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Current Status of Testing for Microdeletion Syndromes and Rare Autosomal Trisomies Using Cell-Free DNA Technology

Yaron, Yuval MD; Jani, Jacques MD; Schmid, Maximilian MD; Oepkes, Dick MD

doi: 10.1097/AOG.0000000000001091
Contents: Current Commentary

Noninvasive prenatal testing using cell-free DNA in maternal blood for trisomy 21 was introduced in 2011. This technology has continuously evolved with the addition of screening for trisomy 18 and trisomy 13 followed by the inclusion of sex chromosome aneuploidies. Expanded noninvasive prenatal test panels have recently become available, which enable screening for microdeletion syndromes such as the 22q11.2 deletion (associated with the velocardiofacial syndrome) and others. However, the performance data for these microdeletion syndromes are derived from a small number of samples, mostly generated in vitro. Rigorous performance evaluation, as was done at least for trisomy 21 testing using cell-free DNA analysis, is difficult to perform given the rarity of each condition. In addition, detection rates may vary considerably depending on deletion size. Importantly, positive predictive values (PPVs), strongly influenced by the low prevalence, are expected to be significantly lower than 10% for most conditions. Thus, screening in an average-risk population is likely to have many more false-positives than affected cases detected. Conversely, testing in a high-risk population such as fetuses with cardiac anomalies may have higher PPVs, but a negative result needs to be considered carefully as a result of uncertain information about detection rates and a significant residual risk for other copy number variants and single gene disorders. This article integrates current knowledge on cell-free DNA testing for microdeletions with the aim to assist clinicians and policymakers in designing optimal programs for screening in pregnancy.

Although noninvasive prenatal testing using cell-free DNA for common trisomies is well established, the inclusion of certain microdeletion syndromes and rare autosomal trisomies is currently unsupported by sufficient clinical evidence.

Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel; University Hospital Brugmann, Université Libre de Bruxelles, Brussels, Belgium; Medical University of Vienna, Vienna, Austria; and Leiden University Medical Centre, Leiden, The Netherlands.

Corresponding author: Yuval Yaron, MD, Prenatal Genetic Diagnosis Unit, Genetic Institute, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel; e-mail:

Financial Disclosure Dr. Yaron is a Clinical Expert Panel Member of the Reproductive and Genetic Health Unit, Illumina, maker of the Verifi Prenatal Test; a consultant for FugeneGenetics, distributor of the Harmony Prenatal Test in Israel; and consultant to Teva Pharmaceuticals, distributor of the Verifi Prenatal Test in Israel. Dr. Schmid is Associate Director of Medical Affairs at Ariosa Diagnostics, Inc., maker of the Harmony Prenatal Test. The other authors did not report any potential conflicts of interest.

© 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.