Concordance between genome-wide cfDNA screening and diagnostic test results for large copy-number variants: a multi-site study from the Global Expanded NIPT Consortium

Fetal copy-number variants (CNVs) have been associated with a broad range of phenotypes and pregnancy outcomes. Noninvasive prenatal screening using genome-wide cell-free (cf) DNA analysis offers an opportunity to detect fetal CNVs early in pregnancy. This retrospective cohort study evaluated concordance between genome-wide cfDNA screening and diagnostic test results for 276 cases with a single isolated cfDNA-identified CNV ≥7 Mb. Cases for this study were submitted by members of the Global Expanded NIPT Consortium. Eight consortium sites in seven countries contributed cases, with 83% of cases submitted from European sites. Seventy-three of 276 cases (26.5%) had no known high-risk indication for cfDNA screening. Mean and median gestational age at the time of cfDNA blood draw was 13 weeks. A deletion was identified for 124 (44.9%) cases and a duplication for 152 (55.1%) cases. Mean CNV size was 33.4 Mb (median 23.1 Mb, range 7–187 Mb). Diagnostic test results were available for 209/276 cases (75.7%). Concordance between cfDNA screening and diagnostic test results was observed for 49/209 cases (23.4%). Mean and median fetal fraction among concordant cases was 8.8% and 8%, respectively. Among 157 discordant cases, a plausible maternal biological explanation was identified for 21 cases (13.4%). Pregnancy outcome information was limited, but available for 116 (42.0%) cases. Parental testing results were available for 38 (13.8%) cases. For six of 15 concordant cases with parental results, fetal CNVs were secondary to a parental translocation or rearrangement. This study contributes to the growing evidence supporting the use of genome-wide cfDNA screening for detection of large fetal CNVs that could affect the current pregnancy and future reproductive risks as well as identify previously unknown maternal conditions.