Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances

Yvette C. Raymond; Shavi Fernando; Melody Menezes; Simon Meagher; Ben W. Mol; Andrew McLennan; Fergus Scott; Karen Mizia; Karen Carey; Gabrielle Fleming; Daniel Lorber Rolnik

doi:10.1002/pd.6233

Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances

Yvette C. Raymond^*
, Shavi Fernando
, Melody Menezes
, Simon Meagher
, Ben W. Mol
, Andrew McLennan
, Fergus Scott
, Karen Mizia
, Karen Carey
, Gabrielle Fleming
, Daniel Lorber Rolnik

^*Corresponding author for this work

Monash University
Monash Health
University of Melbourne
University of Sydney
University of New South Wales
Australian National University
Monash Ultrasound for Women
Sydney Ultrasound for Women
Ultrasound Care

Research output: Contribution to journal › Article › peer-review

24 Citations (Scopus)

11 Downloads (Pure)

Abstract

Objective: To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening. Method: A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia. Positive predictive values (PPVs) were calculated using fetal chromosomal analysis. Results: Among 23,857 women screened, there were 93 high-risk results for RATs (0.39%) and 82 for SIs (0.34%). The PPVs were 3.8% (3/78, 95% CI 0.8%–10.8%) for RATs and 19.1% (13/68, 95% CI 10.6%–30.5%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5% (7/82, 95% CI 3.5%–16.8%). Among 85 discordant cases with birth outcomes available (65.4%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6% (p = 0.022) and 9.8% (p = 0.004), respectively), which was not observed in the SI group (2.9% < 10th (p = 0.168) and 0.0% <3rd (p = 0.305)). Conclusion: The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction.

Original language	English
Pages (from-to)	1349-1357
Number of pages	9
Journal	Prenatal Diagnosis
Volume	42
Issue number	11
Early online date	22 Sept 2022
DOIs	https://doi.org/10.1002/pd.6233
Publication status	Published - 18 Oct 2022

Bibliographical note

Funding Information:
Ben W. Mol is supported by a NHMRC Investigator grant (GNT1176437). Ben W. Mol reports consultancy for ObsEva and Merck and travel support and research grants from Merck. The authors declare no conflict of interest.

The authors wish to acknowledge the staff of Monash Ultrasound for Women, Sydney Ultrasound for Women, and Ultrasound Care for their diligent and compassionate care of the women involved in this study. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.

Data Availability Statement

The data gathered in this study has not been made publicly available to protect the privacy of participants. For data enquiries, please contact corresponding author Yvette Raymond.

Funding

Ben W. Mol is supported by a NHMRC Investigator grant (GNT1176437). Ben W. Mol reports consultancy for ObsEva and Merck and travel support and research grants from Merck. The authors declare no conflict of interest. The authors wish to acknowledge the staff of Monash Ultrasound for Women, Sydney Ultrasound for Women, and Ultrasound Care for their diligent and compassionate care of the women involved in this study. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.

Access to Document

10.1002/pd.6233Licence: CC BY

Raymond_etal_Cell_free_DNA_VOR
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.https://creativecommons.org/licenses/by/4.0/
Final published version, 455 KBLicence: CC BY

Cite this

@article{f8eedce6f93e47fe81843cf5a83df3b9,

title = "Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances",

abstract = "Objective: To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening. Method: A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia. Positive predictive values (PPVs) were calculated using fetal chromosomal analysis. Results: Among 23,857 women screened, there were 93 high-risk results for RATs (0.39\%) and 82 for SIs (0.34\%). The PPVs were 3.8\% (3/78, 95\% CI 0.8\%{\textendash}10.8\%) for RATs and 19.1\% (13/68, 95\% CI 10.6\%{\textendash}30.5\%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5\% (7/82, 95\% CI 3.5\%{\textendash}16.8\%). Among 85 discordant cases with birth outcomes available (65.4\%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6\% (p = 0.022) and 9.8\% (p = 0.004), respectively), which was not observed in the SI group (2.9\% < 10th (p = 0.168) and 0.0\% <3rd (p = 0.305)). Conclusion: The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction.",

