The Future of Prenatal Diagnosis Envisioned by a Pioneer of NIPT – Benefits and Challenges Brought to the Field by Advances in Medical Genetics"

The Future of Prenatal Diagnosis Envisioned by a Pioneer of NIPT  – Benefits and Challenges Brought to the Field by Advances in Medical Genetics

Interview with Dr. Patrick Willems, Founder and Director of GENDIA Inc.

Due to the remarkable advancements in molecular genetics, Non-Invasive Prenatal Testing (NIPT) has become widely utilized. In contrast to traditional methods like maternal serum markers and combined screening, NIPT offers a revolutionary approach to prenatal diagnosis. It can be performed as early as 11 weeks into pregnancy, provides high accuracy, and carries no risk of miscarriage or stillbirth, which is estimated at 1 in 100 for chorionic villus sampling. In Japan, it is often referred to as a "new-type prenatal diagnosis," but ethical concerns regarding the handling of abnormal findings have led to discussions, causing a relatively low participation rate of 7%, lagging behind the rest of the world.

In this interview, we speak with Dr. Patrick Willems, a medical doctor and the Founder and Director of GENDIA, a company based in Belgium, a leading nation with a NIPT participation rate of 90 %. Dr. Willems shares insights into the services and policies of GENDIA, along with his perspective as a specialist on the future of NIPT and prenatal diagnosis.

**Interviewer:**Could you please tell us about your journey in the field of medical genetics?

**Dr. Willems:**After obtaining my medical doctorate from the University of Antwerp in Belgium, I pursued pediatrics at the University of Groningen in the Netherlands and later studied molecular genetics at the University of San Diego in the United States. From 1987 to 2000, I served as a professor of medical genetics at the University of Antwerp, where I was responsible for the diagnostic DNA laboratory and research activities for over a decade. My research primarily focused on the localization and isolation of disease genes associated with conditions such as mental retardation, deafness, and cancer. I have authored over 270 peer-reviewed scientific papers, including publications in renowned journals such as Cell, Nature Genetics, Nature Biotechnology, and the New England Journal of Medicine. Additionally, I founded the GENDIA network of genetic diagnostic labs, where I currently serve as the director.

The Current Status of NIPT and GENDIA's Position

**Interviewer:** Can you provide insights into the current utilization of NIPT worldwide?

**Dr. Willems:** It has been over a decade since Sequenom Inc. in the United States introduced the MaterniT21 test, a method that allows the detection of fetal chromosomal abnormalities from maternal blood. Today, NIPT is the most widely adopted genetic test globally, with the majority of Western countries implementing it as a routine procedure during pregnancy. The actual implementation and guidelines vary by country, but certain trends are evident. For instance, trisomies 13, 18, and 21, which account for approximately 75% of chromosomal abnormalities, are screened for in all pregnant individuals in most countries. Many countries also include sex chromosome aneuploidies (SCAs) in their screening programs. In fact, the 2023 guidelines from the International Society for Prenatal Diagnosis (ISPD) strongly recommend the former for all pregnant individuals and the latter with strong recommendations, acknowledging social, cultural, and legal differences.

**Interviewer:** However, Japan follows a different approach, with specific criteria, including maternal age, determining eligibility. The primary objective of NIPT in Japan is not mass screening but rather the reduction of the burden of invasive prenatal testing, as articulated by committees under the Ministry of Health, Labour and Welfare.

What about the cost?

**Dr. Willems:** The cost aspect is significantly influenced by the extent of insurance coverage and government guarantees in different countries. The most progressive nations in this regard are Belgium and the Netherlands. In the Netherlands, a nationwide state system covers all costs for all pregnant individuals, while in Belgium, insurance almost fully covers the testing expenses.

**Interviewer:** Under the current landscape surrounding NIPT, please provide an overview of GENDIA and its role as a research organization.

**Dr. Willems:** The name GENDIA stands for "GENetic DIAgnostic Network," and it represents an international network comprising over 100 genetic research laboratories in the United States, Europe, Asia, and Australia. GENDIA's mission is to enhance the accessibility, cost-effectiveness, and quality of genetic diagnostic methods on a global scale. The company offers a wide range of genetic testing services, including NIPT, encompassing more than 3,000 different genetic tests, currently available in many countries, including Japan.

**Interviewer:** When did GENDIA begin offering NIPT services?

**Dr. Willems:** GENDIA has been offering NIPT services for over a decade, serving numerous countries across different continents, including Japan. We have been utilizing Illumina's VeriSeq™ NIPT Solution v2, one of the most widely performed NIPT methods globally, for over five years.

