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Introducing array comparative genomic hybridization into routine prenatal diagnosis practice: a prospective study on 1166 consecutive clinical cases

Introducing array comparative genomic hybridization into routine prenatal diagnosis practice: a prospective study on 1166 consecutive clinical cases


Francesco Fiorentino1*, Fiorina Caiazzo1, Stefania Napoletano1, Letizia Spizzichino1, Sara Bono1, Mariateresa Sessa1, Andrea Nuccitelli1, Anil Biricik1, Anthony Gordon2, Giuseppe Rizzo1, Marina Baldi1.

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

2 Bluegnome Ltd, Cambridge CB22 5LD, UK

Objective: Experience with array-based comparative genomic hybridization (aCGH) use for clinical prenatal diagnosis is still relatively limited. Prospective trials on a large sample size are necessary before aCGH can be recommended for routine clinical use in prenatal diagnosis. To assess the feasibility of offering aCGH for prenatal diagnosis as a first-line test, a prospective study was performed on a cohort of 1166 consecutive prenatal samples, comparing the results achieved from aCGH with those obtained from a conventional karyotype.

Methods: Women undergoing amniocentesis or chorionic villus sampling (CVS) for standard karyotype, between 1 October 2010 and 31 May 2011, were offered aCGH analysis. A total of 1166 prenatal samples were processed in parallel using both aCGH, performed on DNA isolated from amniotic fluid (88.7%) or CVS (9.5%) and cultured amniocytes (1.8%), and G-banding for standard karyotyping.

Results: Clinically significant chromosome abnormalities were identified in 37(3.2%) samples, 27(73.0%) of which were also detected by conventional karyotyping. In 10(27.0%) samples, aCGH identified pathogenic copy number variations (CNVs) that would not have been found if only a standard karyotype had been performed. Six were de novo, not recorded as benign CNVs, 4 resulted inherited. Eight of the above CNVs were concerning well-established syndromes. Benign CNVs were identified in 152(13.0%) samples. Following parental studies, no findings of unclear significance remained. aCGH was also able to detect chromosomal mosaicism as lower as 10% level. There was a complete concordance between the conventional karyotyping and aCGH results, except for 2 cases, that were correctly diagnosed by aCGH.

Conclusions: This study demonstrates that aCGH represents an improved diagnostic tool for prenatal detection of chromosomal abnormalities, allowing identification of submicroscopic clinically significant imbalances that are not detectable by conventional karyotyping. The results of the study indicated that the aCGH approach was robust, with no false positive or false negative findings, suggesting that the technique has the potential to replace the traditional cytogenetic analysis without missing significant results. Our findings provide a further evidence on the feasibility of introducing aCGH into routine prenatal diagnosis practice as first-line diagnostic test to detect chromosomal abnormalities in prenatal samples.