Genome-wide cell-free DNA screening: a focus on copy-number variants

Jill Rafalko,Erica Soster,Samantha Caldwell,Eyad Almasri,Thomas Westover,Vivian Weinblatt,Philip Cacheris

doi:10.1038/s41436-021-01227-5

Jill Rafalko, Erica Soster + Show 5 more

Open Access

https://doi.org/10.1038/s41436-021-01227-5

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Abstract

PurposeOf 86,902 prenatal genome-wide cell-free DNA (cfDNA) screening tests, 4,121 were positive for a chromosome abnormality. This study examines 490 cases screen-positive for one or more subchromosomal copy-number variants (CNV) from genome-wide cfDNA screening. MethodsCases positive for one or more subchromosomal CNV from genome-wide cfDNA screening and diagnostic outcomes were compiled. Diagnostic testing trends were analyzed, positive predictive values (PPVs) were calculated, and the type of chromosomal abnormalities ultimately confirmed by diagnostic testing were described. ResultsCNVs were identified in 0.56% of screened specimens. Of the 490 cases screen-positive for one or more CNV, diagnostic outcomes were available for 244 cases (50%). The overall PPV among the cases with diagnostic outcomes was 74.2% (95% CI: 68.1–79.5%) and 71.8% (95% CI: 65.5–77.4%) for “fetal-only” events. Overall, isolated CNVs showed a lower PPV of 61.0% (95% CI: 52.5–68.8%) compared to complex CNVs at 93.9% (95% CI: 86.6–97.5%). Isolated deletions/duplications and unbalanced structural rearrangements were the most common diagnostic outcomes when isolated and complex CNVs were identified by cfDNA screening, respectively. ConclusionGenome-wide cfDNA screening identifies chromosomal abnormalities beyond the scope of traditional cfDNA screening, and the overall PPV associated with subchromosomal CNVs in cases with diagnostic outcomes was >70%.

Highlights

In 2015, a large study using data from the California Prenatal Screening Program[1] found that traditional cell-free DNA screening had the capability to detect approximately 70–80% of the karyotypic abnormalities identified in fetuses and infants
Of 86,902 consecutive, clinical genome-wide cell-free DNA (cfDNA) screening specimens, 4,121 positive results were issued, resulting in an overall positivity rate of 4.7%. Of these 4,121 cases, 11.9% (n = 490) were positive for one or more subchromosomal copy-number variants (CNV), equating to an incidence of 1 in 177 (0.56%) for CNVs in the overall population screened. These cases were comprised of 309 isolated CNVs and 181 complex CNVs, which would translate to an incidence of 1 in 281 (0.36%) for isolated CNVs and 1 in 480 (0.21%) for complex CNVs in the screening population
In the cohort of patients with CNV-positive results from genome-wide cfDNA screening, diagnostic results were available for 50% of these cases

Summary

Introduction

In 2015, a large study using data from the California Prenatal Screening Program[1] found that traditional cell-free DNA (cfDNA) screening (for common aneuploidies and sex chromosome abnormalities) had the capability to detect approximately 70–80% of the karyotypic abnormalities identified in fetuses and infants. The remaining 20–30% of abnormalities missed by traditional cfDNA screening included clinically relevant findings such as subchromosomal deletions/duplications, rare autosomal aneuploidies, and polyploidy, among others, and represented an area for growth of prenatal screening tests. Genome-wide cfDNA screening was developed to expand the abnormalities detectable by prenatal screening. This testing became clinically available in the United States in 2015, and, as described in this study, has been performed in over 85,000 pregnancies since that time.

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