Carrier Screening for Monogenic Disorders in Clinical Practice: Insights from Peking Union Medical College Hospital and BGI Genomics

Over a century ago, Mendel proposed the two fundamental laws of inheritance—the Law of Segregation and the Law of Independent Assortment—through his pea hybridization experiments. Perhaps he never imagined that genetics, founded upon Mendelian principles, would captivate thousands of scientists. Beyond the study and analysis of human identity, the more significant value of genetic research lies in elucidating the deepest mechanisms of disease. Within this context, the prevention and control of birth defects constitute a crucial component.

Relevant data indicate that among the more than 80 million people with disabilities in China, 70% have disabilities caused by birth defects. Eugenics and healthy childbirth have long been key components of China’s reproductive policy, and controlling the incidence of genetic diseases is a fundamental prerequisite for achieving these goals. The advent of non-invasive prenatal testing (NIPT) has provided a powerful tool for the prevention and control of birth defects, while the rapid development of this industry has offered critical support for the prevention and control of chromosomal aneuploidies.

Moreover, the field of birth defect prevention and control has witnessed a surge in sequencing technologies. In addition to chromosomal abnormalities, the prevention and control of other genetically related diseases are also poised to benefit. Genetic testing for monogenic disorders, as a relatively mature technology within the current gene sequencing industry, is gaining favorable attention from professionals. Recently, at the 14th International Conference on Genomics: Reproductive Health Clinical Applications (ICG14·RH), hosted by the China Birth Defects Monitoring Center, co-organized by the Birth Defect Prevention and Control Professional Committee of the Chinese Preventive Medicine Association, and undertaken by BGI Genomics, carrier screening for monogenic genetic diseases emerged as a hot topic among attending experts and scholars. Recognized as a means for large-scale screening and effective prevention of birth defects, this approach drew significant discussion.

In 2018, Peking Union Medical College Hospital, in collaboration with BGI and eight other hospitals across different regions of China, jointly launched the “China Multicenter Carrier Screening Project for Common Monogenic Diseases in Pregnant Women.”, and has achieved certain results through one year of practice. To this end, VCBeat interviewed Professor Jiang Yulin from Peking Union Medical College Hospital and Dr. Peng Zhiyu, Chief Product Officer at BGI Genomics, to discuss their practical experiences in implementing carrier screening for monogenic inherited diseases.

Professor Jiang Yulin, Peking Union Medical College Hospital

Dr. Peng Zhiyu, Chief Product Officer at BGI

Monogenic genetic disorders refer to hereditary diseases controlled by a single pair of alleles. Common examples include thalassemia, hemophilia, and hereditary deafness. Since the 1970s, efforts have been underway to explore screening for monogenic genetic disorders.

“Diseases targeted by early screening mainly fall into two categories: the first is ethnicity-related, with high prevalence in specific populations; the second is region-related, involving screening in specific areas, such as for thalassemia,” explained Jiang Yulin. Since 2001, expanded carrier screening has been implemented abroad to proactively prevent monogenic genetic disorders through screening for hotspot mutations.

In China, as the competitive landscape for NIPT stabilizes, carrier screening for monogenic genetic disorders is becoming a common strategy for market leaders to expand their businesses and for startups to enter the industry. “Domestic attention is also growing; it may not be a hotspot right now, but it will be soon,” he added.

NIPT is currently the most clinically mature application of genomic medicine solutions and is widely recognized by the public; however, carrier screening for monogenic genetic diseases remains in its early stages of adoption in China. Jiang Yulin summarized several reasons for this disparity, one of which is the lack of public awareness regarding the prevention and control of genetic diseases.

“Most people believe that genetic screening is unnecessary if there is no family history of genetic disorders, and even some highly educated couples may not fully understand its importance,” stated Jiang Yulin. Due to a lack of understanding of the pathogenesis of genetic diseases, it is difficult for patients to comprehend when physicians discuss “disease risk.” Furthermore, knowledge among some physicians is also limited, with many encountering these conditions for the first time. “This makes it challenging to educate expectant couples,” he added.

Meanwhile, the role of genetic counseling should not be overlooked. “If both partners are found to carry pathogenic mutations for the same monogenic disorder, they need to seek genetic counseling,” said Jiang Yulin. “However, we still need to make more preparations in this area.”

Of course, the most critical consideration here is ethical in nature. There are many types of monogenic disorders; some are lethal, teratogenic, or disabling, while others present with milder symptoms. Even if screening results indicate a high probability of disease (though not 100% certainty), some couples may still perceive the potential child as imperfect.

“Therefore, we have chosen to screen for severe diseases that are fatal, teratogenic, or disabling, with relatively well-defined pathogenic loci. Although all are genetic disorders, their severity varies,” emphasized Peng Zhiyu. For non-fatal, mild conditions such as certain types of hereditary deafness, he recommends newborn screening instead: “Genetic variants and phenotypes do not always correlate perfectly; some cases may be mild. Furthermore, cochlear implants can be used as an intervention after birth.”

Jiang Yulin expressed agreement, stating that in addition to strict regulations and guidelines, the selection of screening loci must be rigorous. If the pathogenic loci are not clearly defined, screening loses its significance.

Cost is also a significant factor. Although the emergence of domestically produced sequencers has further reduced sequencing costs, the prices of most next-generation sequencing (NGS) testing products remain some distance away from universally affordable levels. “This is a challenging issue that may require joint efforts from the government, insurance providers, and enterprises,” revealed Jiang Yulin. “Our research project in collaboration with BGI offers free enrollment; however, gaining widespread clinical acceptance will take time.”

Peng Zhiyu revealed that at the current stage, with the localization of sequencers, as well as the expansion of sequencing scale and the enhancement of sequencing automation, there is a possibility for product costs to decrease.

Expanded carrier screening for monogenic disorders has been widely adopted in clinical practice abroad. “China’s technological research in this area is already quite mature. The current challenge lies in how to effectively integrate it into clinical practice,” said Jiang Yulin.

As early as 2012, BGI Genomics had already begun building its technical reserves for single-gene disorder screening, developing screening panels covering more than 100 diseases. Its collaboration with Peking Union Medical College Hospital represented an exploration into integrating these technologies with clinical practice.

In addition to technical advancements, screening for monogenic disorders also requires careful consideration of communication and counseling with carriers. “We need to explain the results to carriers, provide them with genetic counseling, and help them undertake early interventions,” said Peng Zhiyu. Jiang Yulin believes that while China’s high-throughput sequencing technology is at the forefront in clinical applications, successful implementation must be tailored to the specific characteristics of each country and ethnic group. “The experience gained from NIPT can serve as a reference,” he added.

“NIPT technology reached maturity relatively early, but it did not gain significant clinical acceptance until 2014. This trajectory can serve as a reference for us,” added Peng Zhiyu. “If all goes well, we may see breakthroughs within the next two to three years.”

In summary, the widespread clinical application of carrier screening for monogenic disorders in China still faces numerous challenges. Issues ranging from the selection of testing panels and determination of the optimal screening stage, to post-screening genetic counseling and reproductive guidance, as well as market awareness and product pricing, require continuous reflection and improvement by clinical and testing institutions. In the future, carrier screening for monogenic disorders may achieve widespread adoption comparable to that of non-invasive prenatal testing (NIPT). However, this will require concerted efforts from government authorities, clinical institutions, and testing laboratories to further advance the prevention and control of birth defects.