Diagnostic utility of array-based comparative genomic hybridization (CMA) in a prenatal setting

The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
Prenatal Diagnosis (Impact Factor: 3.27). 12/2010; 30(12-13):1131-7. DOI: 10.1002/pd.2626
Source: PubMed


Array-based comparative genomic hybridization (aCGH) is a new technique for detecting submicroscopic deletions and duplications. There is limited information regarding its use in the prenatal setting. Here, we present our experience of 269 prenatal aCGHs between 2006 and 2009.
The indications for testing were fetal anomalies on ultrasound (U/S), advanced maternal age (AMA), family history of a disorder of unknown etiology, parental concern, abnormal routine karyotype and abnormal serum biochemical screening for common fetal aneuploidies.
Of 15 cases with a known abnormal karyotype, 11 had a normal aCGH. This enabled us to reassure the families and the pregnancies were continued. The remaining four showed an abnormal aCGH, confirming the chromosomes were unbalanced, and were terminated. Of 254 cases with a normal karyotype, 3 had an abnormal aCGH and were terminated. Overall, new clinically relevant results were detected by aCGH in 18 cases, providing additional information for prenatal genetic counseling and risk assessment.
Our results suggest that prenatal aCGH should be offered particularly in cases with abnormal U/S. We found the rate of detecting an abnormality by aCGH in low-risk pregnancies was 1:84, but larger studies will be needed to expand our knowledge and validate our conclusions.

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    • "As prior studies suggested, about 71% of the clinically significant copy number alterations (CNAs) are smaller than 10 Mb in size, and are unlikely to be detected by routine analysis of fetal chromosomes [24]. Array-based CGH analysis possesses a number of significant advantages over conventional cytogenetic and other molecular cytogenetic techniques, and can enhance the detection rate by 10 to 16 percent of pregnancies with fetal ultrasound anomalies but not detected by routine analysis of fetal chromosomes [1,25-27]. The American Congress of Obstetricians and Gynecologists (ACOG) and the Society of Maternal Fetal-Medicine (SMFM) have recommended prenatal chromosomal microarray analysis as a first-line test in the case of abnormal ultrasound findings. "
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    ABSTRACT: Array-based comparative genomic hybridization possesses a number of significant advantages over conventional cytogenetic and other molecular cytogenetic techniques, providing a sensitive and comprehensive detection platform for unexpected imbalances in the genome wide. The newborn proband, demonstrated with craniofacial dysmorphism and multiple malformations, was born to a family with spontaneous abortions. This pregnancy was uneventful, except the prenatal ultrasound examination showed an increased nuchal translucency at 12+ weeks of gestation. Cytogenetics revealed an apparently normal karyotype, and the couple decided to continue the pregnancy. Array-based CGH analysis was applied to the affected infant, identified a combination of 18p deletion and 7q duplication. Further study indicates that the unbalanced translocation was inherited from a balanced translocation carrier parent. In review of the case, several overlooked points leading to the missed diagnosis should be discussed and certain quality control strategies should be adopted to avoid similar problems in the future. Array-based CGH and karyotyping techniques are complemented by diverse detection spectrum and resolutions, and a combination of these methods could help providing optimal genetic diagnosis. Given that the array-CGH analysis will not introduce additional risk to patients, it is reasonable to recommend those already undergoing invasive testing should take array-based CGH as an adjunct to conventional cytogenetic tests and other molecular cytogenetic analysis.
    Molecular Cytogenetics 04/2014; 7(1):26. DOI:10.1186/1755-8166-7-26 · 2.14 Impact Factor
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    • "Five retrospective [1], [2], [5], [11], [29] and twelve prospective studies [3], [4], [6], [7], [8], [9], [11], [12], [13], [14], [15], [16] of prenatal array-CGH with different resolutions and involving uncultured amniotic fluid have been published (Table 6 and 7). Only one of them matched the aims of the present study, i.e. to describe a new method for DNA extraction from small quantities of AF, but the authors only tested two samples <16 WG [8]. "
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    ABSTRACT: The aim of this study was to develop an improved technique for DNA extraction from 1 ml of uncultured AF from patients with a gestational age less than 16 weeks and to allow the use of array-CGH without DNA amplification. The DNA extraction protocol was tested in a series of 90 samples including 41 of uncultured AF at less than 16 weeks of gestation. Statistical analyses were performed using linear regression. To evaluate the sensitivity and the specificity of array-CGH on 1 ml of uncultured AF, five samples with an abnormal karyotype (three with aneuploidy, two with structural abnormalities) and five with a normal karyotype were studied. This protocol was reproducible and we were able to show a great improvement with higher yield of DNA obtained from all patients, including those with a gestational age less than 16 weeks (p = 0.003). All chromosomal abnormalities were detected and characterized by array-CGH and normal samples showed normal profiles. This new DNA extraction protocol associated with array-CGH analysis could be used in prenatal testing even when gestational age is less than 16 weeks, especially in cases with abnormal ultrasound findings.
    PLoS ONE 04/2013; 8(4):e59956. DOI:10.1371/journal.pone.0059956 · 3.23 Impact Factor
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    • "Even in the studies using whole genome SNP-arrays with a resolution higher than 100 kb clinically relevant aberrations were mainly in the range of 1 Mb or more [13] or larger than 500 kb or 1 Mb [14,25] in all but one case [14]. An overall detection rate of 5-6% also including chromosomal anomalies detectable by conventional karyotyping was shown in array studies dealing with samples of heterogeneous clinical indications including fetal structural anomalies [12,30,31]. Hillman et al. concludes an overall detection rate of 3.6% regardless of the clinical indication and 5.3% for cases with ultrasound anomalies in his review and meta-analysis of this recent heterogeneous literature [32]. "
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    ABSTRACT: To describe the diagnostic performance of array comparative genomic hybridization (aCGH) as a potential first line diagnostic method in first trimester high risk pregnancies. In a retrospective study we performed aCGH using a targeted array BAC platform (Constitutional Chip® 4.0, PerkinElmer, Turku Finland, median resolution 600 kB) and the Affymetrix Cytogenetics® Whole Genome 2.7 M array (at a resolution of 400kB) on 100 anonymized prenatal samples from first trimester high risk pregnancies with normal conventional karyotype. We studied the technical feasibility and turn-around-time as well as the detection rate of pathogenic submicroscopic chromosome anomalies and CNVs of unknown significance. We obtained results in 98 of 100 samples in 3 to a maximum of 5 days after DNA extraction. At the given resolution we did not identify any additional pathogenic CNVs but two CNVs of unknown significance in the chromosomal regions 1q21.1q21.2 (deletion) and 5p15.33 (duplication) (2%). In accordance with a growing number of reports this study supports the concept that aCGH at a resolution of 400-600kB may be used as a first line prenatal diagnostic test with high diagnostic safety and rapid turn-around time in high-risk first trimester pregnancies. Detection rate of CNVs of unknown significance, considered as a major hindrance for replacing conventional karyotyping by aCGH, is 2%, but the diagnosis of additional submicroscopic anomalies in this heterogeneous group of patients seems to be rare.
    Molecular Cytogenetics 09/2012; 5(1):38. DOI:10.1186/1755-8166-5-38 · 2.14 Impact Factor
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