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Chromosome Microarray Analysis In Routine Prenatal Diagnosis Practice: A Prospective Study On 2800 Clinical Cases

Chromosome Microarray Analysis In Routine Prenatal Diagnosis Practice: A Prospective Study On 2800 Clinical Cases


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

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

2 Bluegnome Ltd, Cambridge CB22 5LD, UK

Objectives: Although several studies have demonstrated the usefulness of chromosome microarray analysis (CMA) in clinical prenatal diagnosis practice, only limited conclusions could be drawn due to the small size of the cohorts analysed. Whilst these studies have all provided reassuringly consistent results in term of analytical validity, clinical validity and clinical utility of the technique applied in the prenatal diagnosis setting, their limited data has necessitated undertaking of large-scale prospective clinical trials.

To assess the feasibility of offering CMA for prenatal diagnosis as a first-line diagnostic test, a prospective study was performed on a cohort of 2800 consecutive prenatal samples, with parallel processing for both CMA and conventional cytogenetic analysis.

Method: Women undergoing amniocentesis or chorionic villus sampling (CVS) for standard karyotype, between 1 October 2010 and 31 January 2012, were offered CMA. A total of 2800 prenatal samples were processed in parallel using both CMA, performed on DNA isolated from amniotic fluid (88.4%) or CVS (10.1%) and cultured amniocytes (1.5%), and G-banding for standard karyotyping.

Results: Clinically significant copy number variations (CNVs)were identified in 94(3.4%) samples, 70(74.5%) of which were also detected by conventional karyotyping. In 24 cases (0.9% of the entire cohort of samples and 25.5% of the clinically relevant findings), CMA identified pathogenic CNVs that would have remained undiagnosed if only a conventional karyotype had been performed, 16 of which were concerning well-established syndromes. The selection of an array platform specifically developed for prenatal applications, allowed us to detect a single occurrence of variation of unclear significance out of 2800 samples. CMA was also able to detect chromosomal mosaicisms as lower as 3.3% level. There was a complete concordance between the conventional karyotyping and aCGH results, except for 2 cases, that were correctly diagnosed by aCGH.

Conclusions: The results of this study demonstrate that CMA improves the detection of fetal chromosome aberrations than conventional karyotyping, without missing potential pathogenic chromosomal abnormalities, with no appreciable increase in results of unclear clinical relevance. These findings, combined with those of others previous studies, provide substantial evidence for the feasibility of introducing CMA into routine prenatal diagnosis practice as a first-line diagnostic test.