Cell-free DNA versus intact fetal cells for prenatal genetic diagnostics: what does the future hold?

Abstract

Prenatal screening and diagnosis is currently focused on the development of a noninvasive prenatal diagnostic test capable of detecting abnormalities similar to those attainable with an invasive test. One contender is cell-free fetal DNA circulating in maternal plasma and the other is intact fetal cells either from the maternal blood or the cervix. Once adequate fetal DNA is available, laboratory analytic techniques, such as sequencing and microarray, can be applied allowing detection of most cytogenetic and Mendelian fetal disorders. The question is: how close are we to achieving this feat, and what does the future hold?

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“…This can be greatly aided by recently developed precision approaches such as single‐cell transcriptomics and brain organoids, which can closely recapitulate human brain development . Noninvasive prenatal testing of viral‐triggered changes in the ADAR expression and/or editing biomarkers can be developed using intact fetal cells derived from the maternal blood …”

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“…The analysis of fetal ccfDNA in maternal blood is an emerging and rapidly growing diagnostic field (reviewed in: [31,32]). Epigenetically caused fetal diseases, i.e.…”

Gestation related karyotype, QF-PCR and CGH-array failure rates in diagnostic amniocentesis

“…Developments in prenatal screening, particularly the testing of cell‐free DNA in maternal blood (NIPT), have allowed more accurate prediction of the risk of genetic or chromosomal conditions in a fetus. However, invasive testing still remains important in contemporary prenatal diagnosis for several reasons: to confirm a high risk NIPT result, to test for specific genetic or chromosomal conditions in cases of abnormal genetic family history or following ultrasound findings of fetal structural abnormalities …”

“…Three different technologies are currently available for diagnostic testing of such samples: (1) karyotyping which assesses cytogenetically visible chromosomal abnormalities including full chromosome aneuploidies, partial re‐arrangements and mosaicisms, (2) quantitative fluorescence polymerase chain reaction (QF‐PCR), a molecular test, which provides identification of the common chromosomal trisomies 13, 18 and 21, and sex chromosome aneuploidies, and (3) the newer technique of array comparative genomic hybridisation (CGH‐array), which can detect chromosomal deletions or duplications at a higher resolution than conventional karyotyping …”

“…3,4 Three different technologies are currently available for diagnostic testing of such samples: (1) karyotyping which assesses cytogenetically visible chromosomal abnormalities including full chromosome aneuploidies, partial re-arrangements and mosaicisms, (2) quantitative fluorescence polymerase chain reaction (QF-PCR), a molecular test, which provides identification of the common chromosomal trisomies 13, 18 and 21, and sex chromosome aneuploidies, 5 and (3) the newer technique of array comparative genomic hybridisation (CGH-array), which can detect chromosomal deletions or duplications at a higher resolution than conventional karyotyping. 2,6 CGH-array has been used since the mid-2000s for routine postnatal testing for chromosome imbalance, for genetic testing in miscarriages or stillbirth where a cell culture from necrotic cells for karyotype is more likely to fail and, for prenatal samples, for testing both chorionic villus biopsies and amniocenteses where it can deliver more detailed genetic information than karyotype analysis. [7][8][9] UK best practice guidelines state that an abnormal QF-PCR result requires a repeat test to confirm sample identity prior to reporting.…”