Prenatal Molecular Diagnostics

Arrays and next-gen sequencing are having a dramatic impact on the landscape for prenatal molecular diagnostics. The specifics from one country to another vary widely across Europe, and there are significant differences from key patterns in the U.S. market. The performance and reduced risk from non-invasive tests accounts for a significant drop in the level of invasive diagnostics. European clinics have more options for carrying out non-invasive testing in-house, compared to other parts of the world where the model of sending samples out for central testing services is predominant. And while next-gen sequencing of cell-free DNA has garnered most of the commercial attention, advances in the non-invasive isolation of fetal cells from maternal blood could make this an attractive competitive approach in the next few years.

Besides technology and different business models, there are numerous important issues to be addressed related to implementation of changes in molecular prenatal diagnostics, including who should be offered non-invasive testing, with what timing, testing for single gene disorders, cost analysis and the impact on genetic counseling needs. This program provides a unique opportunity to hear from and compare the leading vendors of non-invasive tests based on cell-free DNA as well as the groups looking to commercialize non-invasive isolation and analysis of fetal cells.


12:00 – 13:00 Registration

13:00 Chairperson’s Opening Remarks

Marta Rodriguez de Alba, Ph.D., Genetics, Fundación Jiménez Díaz, Spain


Wybo DondorpWybo Dondorp, Ph.D., Associate Professor, Biomedical Ethics, Health, Ethics & Society, Maastricht University, The Netherlands

In the light of the thrust of the dynamics in prenatal screening towards genome wide & non-invasive testing, the received ethical framework with its emphasis on facilitating autonomous reproductive choice is in need of qualification, taking account of a) the ‘paradox of choice’, b) the informational privacy interests of the future child and c) the fact that increasingly, prenatal screening will serve prevention-aimed outcomes in addition to reproductive choice.

Invasively-Obtained Samples

13:55 Molecular-Cytogenetic Analysis of Invasively-Obtained Samples, Are We Getting More Comfortable with It? The Lab-Side Point of View

Marta_Rodriguez_de_AlbaMarta Rodriguez de Alba, Ph.D., Genetics, Fundación Jiménez Díaz, Spain

The incorporation of the different emerging technologies applied to the field of prenatal diagnosis has varied throughout Europe. It has been mainly dependent on economic issues but also on the expertise of providers. Since genetic analysis of prenatal samples is usually performed in Services also offering postnatal diagnosis, providers have acquired the expertise testing those samples and therefore started to feel more comfortable with the interpretation of results in prenatal samples. The reasons for referral vary and although many articles support the idea that array-CGH technology should only be applied in specific cases, in many occasions the sample is referred to the Genetic Department with a mild indication and therefore, many concerns arise.

14:25 Prenatal Array Testing – How Unexpected Is the Unexpected?

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

Microarray is still not widely used in diagnostic laboratories across Europe, although it is already recommended for fetuses with congenital anomalies and may also be done in other cases referred for invasive testing. Unexpected diagnoses and incidental findings (in parental samples) are arguments against microarray especially in pregnancies without ultrasound anomalies. We would like to show all unexpected diagnoses as well as incidental findings that we encountered since 2010, to show that whole genome analysis with array may be favorable in prenatal diagnosis and to answer the question how unexpected is the unexpected.

14:55 Refreshment Break

15:30 Why Should We Implement aCGH as the First-Tier Test in All Invasive Prenatal Samples?

Julian_NevadoJulian Nevado, Ph.D., MBA, Genetics, Hospital Universitario La Paz (IdiPAZ), Spain

We evaluated the effectiveness of whole-genome array comparative genomic hybridization (aCGH) in prenatal diagnosis in a routine genetic laboratory. Array CGH was performed on 315 samples recruited prospectively as the first-tier test study during the last 3 years. In addition, 77 prenatal samples with abnormal fetal ultrasound findings found to have normal karyotypes were analyzed as a retrospective study using a custom Agilent-based 60K oligonucleotide array. In both cases, aCGH offered higher yields than conventional karyotype. Thus, for cost-effectiveness reasons among others that we discussed, we proposed aCGH in all invasive prenatal diagnosis as a first-tier test in combination with QFPCR to exclude common aneuploidies, triploidies and maternal cell contamination.

16:00 Invasive Confirmatory Procedure after a High-Risk cfDNA Test Result: May the Type of Detected Chromosomal Abnormality Influence the Choice of Diagnostic Procedure?

