Advances in Prenatal Molecular Diagnostics

There are a variety of similarities, as well as some very important differences, for the prenatal molecular diagnostic landscape in Europe compared to the situation in the U.S. or other parts of the world. Arrays and next-gen sequencing are playing an increased role, but these are not the only technologies being applied to this field. There has been a dramatic decline in the level of invasive testing, predominantly because of the widespread introduction of non-invasive screening based on cell-free DNA. In Europe, where samples are more likely to be evaluated locally, there is a wider range of options available for cell-free DNA testing compared to other parts of the world, where centralized testing is more prevalent.

While cell-free DNA testing moves beyond just aneuploidy testing; including more testing for sub-chromosomal genetic conditions, these changes may involve higher costs as well as additional questions for false positives and issues for implementation. At the same time, those researchers working to commercialize an alternative to cell-free DNA, specifically the non-invasive isolation and analysis of fetal cells from maternal blood, are moving into clinical trials prior to being able to commercialize this approach. It seems clear that before too long these two techniques will both be on the market and will compete with each other. A range of issues related to implementation of newer testing in the prenatal setting will be covered.

Final Agenda


08:00 Short Course Registration and Morning Coffee

12:00 Main Conference Registration


13:00 Chairperson’s Opening Remarks

13:10 Chromosomal Microarray in Prenatal Diagnostics – Lessons from More Than 1500 Analyses

Ida_VogelIda Vogel, M.D., Head of Clinical Genetics, Aarhus University Hospital, Denmark

We found aneuploidy in 4.7% of samples with fetal malformations, pathogenic CNV in additional 5.4% and variants of unknown significance (VOUS), likely pathogenic, in 1.6%. We have successfully replaced conventional karyotyping with CMA with a higher detection rate, a shorter turn-around time in a clinically manageable way for both abnormal ultrasound and increased risk in a government financed system covering the central Denmark region of 1.2 million people.

13:40 Array-CGH (aCGH) as a First-Tier Test in All Invasive Prenatal Samples

Julian_NevadoJulian Nevado, Ph.D., Responsible for Genomics and Quality Manager, INGEMM, Spain

Given the increasing prevalence of NIPD testing for prenatal diagnosis, what is the best course of action with invasively-obtained prenatal samples? aCGH has been recommended by different experts and international guidelines as a first tier-test in many postnatal clinical settings, but should this also apply prenatally? Based on our experience we will try to answer whether aCGH should be applied for all invasive samples and if it should be used as a first test or in parallel to Karyotype. Current data in our lab, we will help to decipher the best option.

14:10 Refreshment Break


15:00 Polymorphism in the Promoter Region of Placental Protein 13/LGALS13 Gene as a Biomarker for Pre-Eclampsia

Hamutal_MeiriHamutal Meiri, Ph.D., MBA, Coordinator of International Research, ASPRE Consortium, Israel

Gene polymorphisms are related to resilience/susceptibility to acquire various medical disorders including preeclampsia (PE). Our aim was to assess DNA polymorphisms in the LGALS13 sequence, encoding for placental protein 13 (PP13), in predicting PE, given PP13’s unique placental expression and its potential role as a PE biomarker. It opens a new avenue for DNA-based prediction of a major pregnancy disorder related to placental dysfunction.

15:30 Risk Factors and Proteomic Biomarkers for Pre-Term Birth

Andres_Lopez_BernalA. Lopez Bernal, M.D., Ph.D., School of Clinical Sciences, Obstetrics and Gynecology, University of Bristol, United Kingdom

The mechanism responsible for the onset of human labour remains a mystery but labour and delivery provoke changes in maternal plasma proteins associated with immune and defence responses and with lipid transport. We have used Tandem Mass Tag (TMT) labelling for a comprehensive analysis of proteins in the maternal circulation, as well as with intrauterine tissues. Prostaglandins (PGs) have been implicated in parturition for many decades. We propose that reduced expression of certain biomarkers as a potential mechanism through which smoking may contribute to preterm labour. Proteomic biomarkers will provide valuable insight into the mechanism of human labour and inform further research to improve the prediction and management of preterm birth.


Topics include:

  • Microarrays and Sequencing for Invasively-Obtained Samples
  • Ethical and Genetic Counseling Issues for Prenatal Testing
  • Developing Biomarkers for Preeclampsia and Pre-Term Birth Risk
  • In-House vs. Service-Based Cell-Free DNA testing
  • Prenatal Testing for Sub-Chromosomal Abnormalities
  • Commercialization Potential for Fetal Cell-Based Non-Invasive Testing

17:15 Close of Day One


08:00 Registration and Morning Coffee


09:00 Chairperson’s Remarks

09:05 Mosaic Whole Chromosome Uniparental/Biparental Disomy: A Common Feature in Trisomic Placentas?

