Cell-based non-invasive prenatal testing for monogenic disorders: confirmation of unaffected fetuses following preimplantation genetic testing

Toft CLF^1,2, Ingerslev HJ³, Kesmodel US^2,3, Hatt L⁴, Singh R⁴, Ravn K⁴, Nicolaisen BH⁴, Christensen IB⁴, Kølvraa M⁴, Jeppesen LD⁴, Schelde P⁴, Vogel I⁵, Uldbjeg N⁶, Farlie R⁷, Sommer S⁸, Østergård MLV⁹, Jensen AN¹⁰, Mogensen H¹¹, Kjartansdóttir KR¹², Degn B¹, Okkels H¹, Ernst A¹, Pedersen IS^1,2.

Journal of Assisted Reproduction and Genetics, 2021, volume 38, pages 1959-1970.

¹Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark

²Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

³Fertility Unit, Aalborg University Hospital, Aalborg, Denmark

⁴ARCEDI Biotech ApS, Vejle, Denmark

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

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

⁷Department of Obstetrics and Gynecology, Viborg Regional Hospital, Viborg, Denmark

⁸Department of Obstetrics and Gynecology, Horsens Regional Hospital, Horsens, Denmark

⁹Department of Obstetrics and Gynecology, Randers Regional Hospital, Randers, Denmark

¹⁰Department of Obstetrics and Gynecology, Aalborg University Hospital, Aalborg, Denmark

¹¹Department of Obstetrics and Gynecology, Kolding Regional Hospital, Kolding, Denmark

¹²Molecular Genetics Laboratory, Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark

DOI: 10.1007/s10815-021-02104-5

PMID: 33677749

Abstract:

Purpose:
Proof of concept of the use of cell-based non-invasive prenatal testing (cbNIPT) as an alternative to chorionic villus sampling (CVS) following preimplantation genetic testing for monogenic disorders (PGT-M).

Method:
PGT-M was performed by combined testing of short tandem repeat (STR) markers and direct mutation detection, followed by transfer of an unaffected embryo. Patients who opted for follow-up of PGT-M by CVS had blood sampled, from which potential fetal extravillous throphoblast cells were isolated. The cell origin and mutational status were determined by combined testing of STR markers and direct mutation detection using the same setup as during PGT. The cbNIPT results with respect to the mutational status were compared to those of genetic testing of the CVS.

Results:
Eight patients had blood collected between gestational weeks 10 and 13, from which 33 potential fetal cell samples were isolated. Twenty-seven out of 33 isolated cell samples were successfully tested (82%), of which 24 were of fetal origin (89%). This corresponds to a median of 2.5 successfully tested fetal cell samples per case (range 1–6). All fetal cell samples had a genetic profile identical to that of the transferred embryo confirming a pregnancy with an unaffected fetus, in accordance with the CVS results.

Conclusion:
These findings show that although measures are needed to enhance the test success rate and the number of cells identified, cbNIPT is a promising alternative to CVS.