Francesca_Romana_GratiFrancesca Romana Grati, Ph.D., Director, R&D, TOMA Advanced Biomedical Assays SpA, Italy

Cell-free DNA (cfDNA) screening tests use cell-free fetal DNA sequences isolated from maternal blood samples to evaluate the presence of fetal chromosome anueploidies and microdeletions. Currently, there is debate about the most appropriate confirmatory invasive method. The present study is aimed to discuss about the criteria for choice of i) the diagnostic invasive procedure basing on the chromosome specific likelihood of fetoplacental mosaicism and of ii) the laboratory diagnostic test that should be applied on invasively collected sample/s basing on the type of chromosome abnormality for which the cfDNA testing provided a high risk result.

16:30 Roundtable Breakout Discussions

  • TABLE 1:  Challenges of Ethics and Genetic Counseling
    Moderator: Wybo Dondorp, Ph.D., Associate Professor, Biomedical Ethics, Health, Ethics & Society, Maastricht University, The Netherlands
  • TABLE 2:  Trends with Analysis of Invasively-Obtained Samples
    Moderator: Marta Rodriguez de Alba, Ph.D., Genetics, Fundación Jiménez Díaz, Spain
  • TABLE 3:  Clinical Implementation Issues with Cell-Free DNA Testing
    Moderator: Dick Oepkes, Professor, Obstetrics and Fetal Therapy, Obstetrics, Leiden University Medical Center, The Netherlands
  • TABLE 4:  Testing beyond Common Aneuploidies
    Moderator: Daniel Grosu, M.D., MBA, CMO, Sequenom, Inc., United States
  • TABLE 5:  Commercialization Potential for Isolated Fetal Cells
    Patrizia Paterlini-Brechot, M.D., Ph.D., Professor, Cellular and Molecular Biology, University of Paris Descartes, France
  • TABLE 6:  Biomarkers for Preeclampsia and Pre-Term Labor
    Moderator to be announced

17:30 Close of Day One

TUESDAY, 5 April

Non-Invasive Testing Based on Cell-Free DNA

8:00 Registration and Morning Coffee

9:00 Chairperson’s Remarks
Dick Oepkes, Professor, Obstetrics and Fetal Therapy, Obstetrics, Leiden University Medical Center, The Netherlands

9:05 Intellectual Property and NIPT: Controversies and Concerns

Naomi Hawkins, DPhil, Senior Lecturer, University of Exeter, United Kingdom

As in other fields of medicine, and human genetics in particular, patents in NIPT generate controversy and concern. Anxieties surrounding the possibility for patents to result in increased costs, administrative burdens and ultimately, a negative effect on healthcare in this developing field of genetic medicine are voiced by many. It is apparent that commercial interests are highly involved in the development and delivery of NIPT, and patents are an important means of leveraging competitive positions. At present, the patent landscape is contested, with various commercial parties in disputes about patents and the legitimacy of their various testing technologies. Such disputes have implications for commercial and public sector testing. Key patent issues relevant to NIPT and the potential impact of patents on the development of this field will be discussed.

9:35 Cell-Free DNA as a First Line Test vs. Contingent Screening: Perspective from Patients

Dick_OepkesDick Oepkes, Professor, Obstetrics and Fetal Therapy, Obstetrics, Leiden University Medical Center, The Netherlands

Screening for chromosomal abnormalities in the fetus is a service to (anxious) pregnant women. For professionals, optimal quality is often equal to highest test performance. For patients, or actually pregnant women since they are not ill themselves, safety, short waiting time and avoidance of living in uncertainty for weeks are equally important. Although on paper, contingent screening may have benefits in terms of reasonably high accuracy against reasonable costs, the prolonged waiting time and especially the ‘intermediate’ bad news message that further testing is needed before we can reassure her, is a very serious drawback for the pregnant woman. Complexity of counseling is another disadvantage. Working towards reducing the costs of a fast and reliable one-step screening appears preferable.

Cartagenia10:05 The Next Generation of Cell-Free DNA Analysis: a Visual Platform for Chromosomal Aneuploidy Research

Steven Van Vooren, Ph.D., Product Marketing Manager, Cartagenia

As the demand for cfDNA testing grows, analytical methods for detecting chromosomal aneuploidies in NGS samples are in high demand. Cartagenia, a part of Agilent Technologies, has developed OneSight, a user friendly, state-of-the art bioinformatics solution for the visual analysis of chromosomal aneuploidies in NGS samples.

10:20 Implementation of Seraseq™ Aneuploidy Reference Materials for Non-Invasive Prenatal Screening

Laurence Lohmann, Ph.D., Medical Genetics Director, Laboratoire CERBA

As the market for NIPT expands from high-risk to general population, there is a greater need for patient-like reference materials to monitor the accuracy of assay results. In this presentation, we describe our NIPT assay development, including the importance of using robust and multiplexed reference materials.

