Widely recognised as one of Korea’s top experts in rare genetic diseases, Prof Jong-Hee Chae serves as Professor in the Department of Clinical Genomic Medicine and Director of the Rare Disease Centre at Seoul National University Hospital (SNUH), one of the country’s leading academic medical institutions.

Among her many responsibilities, Prof Chae plays a key role in several important projects aimed at improving rare disease diagnostics in Korea. In a recent discussion with Lab Insights, she shared updates on her work and reflections on what’s needed to shorten the diagnostic odyssey for patients.

Clinical diagnostics at the SNUH Rare Disease Centre

Established in 2010, the SNUH Rare Disease Centre positions itself as the first multi-disciplinary, integrated medical system for rare disease patients in Korea. As Director of the centre, Prof Chae oversees over 70 individual clinics for paediatric and adult patients (she also practises as a paediatric neurologist and sees patients at SNUH Children’s Hospital).

For patients who are not yet diagnosed, the SNUH Rare Disease Centre offers some of the most sophisticated genetic testing operations in Korea. While most children’s hospitals around the country have the capacity to conduct routine genetic testing, such as with commercially available NGS panels and microarrays, SNUH tends to take on the most complex and challenging cases.

A major area of focus for the SNUH Rare Disease Centre is rapid genomic sequencing of symptomatic patients. Compared to more routine genetic tests, which can often take months to complete, Prof Chae’s centre is typically able to deliver results in a few weeks or less, especially for urgent cases in the neonatal or paediatric intensive care units. These rapid services are not covered by Korea’s national health insurance programme, but funding is sometimes available through the hospital, public health projects, or local NGOs.

Prof Chae and colleagues at the SNUH Rare Disease Centre

One approach to rapid testing at the SNUH Rare Disease Centre is via an NGS panel that Prof Chae co-developed with MedySapiens, a local private company that develops products and services at the intersection of cutting-edge AI, bioinformatics and genomics. The panel covers approximately 270 genes, primarily for conditions for which highly effective treatments are available in Korea. This gene list is updated regularly to keep pace with the latest developments in genomic medicine and reimbursement.

Compared to more comprehensive sequencing services available in Korea, the NGS panel at the SNUH Rare Disease Centre has a lower cost and faster turnaround time, according to Prof Chae. It can also be used with the same dried blood spot (DBS) material from the standard newborn screening tests that virtually all newborns receive in Korea, so it does not necessarily require additional blood draws or large sample volumes, which are sometimes inadvisable with neonates or children in critical condition.

For patients suspected of having a condition that’s not on the panel, or who have already been through more routine genetic testing at other centres, another option is to go for trio-based rapid whole exome or genome sequencing (rWES/rWGS). This is more likely to deliver a result than panel testing, says Prof Chae, but it also requires an additional blood draw from the patient and both parents, as well as more clinical and informatics expertise to interpret the results.

rWES and rWGS are also more costly than panel testing. They are not covered under national insurance, but funding is sometimes available through programmes like the Lee Kun-Hee Childhood Cancer & Rare Disease Project, a 10-year research and public health initiative that includes $60 billion won (USD $44 million) to support diagnostic and clinical services for paediatric rare diseases [1]. Much of the testing and coordination for this initiative happens through SNUH, though funds are distributed across many centres in Korea.

Driving research in rare disease diagnostics

Even with all the high-powered testing available at the SNUH Rare Disease Centre, Prof Chae laments that more than half of patients at her clinic still struggle to get an accurate and timely diagnosis. For that reason, she also spends a lot of time contributing to genomic research projects that aim to drive innovations in testing, increase the diagnostic yield, and improve overall quality, speed and cost.

Korea has a robust entrepreneurial ecosystem in the genetic testing space, and some of these projects are driven through partnerships with private companies. As one example, Prof Chae collaborates with 3billion, a provider of rare disease testing and technology services, to develop an AI-based genetic variant software based on genotype-phenotype data. She says their system already has impressive analytic power for rare variants, and is still improving.