Diane_VanOpstalDiane Van Opstal, Ph.D., Laboratory Specialist in Clinical Genetics, Erasmus Medical Center, The Netherlands

The results of SNP array investigations of first trimester chorionic villi and term placentas, for confirmation of abnormal NIPT results, reflect the cytogenetic chaos that has been described in cleavage-stage embryos. Apart from confined placental mosaicism involving trisomies and different structural chromosome aberrations, we also found mosaic whole chromosome uniparental disomy (UPD)/biparental disomy (BPD) which is rarely described in the literature, but which seems to be common in trisomic placentas. Interesting cases will be presented.

09:35 Lessons from More Than 6000 NIPS from a Single Center, Including Use of NIPS in Complex Obstetrical Situations and Ultrasound Anomalies

Francois_JacquemardFrancois Jacquemard, Ph.D., Gynecology & Obstetrics, American Hospital of Paris, France

From January 2013, more than 6000 NIPS have been processed through the Prenatal Diagnosis Center of the American Hospital of Paris (France). Details related to indications for testing and clinical finds will be reported, including rates for PPV, sensitivity and false-positives. Lessons learned from these results, including that NIPS was also useful in some complex obstetrical situations when the risk of miscarriage or premature delivery was very high and contraindicated any invasive testing, allowing almost full exclusion of main aneuploidies.

SeraCare 10:05 Expediting NIPT Assay Development, Validation and Routine Monitoring  

Ram SanthanamRam Santhanam, MS, MBA, Director, Market Development - Reproductive Health, SeraCare Life Sciences

As non-invasive prenatal testing (NIPT) becomes more mainstream, there is a critical need for patient-like reference materials to expedite new assay development, validation, external quality assurance (EQA) testing, and routine monitoring. We will discuss case studies and performance data from a cross section of laboratories successfully utilizing these reference materials.

Roche10:20 cfDNA Testing for 22q11.2 Deletion Syndrome Using a Targeted Microarray Based Technology

Maximillian_SchmindMaximilian Schmid, M.D., Senior Director of Medical Affairs, Medical Affairs, Roche Sequencing Solutions, United States

Deletion of 22q11.2 is the second most common cause of developmental delay and major congenital heart disease after Down syndrome1. The Harmony® Prenatal Test, used for assessing the probability of Down syndrome (Trisomy 21) and other chromosomal conditions, has extended its menu to include 22q11.2 deletion testing. Top-line results of an analytical validation will be presented.

1. Rauch et al. Am J Med Genet A. 2006 Oct 1;140(19):2063-74

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

11:15 Frequency of Fetal Submicroscopic Chromosome Aberrations in Low-Risk Pregnancies – A Systematic Review of Literature

Malgorzata_SrebniakMalgorzata Srebniak, Ph.D., Laboratory Specialist in Clinical Genetics, Clinical Genetics, Erasmus Medical Center, The Netherlands

A systematic literature search was performed in order to establish the frequency of pathogenic submicroscopic copy number variants (CNVs) in fetuses without ultrasound anomalies and therefore no increased risk for unbalanced structural aberrations. The aim was to determine the clinical value of high resolution fetal testing in the general pregnant population. We will show combined data of the relevant studies indicating the background risk for pathogenic submicroscopic aberrations in ca. 10,000 fetuses without increased a priori risk.

11:45 Clinical Implications of Testing for Sub-Chromosomal Abnormalities with NIPT

Yaron_YuvalYaron Yuval, M.D., Director, Prenatal Genetic Diagnostic Unit, Tel Aviv Sourasky Medical Center, Israel

Detection rates for microdeletions may vary considerably depending on deletion size and positive predictive values (PPVs) - strongly influenced by prevalence - are expected to be low. Whole genome NIPS has recently been introduced, claiming the ability to detect copy number changes throughout the genome. The benefits and limitations of expanded NIPS will be discussed with the aim of assisting clinicians and policymakers in incorporating NIPS into clinical practice.

12:15 Enjoy Lunch on Your Own


13:45 Chairperson’s Remarks

13:50 Non-Invasive Prenatal Testing of Monogenic Disorders by Droplet Digital PCR

Yves_RozenholcYves Rozenholc, Ph.D., Department of Statistics, University of Paris Descartes, France

Recently the use of NGS and digital-PCR using cell-free fetal DNA has been the basis for non-invasive prenatal tests for single-gene disorders. However, to date, it has mainly been offered for paternal and de novo mutation exclusion, the study of the maternal inheritance remaining challenging because of the high levels of maternal background. The development of a digital droplet PCR Uniformly Most Powerful Likelihood Ratio Test has been developed for a range of different single gene disorders. Results using this approach, and recommendations related to blood volume to collect, for each type of single-gene disorder, will be discussed.