author = "Raymond, \{Yvette C.\} and Shavi Fernando and Melody Menezes and Simon Meagher and Mol, \{Ben W.\} and Andrew McLennan and Fergus Scott and Karen Mizia and Karen Carey and Gabrielle Fleming and Rolnik, \{Daniel Lorber\}",

note = "Funding Information: Ben W. Mol is supported by a NHMRC Investigator grant (GNT1176437). Ben W. Mol reports consultancy for ObsEva and Merck and travel support and research grants from Merck. The authors declare no conflict of interest. The authors wish to acknowledge the staff of Monash Ultrasound for Women, Sydney Ultrasound for Women, and Ultrasound Care for their diligent and compassionate care of the women involved in this study. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians. ",

year = "2022",

month = oct,

day = "18",

doi = "10.1002/pd.6233",

language = "English",

volume = "42",

pages = "1349--1357",

journal = "Prenatal Diagnosis",

issn = "0197-3851",

publisher = "John Wiley and Sons Ltd",

number = "11",

}

TY - JOUR

T1 - Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances

AU - Raymond, Yvette C.

AU - Fernando, Shavi

AU - Menezes, Melody

AU - Meagher, Simon

AU - Mol, Ben W.

AU - McLennan, Andrew

AU - Scott, Fergus

AU - Mizia, Karen

AU - Carey, Karen

AU - Fleming, Gabrielle

AU - Rolnik, Daniel Lorber

N1 - Funding Information: Ben W. Mol is supported by a NHMRC Investigator grant (GNT1176437). Ben W. Mol reports consultancy for ObsEva and Merck and travel support and research grants from Merck. The authors declare no conflict of interest. The authors wish to acknowledge the staff of Monash Ultrasound for Women, Sydney Ultrasound for Women, and Ultrasound Care for their diligent and compassionate care of the women involved in this study. Open access publishing facilitated by Monash University, as part of the Wiley - Monash University agreement via the Council of Australian University Librarians.

PY - 2022/10/18

Y1 - 2022/10/18

N2 - Objective: To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening. Method: A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia. Positive predictive values (PPVs) were calculated using fetal chromosomal analysis. Results: Among 23,857 women screened, there were 93 high-risk results for RATs (0.39%) and 82 for SIs (0.34%). The PPVs were 3.8% (3/78, 95% CI 0.8%–10.8%) for RATs and 19.1% (13/68, 95% CI 10.6%–30.5%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5% (7/82, 95% CI 3.5%–16.8%). Among 85 discordant cases with birth outcomes available (65.4%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6% (p = 0.022) and 9.8% (p = 0.004), respectively), which was not observed in the SI group (2.9% < 10th (p = 0.168) and 0.0% <3rd (p = 0.305)). Conclusion: The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction.

AB - Objective: To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening. Method: A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia. Positive predictive values (PPVs) were calculated using fetal chromosomal analysis. Results: Among 23,857 women screened, there were 93 high-risk results for RATs (0.39%) and 82 for SIs (0.34%). The PPVs were 3.8% (3/78, 95% CI 0.8%–10.8%) for RATs and 19.1% (13/68, 95% CI 10.6%–30.5%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5% (7/82, 95% CI 3.5%–16.8%). Among 85 discordant cases with birth outcomes available (65.4%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6% (p = 0.022) and 9.8% (p = 0.004), respectively), which was not observed in the SI group (2.9% < 10th (p = 0.168) and 0.0% <3rd (p = 0.305)). Conclusion: The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction.

UR - https://www.scopus.com/pages/publications/85138557534

U2 - 10.1002/pd.6233

DO - 10.1002/pd.6233

M3 - Article

C2 - 36068932

AN - SCOPUS:85138557534

SN - 0197-3851

VL - 42

SP - 1349

EP - 1357

JO - Prenatal Diagnosis

JF - Prenatal Diagnosis

IS - 11

ER -

Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances

Abstract

Bibliographical note

Data Availability Statement

Funding

Access to Document

Other files and links

Fingerprint

Cite this