GENDIA's technical capabilities and NIPT in practice

**Interviewer:** Tell us about the technological capabilities of GENDIA and the development process of NIPT.

**Dr. Willems:** As mentioned earlier, GENDIA currently offers Illumina's VeriSeq™ NIPT Solution v2. The implementation of this technology at our laboratory in Belgium was accomplished by a technology transfer from Illumina.

VeriSeq™ NIPT Solution v2 incorporates the Sequencing by Synthesis (SBS) chemistry, a system in which Illumina has a strong track record. It also utilizes "paired-end sequencing" technology, which facilitates the detection of gene fusions, novel transcriptional products, genome reconstruction, and repetitive sequence elements.

The actual sequencing is performed using the Illumina NextSeq™ 550Dx system, which has obtained the CE mark, indicating compliance with the In Vitro Diagnostic Devices Regulation (IVDR) when selling IVD medical devices. This platform enables high-throughput and high-speed next-generation sequencing (NGS) at an affordable cost.

Furthermore, this system is characterized by its "load and go" operation, with no time lost during execution, and it takes approximately 30 minutes for the actual process. With an intuitive user interface, minimal training and setup are required to execute the sequencing, and results are obtained approximately 26 hours later.

**Interviewer:** Could you please provide the sensitivity and specificity of the tests for each chromosome?

**Dr. Willems:** The sensitivity and specificity are very high for trisomy 13, 18, and 21, as well as for the sex chromosomes. The table below presents the clinical results for three autosomal chromosomes:

[Table - Sensitivity and Specificity Results]

(Translator's note: Detailed sensitivity and specificity figures would be provided in the actual table.) 

Table: About the three autosomes

**Interviewer:** Could you please explain the data processing of fetal DNA using this software?

**Dr. Willems:** Certainly. The average read count for fetal DNA fragments is 400 million. It's worth noting that the average percentage of fetal DNA present in the sample, which is approximately 10% at 10 weeks of pregnancy, is not influenced by the testing system itself. Biological external factors, such as gestational age, maternal weight, transport conditions, and delays, can affect this ratio.

**Interviewer:** Could you also provide details on the data analysis algorithms and authentication?

**Dr. Willems:** GENDIA utilizes advanced algorithms, with sequencing counted separately for each chromosome. Sequences read by the software undergo filtering and alignment to the reference genome. Scores reflect the normalized coverage of the tested chromosome or chromosomal subregions, aiding in the detection and differentiation of aneuploidies and copy number variations (CNVs).

Furthermore, the software generates estimated fetal fractions for each sample. This data, combined with other values, allows the evaluation of the state of aneuploidy.

**Interviewer:** What are the detection limits for the minimum amount and concentration of fetal DNA?

**Dr. Willems:** There isn't an actual "minimum" amount or concentration for detecting fetal DNA because the cutoff depends on the fetal DNA fraction relative to sequencing depth.

To minimize test failures, the software includes the individual fetal aneuploidy confidence test (iFACT) sample quality scoring index. iFACT takes into account the estimated fetal fraction of the sample and indicates whether sufficient sequence coverage and data quality have been generated for aneuploidy or CNV calling. This dynamic cutoff reduces test failures in cases with lower fetal DNA levels.

**Interviewer:** Regarding false positives and false negatives, what are the main causes?

**Dr. Willems:** The primary cause of false positives or false negatives in NIPT is confined placental mosaicism (CPM). CPM occurs when the genetic makeup of the placenta differs from that of the fetus. Since NIPT analyzes placental DNA, results in cases of CPM can lead to both false positives and false negatives.

**Interviewer:** Can you share any insights into the impact of gestational age and the percentage of samples requiring retesting (failures)?

**Dr. Willems:** If samples are taken from week 11 on the gestational age does not significantly impact the testing results. Overall, GENDIA's NIPT has an error rate, i.e., cases where NIPT results are not obtained, of less than 1%, which is remarkably low.

**Interviewer:** If NIPT results indicate an abnormality, what additional tests are typically conducted?

**Dr. Willems:** In Belgian healthcare facilities, when abnormalities are confirmed through amniocentesis, especially for trisomies 21, 18, and 13, pregnancy termination is usually considered. For sex chromosome aneuploidies (SCAs) such as Turner syndrome, Klinefelter syndrome, Triple X syndrome, and XYY syndrome, genetic counseling is extensively provided due to the milder phenotypic expression of SCAs.