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


Maximillian Schmid, M.D., Associate Director, Medical Affairs, Ariosa, United States

Michael Lutz, Ph.D., CEO, Life Codexx, Germany

Solomon Moshkevich, Vice President, Product & Strategy, Natera, United States

Hari Radhakrishnan, PhD, Commercialization Manager, NIPD Genetics, Cyprus

Stephen Little, Ph.D., CEO, Premaitha Health, United States

Daniel Grosu, M.D., MBA, CMO, Sequenom, Inc., United States

Vanadis Diagnostics12:45 Luncheon Presentation: Non Invasive Prenatal Testing by Digital Counting of Fluorescently Labeled DNA Molecules

Olle Ericsson, Ph.D., CEO, Vanadis Diagnostics

Several countries have implemented Non Invasive Prenatal Testing (NIPT) to analyze chromosomal abnormalities in high-risk pregnancies. The majority of these tests are performed using next generation sequencing technologies that provide both superior specificity and sensitivity compared to traditional first trimester screening. However, in order to provide all women with high performance prenatal screening, the NIPT assay cost and complexity need to be dramatically reduced. We present a new Smart NIPT platform, that by by eliminating sequencing, PCR and complex data analysis enables cost effective automated high throughput NIPT screening.

13:15 Session Break

14:15 Chairperson’s Remarks

Philippos Patsalis, Ph.D., Distinguished Professor, The Cyprus Institute of Neurology & Genetics and CEO, NIPD Genetics, Cyprus

14:20 Multiplexed Parallel Analysis of Targeted Genomic Regions for Non-Invasive Prenatal Testing

Phillipos_PatsalisPhilippos Patsalis, Ph.D., Distinguished Professor, The Cyprus Institute of Neurology & Genetics, and CEO, NIPD Genetics, Cyprus

A novel targeted assay for the detection of fetal aneuploides of chromosomes 21, 18 and 13 has been developed by NIPD Genetics. It is based on the capture and analysis of selected genomic regions of interest. An advanced fetal fraction estimation and aneuploidy determination algorithm has also been developed. The analytical performance of this assay will be reviewed. The potential impact of this assay as an accurate and cost-effective option for non-invasive aneuplody detection will be discussed.

14:50 The IONA Test: CE-IVD – A Technical Update

Stephen Little, Ph.D., CEO, Premaitha Health plc, UK

Mike Risley, Ph.D., Chief Development Officer, Premaitha

Focusing on the technical aspects of the IONA® test and the background to why the test has been developed using certain innovative methods. These include a dynamic fetal fraction assessment method and the result output of a likelihood ratio, ideal for prenatal screening as it can be combined with prior risks. Additional features include Premaitha Workflow Manager, world class Technical Support and bespoke analysis software.

15:20 Genome-Wide Prenatal Cell Free DNA Testing: Validation and Clinical Experience

Grosu_DanielDaniel Grosu, M.D., MBA, CMO, Clinical and Medical Affairs, Sequenom, Inc., United States

A significant proportion of chromosomal and subchromosomal abnormalities in the prenatal setting are not detectable by conventional cfDNA testing. Most of this informational gap can be bridged through a genome-wide approach that reports on CNVs ≥7 Mb in size across the entire genome, in addition to select microdeletions <7 Mb.

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

16:30 Advances in the Non-Invasive Prenatal Diagnosis of Mendelian Disorders using Digital-PCR

Ana_Bustamante_AragonesAna Bustamante Aragones, Ph.D., Assistant Head, Genetics, Fundación Jiménez Díaz, Spain

Non-invasive prenatal diagnosis (NIPD) based on the analysis of maternal blood is currently offered worldwide in prenatal diagnosis units. However, to date NIPD for Mendelian disorders is only being offered for paternal and de novo mutation exclusion and the study of the maternal inheritance remains challenging. This work shows a validation study of digital PCR (ddPCR) technology for the analysis of both paternally and maternally inherited fetal alleles.

17:00 Bringing NIPT to the Next Level: Detection of Fetal Trisomy based on Quantitative Real-Time PCR

Lutz_Michael2Michael Lutz, CEO, LifeCodexx, Germany

We will present data of the PrenaTest® based on a quantitative real-time PCR (qPCR) for the determination of fetal trisomy 21. From a total of 261 samples all 17 samples positive with trisomy 21 were correctly classified, resulting in a sensitivity and specificity of the new assay of 100%. While qPCR presents a more cost-efficient solution over NGS, the new assay will also be able to provide results in 72 hours or less.