Solving many of Korea’s most complex cases through research and collaboration

Prof Chae also collaborates with many public sector research projects, notably the Korea National Project of Bio Big Data (NPBBD), a multi-ministerial initiative to develop datasets that combine genomic and clinical information for the Korean population. Launched in 2020, the project was initially piloted on a cohort of rare disease patients. SNUH was one of the leading centres in this project, bringing in thousands of patients for trio-based WGS testing as part of this initial cohort.

In recruitment efforts for the pilot phase of Korea biobank project, Prof Chae says they focused primarily on undiagnosed cases, as well as patients with known rare diseases where the outcomes have high clinical variability, such as with Duchenne muscular dystrophy or Rett syndrome, and where WGS data holds greater potential to provide clues for treatment development. They are currently analysing these data for that purpose.

Similar to other public sector biobank projects in other countries, NPBBD is now in the process of launching a second phase that aims to recruit a larger cohort of up to 1 million patients, including those with more common diseases and healthy controls, as well as more patients with rare diseases. Prof Chae remains an advisor to this project, encouraging its leaders to develop robust plans for sharing the data with researchers and also to incorporate long-read sequencing data in the next few years.

Prof Chae is also deeply involved in the Korea Undiagnosed Diseases Programme (K-UDP), a member of Undiagnosed Diseases Network International (UDNI). In addition to helping launch the programme in Korea and publish the results of its efforts [2], she is planning to host the 10th anniversary meeting of UDNI on September 5-7, 2024 at SNUH in Seoul.

A vision for newborn screening in Korea

Among its many activities in rare disease research and diagnostics, SNUH operates one of the country’s newborn screening (NBS) labs. Funded by the Korean government, the public NBS system provides biochemical testing for more than 60 conditions, according to Prof Chae.

While many countries around the world are in the process of adding molecular tests to their NBS panels for conditions like SMA and SCID, Prof Chae points out that Korea’s public NBS system does not include any genomic screens. At present, Korea’s national insurance only covers diagnostic-grade genomic testing for symptomatic patients. Moreover, local laws require special consent for genetic testing, creating extra administrative work for clinicians and disincentives for deploying molecular tests in the private market.

To supplement the government-funded NBS panel, many Korean parents purchase services that are known as ‘G-scanning’ in the local market. These are basically chromosomal microarrays for microdeletions and duplications in asymptomatic children, says Prof Chae. They are offered by many local companies and advertised heavily at birthing centres. They are not covered by Korea’s national insurance, but they are included in some private insurance plans.

Prof Chae dreams of improving rare disease screening and diagnostics in Korea

Prof Chae feels this NBS system is suboptimal for patients. She would like to see more molecular tests incorporated into both public and private NBS panels, and also to see large-scale research projects to evaluate the potential of next-generation sequencing for NBS in Korea. Such projects are already happening in many other advanced countries around the world, but not yet in her country.

“We have to make an effort to improve genomic newborn screening,” she says. “Even though the birth rate is decreasing, interest from parents in caring for their babies is increasing more and more. The G-scanning services mostly detect conditions where we don’t have much we can do clinically. We need to find a better way to help the children that can benefit most.”

Given the continued uptake of genomic NBS in so many other countries, its adoption in Korea might seem inevitable. Even so, it will take hard work from stakeholders across the ecosystem and leadership from rare disease pioneers like Prof Chae to deliver the change that rare disease patients and their caregivers so desperately need.

This article was written by Will Greene, Healthcare Engagement Lead at Roche Diagnostics Asia Pacific, with support from the team at Roche Diagnostics Korea and Roche Pharmaceuticals Korea. The author wishes to acknowledge the input of other experts in rare disease diagnostics that provided background information for this writeup, including Dr Myungshin Kim, Professor in the Department of Laboratory Medicine at Seoul St Mary’s Hospital, College of Medicine, Catholic University of Korea; Sanggo Kang, CEO of MedySapiens; and Changwon Keum, CEO of 3billion.

References:

[1] http://www.snuh.org/global/en/about/newsView.do?bbs_no=6483
[2] Kim, S.Y. et al. (2022) ‘The Korean undiagnosed diseases program phase I: Expansion of the Nationwide Network and the development of long-term infrastructure’, Orphanet Journal of Rare Diseases, 17(1). doi:10.1186/s13023-022-02520-5.

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