Laboratory performance of genome-wide cfDNA for copy number variants as compared to prenatal microarray

Erica Soster; John Tynan; Clare Gibbons; Wendy Meschino; Jenna Wardrop; Eyad Almasri; Stuart Schwartz; Graham McLennan

doi:10.1186/s13039-023-00642-4

Laboratory performance of genome-wide cfDNA for copy number variants as compared to prenatal microarray

Mol Cytogenet. 2023 Jun 10;16(1):10. doi: 10.1186/s13039-023-00642-4.

Authors

Erica Soster¹, John Tynan^{2

3}, Clare Gibbons⁴, Wendy Meschino^{4

5}, Jenna Wardrop², Eyad Almasri², Stuart Schwartz⁶, Graham McLennan²

Affiliations

¹ Labcorp®, La Jolla, CA, USA. erisoster@gmail.com.
² Labcorp®, La Jolla, CA, USA.
³ PetDx, The Center for Novel Therapeutics, La Jolla, CA, USA.
⁴ Genetics Program, North York General Hospital, Toronto, ON, Canada.
⁵ Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
⁶ Labcorp®, Research Triangle Park, NC, USA.

Abstract

Background: Noninvasive prenatal testing (NIPT) allows for screening of fetal aneuploidy and copy number variants (CNVs) from cell-free DNA (cfDNA) in maternal plasma. Professional societies have not yet embraced NIPT for fetal CNVs, citing a need for additional performance data. A clinically available genome-wide cfDNA test screens for fetal aneuploidy and CNVs larger than 7 megabases (Mb).

Results: This study reviews 701 pregnancies with "high risk" indications for fetal aneuploidy which underwent both genome-wide cfDNA and prenatal microarray. For aneuploidies and CNVs considered 'in-scope' for the cfDNA test (CNVs ≥ 7 Mb and select microdeletions), sensitivity and specificity was 93.8% and 97.3% respectively, with positive and negative predictive values of 63.8% and 99.7% as compared to microarray. When including 'out-of-scope' CNVs on array as false negatives, the sensitivity of cfDNA falls to 48.3%. If only pathogenic out-of-scope CNVs are treated as false negatives, the sensitivity is 63.8%. Of the out-of-scope CNVs identified by array smaller than 7 Mb, 50% were classified as variants of uncertain significance (VUS), with an overall VUS rate in the study of 2.29%.

Conclusions: While microarray provides the most robust assessment of fetal CNVs, this study suggests that genome-wide cfDNA can reliably screen for large CNVs in a high-risk cohort. Informed consent and adequate pretest counseling are essential to ensuring patients understand the benefits and limitations of all prenatal testing and screening options.

Keywords: Circulating cell-free DNA (cfDNA); Copy number variants; Genome-wide NIPT; Microarray; Non-invasive prenatal testing (NIPT); Prenatal diagnosis; Prenatal screening; Rare aneuploidies.