17:30 Genomic Signatures Associated with Spontaneous Preterm Birth

Iya_KhalilIya Khalil, Ph.D., Executive Vice President and Co-Founder, GNS Healthcare, United States

Molecular markers associated with spontaneous premature birth (<37 weeks gestation) have been difficult to identify owing to heterogeneous clinical presentations and a multiplicity of pathways that regulate parturition. We analyzed genetic, molecular, and clinical data of expectant families to identify markers for longitudinal prenatal analysis and risk prediction using a big data machine learning analytics approach. Preterm birth was found to be associated with multiple markers and risk factors, which are potentially useful to predict gestational duration.

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

19:00 Close of Day Two


Fetal Cell Isolation and Analysis

8:00 Registration and Morning Coffee

8:40 Chairperson’s Remarks

Patrizia Paterlini-Brechot, M.D., Ph.D., Professor, Cellular and Molecular Biology, University of Paris Descartes, France

8:45 Advances in the Use of Trophoblastic Cells for Prenatal Non-Invasive Diagnostics of Genetic Disorders

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

Non-Invasive Prenatal Diagnosis is technically bound to the challenge of analyzing rare fetal DNA sequences, extracted from blood along with maternal DNA sequences, or rare trophoblastic cells, extracted from blood or cervical samples along with maternal cells. Our results show that ISET allows the consistent recovery of trophoblastic cells from blood and cervical samples and the feasibility of using the trophoblast-derived fetal DNA for noninvasive prenatal diagnosis (NIPND). The advantages and limitations of using fetal cells versus those of using cell-free DNA for developing non-invasive prenatal diagnostic tests will also be discussed.

9:15 Recent Advances in the Enrichment and Characterization of Fetal Cells in Maternal Blood

Steen_KlovraaSteen Kolvraa, Ph.D., CSO, ARCEDI Biotech, Denmark

Using expression array data, we have previously indicated that a major fraction of the fetal cells circulating in the blood of pregnant women are endovascular trophoblasts. Based on this, we had developed a method for the isolation of these fetal cells with the aim of doing cell-based NIPT. We have since then refined our procedure resulting in both higher fetal cell yield and better fetal cell specificity. These new results will be presented and discussed. Fetal DNA from circulating fetal cells is most likely of higher quality than free circulating fetal DNA and may therefore enable detection of more sub-chromosomal aberrations than NIPT based on circulating free fetal DNA. Knowledge on the present status on cell-based NIPT will also be presented.

9:45 Progress in Isolation and Analysis of Fetal Nucleated Red Blood Cells

Leonard Kellner, M.S., President, KellBenx, Inc., United States

Prenatal screening and diagnostics have changed forever. Karyotype (55 years) and MSS (35 years), since they were introduced, are feeling the pressures of the introduction of microarrays, next-gen and newer sequencing. The performance and reduced risk from non-invasive tests account for a significant drop in the level of invasive diagnostics. NIPT alone or as a reflex test in combination with MSS are being accepted around the world. With techniques used in pre-implantation genetics, and the ability to isolate fNRBC; the elusive diagnostic test using fetal cells may soon be realized.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Image-Based Single Cell Sorting to Identify and Recover Fetal Cells Using the Deparray Platform

Farideh_BischoffFarideh Bishoff, Ph.D., Executive Director, Scientific Affairs, Silicon Biosystems, United States

DEPArrayTM is an innovative technology platform capable of sorting and isolating 100% pure single or pooled cells through a digitally controlled Dielectrophoretic field using a semiconductor chip. Single target cells can be isolated from enriched blood while pools of tens to hundreds of pure cells can be recovered from fixed tissue blocks. Thus, the DEPArray offers the potential for pre-analytical cell-type purification for downstream molecular analysis, which is a major step forward for precision medicine in oncology and prenatal genetics. Applications for recovery of fetal cells from maternal blood, placental tissue (to address heterogeneity and confined mosaicism) and products of conception will be addressed.

11:15 PANEL DISCUSSION Predicting the Landscape for Prenatal Molecular Diagnostics in Europe

Marta_Rodriguez_de_AlbaMarta Rodriguez de Alba, Ph.D., Genetics, Fundación Jiménez Díaz, Spain


Wybo_DondorpWybo Dondorp, Ph.D., Associate Professor, Biomedical Ethics, Health, Ethics & Society, Maastricht University, The Netherlands

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

11:45 Close of Conference