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The Use Of Chromosome Microarray Analysis As A First-Line Test In Low Risk Pregnancies

The Use Of Chromosome Microarray Analysis As A First-Line Test In Low Risk Pregnancies

Francesco Fiorentino1*, Stefania Napoletano1, Fiorina Caiazzo1, Mariateresa Sessa1, Sara Bono1, Letizia Spizzichino1, Silvia Michiorri1, Anthony Gordon2, Andrea Nuccitelli1, Giuseppe Rizzo1, Marina Baldi1.


1 GENOMA”- Molecular Genetics Laboratory, Via Po, 102 00198 Rome – Italy

2 Bluegnome Ltd, Cambridge CB22 5LD, UK

Objectives: Although several large-scale prospective clinical trials have demonstrated the usefulness of chromosome microarray analysis (CMA) in clinical prenatal diagnosis practice, at present it is not clear yet which indications could benefit from this assay. In the absence of specific guidelines, it has been suggested that CMA should be offered to selected groups of high risk pregnancies, using the technique as a second-line test only.

In this study we aimed to explore the usefulness of 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 the assess if CMA improves the prenatal detection rate of chromosomal aberrations.

Method: A total of 2800 prenatal samples were processed in parallel using both CMA and G-banding for conventional karyotyping. The indications for prenatal testing included: 1033(36.9%) advanced maternal age (AMA), 27(1.0%) abnormal results of maternal serum screening tests (MSS), 90(3.2%) abnormal ultrasound findings (AUS), 24(0.9%) known abnormal fetal karyotype (AFK), 1569(56.0%) parental anxiety (PA), 24(0.9%) family history of a genetic condition (FIS), 33(1.2%) cell culture failure (CCF).

Results: the use of CMA resulted in an increased detection rate regardless of the indication for analysis. This became especially evident in high-risk groups (AUS, AFK), in which the percentage of detection was 6.1%(7/114), and also in low risk groups, such as AMA (7/1033, 0.7%) and PA (10/1569, 0.6%). A total of  24 fetal conditions (0.9% of the entire cohort of samples and 25.0% of the clinically relevant findings), would have remained undiagnosed if only a standard karyotype had been performed. More importantly, 17(0.6%) of such findings would have otherwise been overlooked offering CMA to high risk pregnancies only.

Conclusions: The results of this study demonstrate that more widespread testing by CMA in fetuses would result in a higher detection of chromosome abnormalities prenatally, also in low risk pregnancies. Offering CMA only for selected groups of pregnancies substantially limit the diagnostic potential of this assay, missing pathological copy number variations. Our findings provide substantial evidence for the utility of using CMA as a first-line diagnostic test to all pregnant women undergoing invasive prenatal testing, regardless of risk factors.