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Adv."],"published-print":{"date-parts":[[2026,10,2]]},"abstract":"<jats:p>Noninvasive prenatal testing (NIPT) is a pregnancy screening test that analyses cell-free fetal DNA (cffDNA) in maternal plasma to detect fetal genetic abnormalities during pregnancy. Earlier and safer detection of fetal genetic abnormalities facilitated by NIPT has markedly transformed maternal-fetal medicine. However, NIPT is currently limited to be only a screening test due to fundamental biological bottlenecks, namely, the small proportion of cffDNA compared to cell-free maternal DNA in maternal plasma, the challenge to reliably distinguish between fetal and maternal DNA, and discordance between cffDNA and the true fetal genotype. Despite millions of NIPT being conducted each year, the exact origin and structural topology of cffDNA remain unexpectedly unclear. Elucidating the origin and structure of cffDNA could unlock new technological advances that address the current bottlenecks limiting NIPT toward realizing the full potential of state-of-the-art sequencing approaches for NIPT. In this Review, we critically discuss current cffDNA knowledge, including its origin, release into maternal blood circulation, and structures relevant to contemporary NIPT.<\/jats:p>","DOI":"10.1126\/sciadv.aef5425","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:59:16Z","timestamp":1790963956000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Reappraising the topology of cell-free fetal DNA in maternal blood toward improved prenatal genetic diagnostics"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8517-6201","authenticated-orcid":true,"given":"Kieran","family":"Sparkes","sequence":"first","affiliation":[{"name":"Future Industries Institute, Adelaide University, Mawson Lakes, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7499-789X","authenticated-orcid":true,"given":"Marnie","family":"Winter","sequence":"additional","affiliation":[{"name":"Future Industries Institute, Adelaide University, Mawson Lakes, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustaaf A.","family":"Dekker","sequence":"additional","affiliation":[{"name":"Division of Women\u2019s Health, Lyell McEwin Hospital and Robinson Institute, Adelaide University, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7501-1340","authenticated-orcid":true,"given":"Lawrence","family":"Chamley","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4107-8771","authenticated-orcid":true,"given":"Martin J.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Odense University Hospital, Odense, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6757-2842","authenticated-orcid":true,"given":"Benjamin","family":"Thierry","sequence":"additional","affiliation":[{"name":"Future Industries Institute, Adelaide University, Mawson Lakes, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-083118-015053"},{"key":"e_1_3_2_3_2","unstructured":"Towards Healthcare Research & Consulting \u201cNon-invasive prenatal testing market to lead USD 18.94 Bn by 2034\u201d (2026); 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