Background on the NIPT penetration rate of "over 90 %."

**Interviewer:** Please explain the reason behind the NIPT participation rate of over 90 % in Belgium.

**Dr. Willems:** Even before the introduction of NIPT, the uptake of traditional tests like maternal serum markers and combined screening in Belgium was exceptionally high, at around 75%. Starting from 2017, the cost of NIPT is almost fully reimbursed by the Belgian national insurance, with a patient contribution of only 9 euros. Additionally, nearly all pregnant individuals have multiple obstetric visits, providing opportunities to learn about NIPT. Furthermore, in Belgium, medical reasons, including Down syndrome, are widely accepted as grounds for pregnancy termination, resulting in a high NIPT participation rate of approximately 90 % as of 2023.

**Interviewer:** What is the scope of conditions targeted by NIPT in Japan?

**Dr. Willems:** Currently, NIPT-certified facilities in Japan primarily focus on trisomies 21, 18, and 13, whereas there is a notable trend in non-certified facilities opting to test for chromosomes other than these three trisomies. The rationale for limiting the scope to these three common autosomal trisomies is partially based on the understanding that other autosomal trisomies rarely result in live births. Furthermore, these rare autosomal trisomies (RAT) usually are false-positive results.

Ethical point of view

**Interviewer:** Please explain the measures taken for protecting the privacy of test participants.

**Dr. Willems:** GENDIA complies with the European General Data Protection Regulation (GDPR) regarding the handling of personal information. GDPR came into effect on May 25, 2018, and automatically applies to individuals and companies processing personal data for business purposes. All personal data must be processed in compliance with GDPR.

To maximize the protection of personal information, GENDIA does not use patient names associated with personal information. Instead, codes are used. Consequently, personal information is always anonymized, and clients cannot submit patient names associated with personal information to GENDIA. If such information were submitted, it would be deleted from all networks and computer systems.

**Interviewer:** What are your thoughts on genetic selection?

**Dr. Willems:** GENDIA only offers optional gender determination upon client request. If there is suspicion that the client is considering termination based on gender, testing is declined. Moreover, testing is also refused if the purpose is non-invasive paternity testing.

From a DNA research perspective

**Interviewer:** What are the current challenges, issues, strategies to overcome them, and future prospects?

**Dr. Willems:** From the perspective of NIPT, the majority of cases target mild conditions (e.g., Down syndrome) or extremely rare chromosomal disorders characterized by fetal demise. In this regard, NIPT contributes only partly to reducing the number of children born with genetic conditions.

More than 1% of babies are born with single-gene disorders, which are often more severe than Down syndrome and include conditions like spinal muscular atrophy, cystic fibrosis, and Duchenne muscular dystrophy. Detecting these disorders requires whole exome sequencing along with invasive procedures like chorionic villus sampling (CVS) or amniocentesis (AC). Carrier screening for over 500 common and severe genetic disorders (STID) is available at GENDIA, serving as an affordable and non-invasive means of identifying carrier status for recessive genetic conditions.

Therefore, carrier testing may have a more significant potential impact than NIPT on reducing the number of children born with genetic conditions.

**Interviewer:** Finally, please comment on the current state of reproductive health in Japan from a reproductive health perspective.

**Dr. Willems:** In the context of reproductive health, every couple has the right to:

  1. Genetic counseling
  2. Affordable NIPT for chromosomal disorders
  3. Affordable carrier testing for single-gene disorders
  4. Pregnancy termination in cases of genetic conditions.

Japan is lagging behind most Western countries in these aspects. The World Health Organization (WHO) has issued a warning about low levels of reproductive health and rights in Japan. Greater awareness and efforts in this regard are much needed.


Patrick Willems received his MD from the University of Antwerp in Belgium. He was trained in Pediatrics at the University of Groningen in The Netherlands (Prof John Fernandes), and Molecular Genetics at the University of San Diego (Prof John O’ Brien). From 1987 to 2000 he worked at the University of Antwerp where he was Professor of Medical Genetics. For more than 10 years he was responsible for the diagnostic DNA laboratory and research activities.
Dr. Willems was involved in the localisation and isolation of several disease genes involved in mental retardation, deafness and cancer. He is the author of more than 270 peer-reviewed scientific papers in international journals, including many papers in top scientific journals such as Cell, Nature Genetics, Nature Biotechnology and the New England Journal of Medicine. Dr. Willems is director and founder of GENDIA, a network of diagnostic genetic labs.



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