Detection of copy number variants with chromosomal microarray in 10 377 pregnancies at a single laboratory

Abstract

Introduction: Invasive prenatal testing with chromosomal microarray analysis may be a relevant option for all pregnant women, but there is only moderate-quality evidence for such an offer. We intended to study the prevalence of copy number variants (CNVs) in prenatal samples using a single SNP-array platform stratified by indication.

Material and methods: A cross-sectional study was performed based on a cohort. From January 2015 to December 2017, a total of 10 377 prenatal samples were received for prenatal single nucleotide polymorphism (SNP)-array in the laboratory of the Genetics Generation Advancement Corporation. Indications for chromosomal microarray analysis studies included the confirmation of an abnormal karyotype, ultrasound abnormalities, advanced maternal age and parental anxiety. CNVs and region of homozygosity identified by the SNP-array were analyzed.

Results: Of 10 377 cases, 689 had ultrasound abnormalities and 9688 were ascertained to have other indications. The overall prevalence of CNVs was 2.1% (n = 223/10 377, 95% confidence interval [CI] 1.9-2.4), but the prevalence was 4.4% (95% CI 3.0-6.1) for cases referred with abnormal ultrasound findings and 2.0% (95% CI 1.7-2.3) for other indications. Of the 223 CNVs detected, 42/10 377 were pathogenic (0.4%, 95% CI 0.3-0.6), 84 were susceptibility CNV (0.8%, 95% CI 0.6-1.0) and 97 were variants of uncertain significance (0.9%, 95% CI 0.8-1.1). Using an SNP-based platform allowed for the detection of paternal uniparental disomy of chromosome 14 in a fetus with ultrasound abnormality.

Conclusions: With an indication of advanced maternal age but normal ultrasound scans, the prevalence of pathogenic CNVs was 0.4% and that of susceptibility CNV 0.7%. As CNVs are independent of maternal age, the prevalence is likely the same for younger women. Thus, this study provides further evidence that chromosomal microarray analysis should be available for all women who wish to receive diagnostic testing, as this risk is above the cut-off of 1:300 for Down syndrome, leading to the suggestion of invasive testing. A chromosomal microarray analysis based on SNP-array platform is preferable, as it can also detect uniparental disomy in addition to copy number variants.

Keywords: abnormal ultrasound findings; absence of heterozygosity; copy number variant; pathogenic CNV; prenatal chromosomal microarray analysis; variants of uncertain significance.

FIGURE 1

Classifications and reporting of CNVs in prenatal microarray. CNV, copy number variants; del, deletion; dup, duplication; mat, maternally inherited; pat, paternally inherited; VOUS, variant of unknown significance

FIGURE 2

Cytogenomic profile of cases with vs without abnormal ultrasound as an indication. ^†UPD 14 and 16. ^‡UPD 1 and 2. ^§One fetus carried trisomy X and a CNV <5 Mb. AUS, abnormal ultrasound finding; CNV, copy number variant; del/dup, deletion/duplication; mar, marker chromosome; pCNV, pathogenic CNV; sCNV, susceptibility CNV; UPD, uniparental disomy; VOUS, variants of unknown significance