Reporting Criteria for Prenatally Identified Variants of Uncertain Significance Differs Among Cytogenetics Laboratories in North America

Matthew A Shear; Arun P Wiita; Jingwei Yu; Brette Wayman; Teresa N Sparks; Mary E Norton; Kate Swanson

doi:10.1002/pd.6785

Reporting Criteria for Prenatally Identified Variants of Uncertain Significance Differs Among Cytogenetics Laboratories in North America

Prenat Diagn. 2025 May 6. doi: 10.1002/pd.6785. Online ahead of print.

Authors

Matthew A Shear^{1

2}, Arun P Wiita³, Jingwei Yu³, Brette Wayman³, Teresa N Sparks¹, Mary E Norton¹, Kate Swanson^{1

2}

Affiliations

¹ Division of Maternal-Fetal Medicine and Reproductive Genetics, University of California, San Francisco, California, USA.
² Division of Medical Genetics and Genomics, University of California, San Francisco, California, USA.
³ Department of Laboratory Medicine, University of California, San Francisco, California, USA.

PMID: 40326825
DOI: 10.1002/pd.6785

Abstract

Objective: Current technical standards for chromosomal microarray (CMA) interpretation are not prescriptive for reporting variants of uncertain significance (VUS) identified prenatally. We sought to compare prenatal CMA reporting among cytogenetic labs and identify potential drivers of practice variation.

Methods: We conducted an electronic cross-sectional survey of cytogeneticists in the United States and Canada from July-December 2023. Participants were identified through the American Cytogenetics Forum List.

Results: Labs reported differences in their size threshold used when reporting CNVs lacking OMIM annotated genes as a VUS, variable use of clinical data such as ultrasound or family history when deciding to report a VUS, and differences in opinion regarding the underlying pathogenicity of certain CNVs. Many cytogeneticists reported concerns about legal liability related to prenatal CMA reporting, and many shared concerns that a patient may terminate a pregnancy based on a VUS.

Conclusion: Reporting criteria for prenatally identified variants of uncertain significance differs among cytogenetic laboratories in North America. Many possible drivers of this practice variation were identified, including a lack of national guidelines that comprehensively address the unique considerations for prenatal CMA reporting.