The Australian PreGen Study: Results From Prospective Prenatal Exome Sequencing in 275 Pregnancies

ABSTRACT Objective Prenatal exome sequencing (pES) is increasingly to standard care for diagnosing the etiology of fetal structural anomalies (FSA). We evaluated trio pES outcomes in the national multicentre, prospectively recruited Australian Government‐funded cohort, including diagnostic yield, frequency of variants of uncertain significance (VOUS), incidental findings and impacts on pregnancy management. Method Prospective referral and analysis were undertaken for 275 consented families nation‐wide for trio pES. Eligibility was based on predefined FSA criteria and an uninformative chromosome microarray. Sequencing was performed in one of three clinically accredited national referral laboratories. Results The pES diagnostic yield for pathogenic/likely pathogenic variants was 31.6% (87/275, 95% CI; 26.4–37.4). VOUS and incidental findings occurred at a rate of 4.4% (12/275) and 1.5% (4/275) respectively. Termination of pregnancy (TOP) occurred more frequently in diagnosed families, whereas live births were more common in the uninformative cohort. Conclusion pES demonstrated a high diagnostic yield with low VOUS and incidental finding rates. Outcomes differed between diagnosed and uninformative families, with TOP more frequent after genomic diagnoses. These findings support pES as a core diagnostic test for antenatal FSA evaluation and emphasise the importance of consistent phenotype ontology, body system classification, and eligibility criteria for fetal genomic sequencing.

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Publication Details

Journal
Prenatal Diagnosis
Published
2026-09-24
DOI
https://doi.org/10.1002/pd.70256
Primary Topic
Prenatal Screening and Diagnostics
Type
article
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article

The Australian PreGen Study: Results From Prospective Prenatal Exome Sequencing in 275 Pregnancies

Luke Rynehart, Jon Anthony Hyett, Mandi MacShane, Sebastian Lunke et al.
Prenatal Diagnosis
Prenatal Screening and Diagnostics
article

The Australian PreGen Study: Results From Prospective Prenatal Exome Sequencing in 275 Pregnancies

Luke Rynehart, Jon Anthony Hyett, Mandi MacShane, Sebastian Lunke, Rachael Stenhouse, Benjamin Kamien, Tony Roscioli, Hamish S. Scott, Edwin Philip Kirk, John Smoleniec, Matilda R. Jackson, Di Milnes, Abhijit Kulkarni, Mohammad Al-Shinnag, Karin S. Kassahn, Natalie Hart, A. M. Wilson, Rebecca Vink, Meaghan Wall, Martin A. Smith, DEBORAH J. SCHOFIELD, Joshua Kraindler, Jan Elizabeth Dickinson, George McGillivray, Rupendra N. Shrestha, Sarah S. Long, Kate Ross, Lucas De Jong, Jinghua Feng, Gemma Fernihough, Conor Rowntree, Michael F. Buckley, Ying Zhu, Lesley McGregor, Rosalie Kenyon, Futao Zhang, Jayamala Parmar
article en

Abstract

ABSTRACT Objective Prenatal exome sequencing (pES) is increasingly to standard care for diagnosing the etiology of fetal structural anomalies (FSA). We evaluated trio pES outcomes in the national multicentre, prospectively recruited Australian Government‐funded cohort, including diagnostic yield, frequency of variants of uncertain significance (VOUS), incidental findings and impacts on pregnancy management. Method Prospective referral and analysis were undertaken for 275 consented families nation‐wide for trio pES. Eligibility was based on predefined FSA criteria and an uninformative chromosome microarray. Sequencing was performed in one of three clinically accredited national referral laboratories. Results The pES diagnostic yield for pathogenic/likely pathogenic variants was 31.6% (87/275, 95% CI; 26.4–37.4). VOUS and incidental findings occurred at a rate of 4.4% (12/275) and 1.5% (4/275) respectively. Termination of pregnancy (TOP) occurred more frequently in diagnosed families, whereas live births were more common in the uninformative cohort. Conclusion pES demonstrated a high diagnostic yield with low VOUS and incidental finding rates. Outcomes differed between diagnosed and uninformative families, with TOP more frequent after genomic diagnoses. These findings support pES as a core diagnostic test for antenatal FSA evaluation and emphasise the importance of consistent phenotype ontology, body system classification, and eligibility criteria for fetal genomic sequencing.

Prenatal Diagnosis
South Australia Pathology (AU), Royal Women's Hospital (AU), Alfaisal University (SA), The University of Melbourne (AU), The University of Western Australia (AU), Royal Brisbane and Women's Hospital (AU), Liverpool Hospital (AU), Women's and Children's Hospital (AU), King Edward Memorial Hospital (AU), Canberra Hospital (AU), UNSW Sydney (AU), Prince of Wales Hospital (AU), Victorian Clinical Genetics Services (AU), Northern Sydney Local Health District (AU), Sydney Children's Hospital (AU), Centre for Cancer Biology (AU), Ingham Institute (AU), Western Sydney University (AU), Neuroscience Research Australia (AU), Macquarie University (AU)
Good health and well-being
Openalex Percentile: Top 7%
Prenatal Screening and Diagnostics
DOISourceOpenAlex
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