14:20 Toward Refined Non-Invasive Prenatal Testing by Digital Droplet PCR and Free Fetal DNA Enrichment

Neil_AventNeil Avent, Ph.D., Molecular Diagnostic and Transfusion Medicine, School of Biomedical & Healthcare Sciences, Plymouth University, United Kingdom

Digital droplet PCR (ddPCR) is a significant enhancement over quantitative real-time PCR, and previous hardware associated with performing digital PCR. It has greater sensitivity and specificity than previously described methods, and has yet to impact fully on its application in non-invasive prenatal testing. We have performed ddPCR on maternal plasma samples to detect paternally inherited genes (RHD and SRY), and have proved its superiority over real-time methods. By pre-enrichment of maternal plasma samples this technique could readily be applied to the assessment of aneuploidy, providing a cheaper and more straightforward approach than current next-generation sequencing dependent methods to define aneuploidy.

14:50 Developing and Delivering a Non-Invasive Prenatal Diagnostic Service for Monogenic Disorders

Lucy_JenkinsLucy Jenkins, FRCPath, Lab Director, Great Ormand Street Hospital, London, United Kingdom

The development of NIPD for single gene disorders, and particularly the impact of next-generation sequencing technologies that have been used to extend our service repertoire, will be presented. Previously limited to de novo mutations or paternal exclusion testing, we have extended this approach to the implement bespoke test development for families with rare disease. NGS has now facilitated relative haplotype dosage analysis (RHDO) for the diagnosis of recessive conditions, even where parents carry the same mutation. Uptake of testing in the UK will be discussed along with issues that arise during NIPD delivery.

15:20 FEATURED POSTER: Looking to the Experience Obtained from Implementing Non-Invasive Prenatal Testing of Common Chromosomal Aneuploidies Using Cell-Free Fetal DNA in Iran

Mohammad Keramatipour, Ph.D., Assistant Professor, Genetics, Tehran University of Medical Science, Iran

15:35 FEATURED POSTER: Maternal Aneuploidy as a Cause of False Positive Noninvasive Prenatal DNA Screening Results

Jekaterina Shubina, Junior Researcher, Research Center for Obstetrics, Gynecology, & Perinatology, Russia

15:50 Refreshment Break in the Exhibit Hall with Poster Viewing

16:30 Panel Discussion with Cell-Free DNA Assay Providers

Michael_LutzMichael Lutz, CEO, Life Codexx AG, Germany

Samantha Leonard, International Medical Director, Natera, France

Stephen_LittleStephen Little, Ph.D., Chief Executive Officer, Premaitha Health, United Kingdom

Daniel_GrosuDaniel Grosu, M.D., MBA, Consultant, Integrated Genetics, United States

Gautam Kollu, Head of Market Development, RGH Market, Illumina Inc., United States

Maximillian_SchmindMaximilian Schmid, M.D., Senior Director of Medical Affairs, Medical Affairs, Roche Sequencing Solutions, United States

18:00 Welcome Reception in the Exhibit Hall with Poster Viewing

19:00 Close of Day Two


08:00 Registration and Morning Coffee


08:30 Chairperson’s Remarks

Patrizia Paterlini-Brechot, Ph.D., Cellular & Molecular Biology, University of

Paris Descartes, France

08:35 The Case for Cell-Based NIPT Using DNA from Fetal Cells

Ripudaman_SinghRipudaman Singh, Ph.D., COO, ARCEDI Biotech Aps, Denmark

In our previous studies we have shown that extravillous trophoblasts enriched from maternal blood using specific markers can be used to detect chromosomal and sub-chromosomal variations in the fetal genome. We present data from our clinical validation study which brings us a step closer to pursuing cell-based NIPT on all pregnancies, avoiding the use of invasive procedures.

09:05 Updated Results for Isolation and Genetic Characterization of Trophoblastic Cells for Prenatal Diagnosis of Genetic Diseases

Patrizia_Paterlini-BrechotPatrizia Paterlini-Brechot, Ph.D., Cellular & Molecular Biology, University of Paris Descartes, France

The development of a non-invasive alternative to the invasive approaches for prenatal diagnosis of genetic diseases requires the use of fetal DNA non-mixed with maternal DNA, thus the availability of cells carrying the fetal DNA. We have developed ISET, allowing the consistent recovery of trophoblastic cells from blood and cervical samples, and have developed methods for the extensive genetic analyses of the collected cells. We will present results of the use of trophoblastic cells isolated by ISET for non-invasive prenatal diagnosis of trisomy 21 and monogenic disorders and discuss the technical issues involved in bringing to the market this new approach.

09:35 Advances in the Isolation of Fetal Cells from Maternal Blood

Leonard Kellner, President, KellBenx, United States

The isolation of fetal nucleated red blood cells (fnRBC) in maternal blood allows for a non-invasive diagnostic test of the fetal genome. Methods to analyze these cells will be presented and discussed.

10:05 FEATURED POSTER: Performance of Four Modern Whole Genome Amplification Methods for Copy Number Variant Detection in Single Cells

Lieselot Deleye, Ph.D. Student, Pharmaceutical Sciences, Ghent University

10:35 Coffee Break in the Exhibit Hall with Poster Viewing

11:05 Closing Panel Discussion: Predicting the Landscape for Prenatal Molecular Diagnostics over the Next Few Years

Panelists to be Announced

12:05 Close of Advances in Prenatal Molecular Diagnostics Conference