Smelling a RAT: a reanalysis of suspected common aneuploidy results for the presence of rare autosomal trisomies (RATs) in non-invasive prenatal testing
- 1CooperSurgical, London, UK
- 2Preimplantation Genetics Group, University College London, London, UK
- 3School of Natural Sciences, University of Kent, Canterbury, UK
Abstract
Introduction Rare autosomal trisomies (RATs) involve chromosomes other than 21, 18, 13 and XY and have come to prominence since the advent of non-invasive prenatal testing (NIPT). Occurring in ~1% of pregnancies, RATs can lead to pregnancy loss but usually appear in mosaic form and are confined to the placenta. Earlier versions of NIPT focused only on the common trisomies but some clinics subsequently expanded to all chromosomes to take account of RATs. This received some criticism as many detected RATs may not be clinically significant, possibly leading to unnecessary pregnancy anxiety. Of particular concern are ‘suspected aneuploidy’ calls, where the result shows evidence of aneuploidy by visual inspection but is not called by the analysis algorithm. Here, presence of a RAT could be skewing the algorithm, which was calibrated on the assumption that the RAT chromosomes were disomic.Methods In a study of 21 396 NIPT cases, 485 common (not RAT) aneuploidies and 110 ‘suspected aneuploidies’ 43 had follow-up information available by amniocentesis or live birth; 14 were ‘suspected aneuploidy’ with normal follow-up information. We tested the hypotheses that the discordance was due to a RAT disrupting the calling algorithm (discordance because of biological reasons) by rerunning the NIPT with a protocol capable of detecting RATs.Results All had full concordance with follow-up and outcome data. We thus reject the hypothesis that ‘suspected aneuploidies’ with discordant follow-up results were due to RATs.Conclusions Suspected aneuploidy results are, most likely, not the result of a RAT; we provide much-needed information to improve analysis algorithms in terms of calling thresholds, allowing increased sensitivity from paired-end sequencing results.
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BibTeX
@article{gordon2026smelling,
title = {{Smelling a RAT: a reanalysis of suspected common aneuploidy results for the presence of rare autosomal trisomies (RATs) in non-invasive prenatal testing}},
author = {Anthony Gordon and Darren Griffin and Kathryn Dawn Sanders and Leoni Xanthopoulou and Evangelia Bakosi},
journal = {BMJ Connections Clinical Genetics and Genomics},
year = {2026},
month = oct,
doi = {10.1136/bmjccgg-2026-000076},
url = {https://doi.org/10.1136/bmjccgg-2026-000076},
note = {CC BY},
}
RIS
TY - JOUR
TI - Smelling a RAT: a reanalysis of suspected common aneuploidy results for the presence of rare autosomal trisomies (RATs) in non-invasive prenatal testing
AU - Anthony Gordon
AU - Darren Griffin
AU - Kathryn Dawn Sanders
AU - Leoni Xanthopoulou
AU - Evangelia Bakosi
PY - 2026
DA - 2026/10/26
JO - BMJ Connections Clinical Genetics and Genomics
DO - 10.1136/bmjccgg-2026-000076
UR - https://doi.org/10.1136/bmjccgg-2026-000076
AB - Introduction Rare autosomal trisomies (RATs) involve chromosomes other than 21, 18, 13 and XY and have come to prominence since the advent of non-invasive prenatal testing (NIPT). Occurring in ~1% of pregnancies, RATs can lead to pregnancy loss but usually appear in mosaic form and are confined to the placenta. Earlier versions of NIPT focused only on the common trisomies but some clinics subsequently expanded to all chromosomes to take account of RATs. This received some criticism as many detected RATs may not be clinically significant, possibly leading to unnecessary pregnancy anxiety. Of particular concern are ‘suspected aneuploidy’ calls, where the result shows evidence of aneuploidy by visual inspection but is not called by the analysis algorithm. Here, presence of a RAT could be skewing the algorithm, which was calibrated on the assumption that the RAT chromosomes were disomic.Methods In a study of 21 396 NIPT cases, 485 common (not RAT) aneuploidies and 110 ‘suspected aneuploidies’ 43 had follow-up information available by amniocentesis or live birth; 14 were ‘suspected aneuploidy’ with normal follow-up information. We tested the hypotheses that the discordance was due to a RAT disrupting the calling algorithm (discordance because of biological reasons) by rerunning the NIPT with a protocol capable of detecting RATs.Results All had full concordance with follow-up and outcome data. We thus reject the hypothesis that ‘suspected aneuploidies’ with discordant follow-up results were due to RATs.Conclusions Suspected aneuploidy results are, most likely, not the result of a RAT; we provide much-needed information to improve analysis algorithms in terms of calling thresholds, allowing increased sensitivity from paired-end sequencing results.
SN - 3050-2551
ER -