

Mellis, R., Chandler, N. and Chitty, L. S. (2018) ‘Next-generation sequencing and the impact on prenatal diagnosis’, Expert Review of Molecular Diagnostics. Taylor & Francis, 18(8), pp. 689–699. doi: 10.1080/14737159.2018.1493924.

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