The Future of Prenatal Cytogenetics: From Copy Number Variations to Non-invasive Prenatal Testing
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CYTOGENETICS (CL MARTIN, SECTION EDITOR)
The Future of Prenatal Cytogenetics: From Copy Number Variations to Non-invasive Prenatal Testing Paul Brady • Simon Ardui • Joris Robert Vermeesch
Springer Science+Business Media New York 2013
Abstract The conventional methods of prenatal diagnosis are being challenged by recent technologies. Chromosomal microarrays already in mainstream use for postnatal genetic diagnosis are increasingly used for prenatal diagnosis, mainly in pregnancies with sonographic anomalies but also for routine screening after any invasive procedure. Arrays have demonstrated the ability to detect submicroscopic copy number variations, providing an approximately 2.1 % increase in the detection rate of pathogenic copy number variations regardless of the referral indication, and rising to an approximately 5.3 % increase above conventional karyotyping in the presence of sonographic anomalies. More recently, novel technologies and methods of non-invasive prenatal testing are reaching clinical applications beyond fetal sex determination and rhesus blood group genotyping. Massively parallel sequencing methods have been shown to confidently detect trisomy 21 from cell-free DNA isolated from a maternal plasma sample and are rapidly entering clinical use. Targeted methods including epigenetic differences between the fetal and maternal genomes such as differential methylation are also being applied for non-invasive aneuploidy detection. It can be anticipated that very soon chromosomal microarrays will become the first-tier test for invasive prenatal diagnosis. In addition, we believe that non-invasive prenatal testing will gradually replace the need for invasive prenatal diagnosis with the associated risk of pregnancy loss.
P. Brady S. Ardui J. R. Vermeesch (&) Centre for Human Genetics, KU Leuven, University Hospital Leuven, O & N I Herestraat 49, P.O. Box 602, 3000 Leuven, Belgium e-mail: [email protected]
Keywords Prenatal diagnosis Copy number variation Chromosomal microarrays Non-invasive prenatal diagnosis Cell-free fetal DNA Massively parallel sequencing Aneuploidy Trisomy 21
Introduction Conventional prenatal diagnosis relies on invasive procedures, such as amniocentesis or chorionic villi sampling, followed by genetic diagnostic tests. Karyotyping, typically by G-banding, was the gold standard for prenatal genetic diagnosis in the past decades. Although karyotyping provides genome-wide numerical and structural information, the resolution is limited to 5–10 Mb at best, and culturing of cells is required, which requires at least 7–10 days. To overcome the resolution limitations and the time constraints of karyotyping, targeted analysis by cytogenetic and molecular-based methods has been introduced, such as fluorescence in situ hybridization and multiplex ligation-dependent probe amplification [1]. Although these techniques are capable of detecting submicroscopic imbalances, they rely on the presence of recognizable sonographic phenotypic features to direct the approp
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