Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing: Follow-up results of the TRIDENT-2 study

Lisanne van Prooyen Schuurman, Erik A. Sistermans, the Dutch NIPT Consortium, Diane Van Opstal, Lidewij Henneman, Mireille N. Bekker, Caroline J. Bax, Mijntje J. Pieters, Katelijne Bouman, Sonja de Munnik, Nicolette S. den Hollander, Karin E.M. Diderich, Brigitte H.W. Faas, Ilse Feenstra, Attie T.J.I. Go, Mariëtte J.V. Hoffer, Marieke Joosten, Fenne L. Komdeur, Klaske D. Lichtenbelt, Maria P. LombardiMarike G. Polak, Fernanda S. Jehee, Heleen Schuring-Blom, Servi J.C. Stevens, Malgorzata I. Srebniak, Ron F. Suijkerbuijk, Gita M. Tan-Sindhunata, Karuna R.M. van der Meij, Merel C. van Maarle, Vivian Vernimmen, Shama L. van Zelderen-Bhola, Nicolien T. van Ravesteyn, Maarten F.C.M. Knapen, Merryn V.E. Macville, Robert Jan H. Galjaard*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weight <2.3rd percentile (13.6% [24/177] vs 2.5% [3,892/155,491]; RR 5.5) were significantly increased compared to the general obstetric population. Of the 90 maternal findings, 12 (13.3%) were malignancies and 32 (35.6%) (mosaic) pathogenic copy number variants, mostly associated with mild or no clinical phenotypes. Data from this large cohort study provide crucial information for deciding if and how to implement GW-NIPT in screening programs. Additionally, these data can inform the challenging interpretation, counseling, and follow-up of additional findings.

Original languageEnglish
Pages (from-to)1140-1152
Number of pages13
JournalAmerican Journal of Human Genetics
Volume109
Issue number6
DOIs
Publication statusPublished - 2 Jun 2022

Bibliographical note

Funding Information:
The authors would like to thank all participating women for their contribution to the TRIDENT-2 study. We also thank all who have contributed to the organization and execution of the study, including health professionals, laboratory staff, and other supporting staff. Staff members of RIVM/CvB, the Regional Centers for Prenatal Screening, Peridos the online national digital registration system for prenatal screening, and EUROCAT are acknowledged for their collaboration. Beau van Hulst and Maurits van Prooyen Schuurman are acknowledged for their contribution to the data collection for this study, and Sandra van ‘t Padje is acknowledged for her work as functional manager of the NIPT Consortium. This work was supported by a grant from the Netherlands Organisation for Health Research and Development (ZonMw, No. 543002001). E.A.S. was one of the applicants of the ZonMW grant and is a member of the GenQA advisory board (unpaid) and the associate editor of Extracellular Vesicles and Circulating Nucleic Acids. D.V.O. is a member of the project group NIPT additional findings and Project group NIPT Laboratories of the National Institute for Public Health & Environment (RIVM) – Center for Population Screening (CvB). L.H. was one of the applicants of the ZonMW grant. M.N.B. is a member of the project group NIPT additional findings, of the RIVM-CvB (unpaid). C.J.B. is a member of the project group NIPT additional findings, of the RIVM-CvB (unpaid). M.J.P. is a member of the Project group NIPT Quality, and Project group NIPT additional findings, all of the RIVM-CvB (unpaid). M.V.E.M. is a member of the Program Committee Prenatal Screening, Project group NIPT Quality, and Project group NIPT Laboratories, all of the RIVM-CvB (unpaid). Part of the ZonMW grant was paid to his institution for TRIDENT-2 bio-informatic research. R.-J.H.G. was one of the applicants of the ZonMW grant, and he is a member of the Program Committee Prenatal Screening, Project group NIPT Quality, and Project group NIPT additional findings, all of the RIVM-CvB (unpaid).

Funding Information:
The authors would like to thank all participating women for their contribution to the TRIDENT-2 study. We also thank all who have contributed to the organization and execution of the study, including health professionals, laboratory staff, and other supporting staff. Staff members of RIVM/CvB, the Regional Centers for Prenatal Screening, Peridos the online national digital registration system for prenatal screening, and EUROCAT are acknowledged for their collaboration. Beau van Hulst and Maurits van Prooyen Schuurman are acknowledged for their contribution to the data collection for this study, and Sandra van ‘t Padje is acknowledged for her work as functional manager of the NIPT Consortium. This work was supported by a grant from the Netherlands Organisation for Health Research and Development (ZonMw, No. 543002001 ).

Publisher Copyright:
© 2022 The Authors

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