Chromosomal microarray analysis as a first-line test in pregnancies with a priori low risk for the detection of submicroscopic chromosomal abnormalities

Abstract

In this study, we aimed to explore the utility of chromosomal microarray analysis (CMA) in groups of pregnancies with a priori low risk for detection of submicroscopic chromosome abnormalities, usually not considered an indication for testing, in order to assess whether CMA improves the detection rate of prenatal chromosomal aberrations. A total of 3000 prenatal samples were processed in parallel using both whole-genome CMA and conventional karyotyping. The indications for prenatal testing included: advanced maternal age, maternal serum screening test abnormality, abnormal ultrasound findings, known abnormal fetal karyotype, parental anxiety, family history of a genetic condition and cell culture failure. The use of CMA resulted in an increased detection rate regardless of the indication for analysis. This was evident in high risk groups (abnormal ultrasound findings and abnormal fetal karyotype), in which the percentage of detection was 5.8% (7/120), and also in low risk groups, such as advanced maternal age (6/1118, 0.5%), and parental anxiety (11/1674, 0.7%). A total of 24 (0.8%) fetal conditions would have remained undiagnosed if only a standard karyotype had been performed. Importantly, 17 (0.6%) of such findings would have otherwise been overlooked if CMA was offered only to high risk pregnancies.The results of this study suggest that more widespread CMA testing of fetuses would result in a higher detection of clinically relevant chromosome abnormalities, even in low risk pregnancies. Our findings provide substantial evidence for the introduction of CMA as a first-line diagnostic test for all pregnant women undergoing invasive prenatal testing, regardless of risk factors.

Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs

“…The frequency of UDs in our cohort matches the frequency of pathogenic submicroscopic array findings in pregnancies without ultrasound abnormalities after excluding SL for neurodevelopmental diseases published in the literature. 7,9,28,29 Thus our results support the hypothesis that there is a background risk of~0.5% for a clinically relevant submicroscopic chromosome abnormality (exclusive SL) in the general population. 30 In our opinion, UDs found in our cohort are of additional value in routine prenatal genomic array testing as most (4/5) of them lead to (possibly) severe (including intellectual disability and/or a reduced life expectancy) early-onset diseases, which can be missed by ultrasound examination.…”

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature

“…12 The results suggest that fetal anomalies on ultrasonography would be expected to be rare, consistent with the low prevalence of 15q13.3 deletions detected by prenatal chromosomal microarray studies. 11,23,24 Postnatal chromosomal microarray detection, perhaps secondary to referral for DD/ID, is higher. 9 By contrast, the most common large rare CNVs, 22q11.2 deletions, have high penetrance for both neuropsychiatric disorders and congenital anomalies, 25 and higher prenatal detection (0.29%) as compared with 15q13.3 deletions (0.02-0.09%).…”

Prenatal Genetic Testing With Chromosomal Microarray Analysis Identifies Major Risk Variants for Schizophrenia and Other Later-Onset Disorders

“…Chromosomal microarray analysis may soon become the standard of care in the prenatal setting (1,2). Not discussed is the potential for later-onset phenotypes of findings identified in utero and the resultant ethical and societal challenges.…”

“…Recent studies (1,2) have demonstrated the advantages of genome-wide chromosomal microarray analysis over karyotype for the prenatal detection of pathogenic copy number variants. Chromosomal microarray analysis may soon become the standard of care in the prenatal setting (1,2).…”