Whole-genome paternal uniparental disomy identified through prenatal single-nucleotide polymorphism-based cell-free DNA screening.

objectivePrenatal single-nucleotide polymorphism (SNP)-based cell-free DNA (cfDNA) screening can identify genome-wide paternal uniparental disomy (GW-UPDpat), including cases with complete hydatidiform mole with a coexisting fetus (CHMCF), those with placental mesenchymal dysplasia (PMD) and those with a mosaic/chimeric GW-UPDpat syndrome. Our objective was to review laboratory data and pregnancy outcome for SNP-based cfDNA screening tests with results compatible with GW-UPDpat and a normal cell line.

methodsThis was a retrospective study of all cfDNA screening results from a single commercial laboratory between June 2014 and November 2023 that were reported as twins or triploidy, with apparent GW-UPDpat. Two-dimensional representations of the relative ratios of SNP alleles (SNP plots) were used to identify and quantify the proportion of cfDNA from the mole ('molar fraction') and that from the coexisting non-molar pregnancy ('fetal fraction'). Test referral and follow-up information, including ultrasound findings, laboratory testing and pregnancy outcome, were reviewed.

resultsOf 5 699 009 tests reviewed, 89 were reported as twins or triploidy, with apparent GW-UPDpat. Retrospective review of SNP plots excluded 12 cases that were reinterpreted as triploidy with an extra set of paternal chromosomes. Of the remaining 77 cases, 24 had follow-up pregnancy information available, and of these, 21 (87.5%) had ultrasound and/or pathology findings that were consistent with CHMCF. The fetal cfDNA fraction was often very low (≤ 2% in 28 cases). The molar cfDNA fraction was in the range of 10-58%. Fetal sex was male in 35 cases, female in 40 cases and uncertain in two cases. No case showed clear evidence of a Y-chromosome in the GW-UPDpat line. All 77 cases had isodisomy; none showed clear evidence of regions of heterodisomy.

conclusionsSNP-based cfDNA screening can help to identify CHMCF and distinguish between CHMCF and triploidy. For CHMCF, early detection is important for evaluating the risk of adverse outcome and gestational trophoblastic neoplasia. Some of our test-positive cases could have included unrecognized PMD or mosaic/chimeric GW-UPDpat syndrome. These preliminary observations do not allow assessment of the sensitivity or positive predictive value of this test. © 2025 Natera, Inc. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.