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

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. Trial registration number N-20180001

Patients' choices and opinions on chorionic villous sampling and non‐invasive alternatives for prenatal testing following preimplantation genetic testing for hereditary disorders: A cross‐sectional questionnaire study

“…Importantly, the sensitivity and specificity as well as the risk of inconclusive results have to be properly evaluated prior to clinical implementation. In the case of cbNIPT using short tandem repeat marker analysis as detailed in our recent paper, 15 the accuracy is expected to be similar compared to CVS, as in both cases, intact cells stemming from the placenta are analyzed and informative DNA markers used to ensure that the origin of the DNA can be indisputably determined (or else called as inconclusive). A higher risk of inconclusive test results from non‐invasive alternatives should not disqualify it from being used in clinical practice, as long as it can be performed sufficiently early to allow for invasive testing as a second‐line option in case of an inconclusive test result.…”

“…Practically, non-invasive testing should be more manageable compared to invasive testing, as blood sampling is less challenging and time-consuming compared to chorionic villus sampling and amniocentesis. NIPT has been around for 2 decades 23 and has been used clinically for the detection of unbalanced translocations, 24 subchromosomal deletions, 24,25 duplications, 25 copy number variations, 26 and monogenic disorders, 15,[27][28][29] indicating its potential for prenatal testing. Despite the technology being available, implementation of NIPT is challenged by the cost of 30,31 and lack of education of health care professionals on the procedure.…”

“…following PGT for different types of monogenic disorders, 15 testing following PGT. Practically, non-invasive testing should be more manageable compared to invasive testing, as blood sampling is less challenging and time-consuming compared to chorionic villus sampling and amniocentesis.…”

“…[11][12][13][14] We recently published a proof of concept on cell-based non-invasive prenatal testing (cbNIPT) following PGT for monogenic disorders showing promising results. 15 However, the difficulties associated with communicating information to patients might only increase as the number of prenatal test options increases (e.g. CVS, cell-free fetal NIPT and cbNIPT).…”

“…If these are in fact the primary reasons for declining prenatal testing, non‐invasive alternatives are likely to be embraced by patients resulting in higher adherence to prenatal testing, as previously described 11–14 . We recently published a proof of concept on cell‐based non‐invasive prenatal testing (cbNIPT) following PGT for monogenic disorders showing promising results 15 . However, the difficulties associated with communicating information to patients might only increase as the number of prenatal test options increases (e.g.…”