Diagnostic utility of array-based comparative genomic hybridization (aCGH) in a prenatal setting
ABSTRACT 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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ABSTRACT: Novel methodologies for detection of chromosomal abnormalities have been made available in the recent years but their clinical utility in prenatal settings is still unknown. We have conducted a comparative study of currently available methodologies for detection of chromosomal abnormalities after invasive prenatal sampling. A multicentric collection of a 1-year series of fetal samples with indication for prenatal invasive sampling was simultaneously evaluated using three screening methodologies: (1) karyotype and quantitative fluorescent polymerase chain reaction (QF-PCR), (2) two panels of multiplex ligation-dependent probe amplification (MLPA), and (3) chromosomal microarray-based analysis (CMA) with a targeted BAC microarray. A total of 900 pregnant women provided informed consent to participate (94% acceptance rate). Technical performance was excellent for karyotype, QF-PCR, and CMA (~1% failure rate), but relatively poor for MLPA (10% failure). Mean turn-around time (TAT) was 7 days for CMA or MLPA, 25 for karyotype, and two for QF-PCR, with similar combined costs for the different approaches. A total of 57 clinically significant chromosomal aberrations were found (6.3%), with CMA yielding the highest detection rate (32% above other methods). The identification of variants of uncertain clinical significance by CMA (17, 1.9%) tripled that of karyotype and MLPA, but most alterations could be classified as likely benign after proving they all were inherited. High acceptability, significantly higher detection rate and lower TAT, could justify the higher cost of CMA and favor targeted CMA as the best method for detection of chromosomal abnormalities in at-risk pregnancies after invasive prenatal sampling. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-1095-5) contains supplementary material, which is available to authorized users.Human Genetics 10/2011; 131(3):513-23. DOI:10.1007/s00439-011-1095-5 · 4.52 Impact Factor
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ABSTRACT: Evaluation of copy number variation by microarray analysis has significant advantages over standard metaphase karyotyping and is quickly becoming the primary means of postnatal genetic evaluation for neonates and infants with dysmorphic features or cognitive difficulties. Before this technology is routinely used for prenatal diagnosis, further evaluation of its value and the clinical dilemmas it may introduce requires further study. This article reviews the recent literature on array technology use in prenatal diagnosis. The use of microarray analysis for routine prenatal diagnosis is still being investigated. Use in certain prenatal situations such as the fetus with structural anomalies or those who are stillborn appears to add important, clinically relevant information. There are a broad range of array designs available and recent research has focused on the appropriate design for prenatal testing. Patient counseling may occasionally be difficult because of the uncertain phenotype associated with some array findings. We present a brief overview of microarray technology including benefits and limitations. Previous research regarding use of microarray in prenatal diagnosis including specific scenarios of anomalous fetuses and abnormal karyotype is reviewed. Current guidelines and the authors' recommendations are presented.Current opinion in obstetrics & gynecology 02/2011; 23(2):103-8. DOI:10.1097/GCO.0b013e32834457c7 · 2.37 Impact Factor
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ABSTRACT: New discoveries using high-resolution methods for detecting genetic aberrations indicate that the genetic contribution to congenital heart disease has been significantly underestimated in the past. DNA diagnostics have become more accessible and genetic test results are increasingly being used to guide clinical management. Adult congenital heart disease specialists seeking to counsel adults with congenital heart disease about the genetic aspects of their condition face the challenge of keeping abreast of new genetic techniques and discoveries. The emphasis of this review is on the genetic basis of structural cardiovascular defects. A framework for identifying adult congenital heart disease patients most likely to benefit from genetic testing is suggested, along with a summary of current techniques for genetic testing. The clinical and ethical challenges associated with genetic counseling are highlighted. Finally, emerging technologies and future directions in genetics and adult congenital heart disease are discussed.Current Cardiology Reports 05/2011; 13(4):347-55. DOI:10.1007/s11886-011-0188-z