Clinical interpretation of cell-based non-invasive prenatal testing for monogenic disorders including repeat expansion disorders: potentials and pitfalls

Jeppesen et al., 2023, Frontiers in Genetics

Line Dahl Jeppesen1,2, Lotte Hatt1, Ripudaman Singh1,  Palle Schelde1, Katarina Ravn1, Christian Liebst Frisk Toft3,4, Maria Bach Laursen1, Jakob Hedegaard1, Inga Baasch Christensen1, Bolette Hestbek Nicolaisen1, Lotte Andreasen5, Lars Henning Pedersen6,7,8, Ida Vogel2,6 and Dorte Launholt Lildballe2,9

Frontiers in Genetics, 2023


1ARCEDI, Vejle, Denmark

2Center for Fetal Diagnostics, Aarhus University, Aarhus, Denmark

3Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark

4Center for Preimplantation Genetic Testing, Aalborg University Hospital, Aalborg, Denmark

5Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark

6Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark

7Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

8Department of Biomedicine, Aarhus University, Aarhus, Denmark

9Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

DOI: 10.3389/fgene.2023.1188472

PMID: 16648021



Circulating fetal cells isolated from maternal blood can be used for prenatal testing, representing a safe alternative to invasive testing. The present study investigated the potential of cell-based noninvasive prenatal testing (NIPT) for diagnosing monogenic disorders dependent on the mode of inheritance.


Maternal blood samples were collected from women opting for prenatal diagnostics for specific monogenic disorders (N = 7). Fetal trophoblasts were enriched and stained using magnetic activated cell sorting and isolated by fluorescens activated single-cell sorting. Individual cells were subject to whole genome amplification, and cells of fetal origin were identified by DNA-profiling using short tandem repeat markers. The amplified fetal DNA was input for genetic testing for autosomal dominant-, autosomal recessive-, X-linked and repeat expansion disorders by direct variant analysis and haplotyping. The cell-based NIPT results were compared with those of invasive testing. 


In two cases at risk of skeletal dysplasia, caused by variants in the FGFR3 gene (autosomal dominant disorders), cell-based NIPT correctly stated an affected fetus, but allelic dropout of the normal alleles were observed in both cases. Cell-based NIPT gave an accurate result in two cases at risk of autosomal recessive disorders, where the parents carried either different diastrophic dysplasia causing variants in the SLC26A2 gene or the same cystic fibrosis disease-causing variant in the CFTR gene. Cell-based NIPT accurately identified an affected male fetus in a pregnancy at risk of Duchenne muscular dystrophy (DMD gene, X-linked recessive disorders). In two cases at risk of the myotonic dystrophy type 1 (DMPK gene, repeat expansion disorder), cell-based NIPT correctly detected an affected and an unaffected fetus, respectively.


Circulating fetal cells can be used to detect both maternally- and paternally inherited monogenic disorders irrespective of the type of variant, however, the risk of allelic dropout must be considered. We conclude that the clinical interpretation of the cell-based NIPT result thus varies depending on the disorders’ mode of inheritance.


noninvasive prenatal testing, fetal cells, extravillous trophoblasts, monogenic disorders, repeat expansion disorders, clinical interpretation

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