Clinical implementation of whole-genome array CGH as a first-tier test in 5080 pre and postnatal cases

Abstract

BackgroundArray comparative genomic hybridization (CGH) is currently the most powerful method for detecting chromosomal alterations in pre and postnatal clinical cases. In this study, we developed a BAC based array CGH analysis platform for detecting whole genome DNA copy number changes including specific micro deletion and duplication chromosomal disorders. Additionally, we report our experience with the clinical implementation of our array CGH analysis platform. Array CGH was performed on 5080 pre and postnatal clinical samples from patients referred with a variety of clinical phenotypes.ResultsA total of 4073 prenatal cases (4033 amniotic fluid and 40 chorionic villi specimens) and 1007 postnatal cases (407 peripheral blood and 600 cord blood) were studied with complete concordance between array CGH, karyotype and fluorescence in situ hybridization results. Among 75 positive prenatal cases with DNA copy number variations, 60 had an aneuploidy, seven had a deletion, and eight had a duplication. Among 39 positive postnatal cases samples, five had an aneuploidy, 23 had a deletion, and 11 had a duplication.ConclusionsThis study demonstrates the utility of using our newly developed whole-genome array CGH as first-tier test in 5080 pre and postnatal cases. Array CGH has increased the ability to detect segmental deletion and duplication in patients with variable clinical features and is becoming a more powerful tool in pre and postnatal diagnostics.

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

“…Similar results have also been reported by other independent largescale prospective studies (Table 1). [26][27][28][29][30] A point to note was how CMA was able to robustly detect copy numbers changes in all cases, such as case 2 (in which the G-banded karyotyping failed to detect the chromosomal abnormality) and case 3 (in which a cell culture failure occurred). For these cases, a good quality traditional karyotyping at the 400-band level should have been able to reliably detect the aberrations, but it failed to do so.…”

“…[37][38][39] At present, numerous independent prospective studies, [17][18][19][22][23][24][26][27][28][29][30] involving the use of various strategies and validated with several different array platforms, have demonstrated the effectiveness and usefulness of CMA in prenatal diagnosis compared to conventional karyotyping.…”

“…[27][28][29][30] The combined data from published prospective studies represent now a cohort of over 13 000 prenatal samples [7][8][9][10][11][12][13][14][15][16][17][18][19][22][23][24][26][27][28][29][30] (Table 1). Taken together, their findings clearly indicate that the use of CMA in prenatal diagnosis produces a substantial improvement in the detection rate of pathogenic chromosome abnormalities compared with conventional karyotyping.…”

“…In addition to our study, other similar large cohort prospective trials have been published, all reporting results concordant with our findings. [27][28][29][30] The above large-scale clinical trials, combined with previously reported small cohorts studies, have shown that the use of CMA in prenatal diagnosis produces a substantial improvement of B1-3% in detection rate of genetic aberrations compared with conventional karyotyping, without missing potentially pathogenic chromosomal abnormalities and with no appreciable increase in results of unclear clinical significance. These findings provided evidence for the feasibility of introducing CMA into routine prenatal diagnosis practice, indicating that it could be already acceptable to apply CMA as a first-line diagnostic test, at least concurrently with conventional karyotyping.…”

Investigation of the diagnostic value of chromosome analysis and bacterial artificial chromosome-based array comparative genomic hybridization in prenatal diagnosis

“…It is possible to use aCGH, also called molecular karyotyping, to screen genome-wide segmental genomic copy number variations, such as deletions and duplications, and also all aneuploidies (8,9).…”