With ongoing advances in next-generation sequencing (NGS) technology, clinical geneticists and researchers around the world are exploring the role of whole exome sequencing for rare disease diagnostics. In the Asia Pacific region, Taiwan is emerging as a leader in the use of exome sequencing for both research and clinical applications.

Compared to single gene or panel testing, whole exome sequencing (WES) holds substantial promise to improve the speed and accuracy of diagnostics for rare genetic diagnostics. By interrogating the entire exome—the portion of the genome that codes for proteins—WES increases the odds that a diagnosis will be obtained quickly and decisively.

For rare genetic diseases, the benefits of rapid and accurate diagnosis are getting clearer all the time. For patients and their caregivers, it reduces the cost and emotional challenges associated with lengthy diagnostic journeys, and also opens opportunities for early treatment that can save or improve lives. For healthcare systems, a growing body of evidence suggests that speedy diagnosis through sequencing can reduce total healthcare spending as well [1].

To explore how WES is being used in Taiwan, a country that excels in many aspects of clinical genetics research and rare disease care, Lab Insights recently spoke with several of Taiwan’s leading geneticists. They all expressed a strong preference for WES over panel testing, but point to various barriers that still limit access for some patients.

Regular and rapid exome sequencing at NTUH

One institution that is ramping up its use of WES is National Taiwan University Hospital (NTUH), a leading public hospital in Taipei with deep experience in paediatric genomic medicine. Its facilities include an NGS lab that conducts research and supports rare disease diagnostics (it also houses one of Taiwan’s three main newborn screening centres). Approximately three thousand WES tests have already been performed at the hospital.

Despite having developed several of its own genetic disease panels over the years, NTUH is phasing some of them out in favour of WES, according to Dr Ni-Chung Lee, a Clinical Professor in the Department of Pediatrics who leads various NGS projects alongside Dr Wuh Liang Hwu, Dr Yin-Hsiu Chien, and other leading NTUH researchers in the field.

“In the lab, we often prefer to do exome sequencing because we’re not always sure if the gene lists covered behind a panel order are comprehensive enough to solve this patient,” says Lee. “We hope to find the answer in one test, but the decision of what to order is still usually driven by the clinician in consultation with the patient.”

In addition to regular WES testing, Dr Lee and colleagues also developed a rapid trio exome test for children in need of urgent diagnosis, such as those who end up in neonatal or paediatric intensive care units for unknown causes. This testing is available with a turnaround time of roughly one week (routine and non-urgent cases sometimes take closer to 2-3 months to ensure adequate time for interpretation).

Since 2016, the NTUH Genetics team has also developed an AI-based variant prioritiser to facilitate the diagnosis of rare diseases from WES/WGS. This tool won several major awards in Taiwan [2].

Managing costs and improving analytics at VGH

At Taipei Veterans General Hospital (VGH), another leading public hospital in Taipei with a strong reputation in paediatric genomic medicine, a similar commitment to research and innovation is driving greater uptake of exome sequencing.

“We used to use targeted panels but now we’re totally abandoning this approach for whole exomes or genomes,” observes Dr Dau-Ming Niu, Director of the Department of Pediatrics, the Genetic Counseling Center and the Rare Disease Medical Research Center at VGH. “Cost is still a factor for some patients, but we do everything we can to minimise the burden and make these tests accessible.”

As one of the country’s leading clinician-researchers, Dr Niu says he has performed whole exome or genome sequencing more than a thousand times, a process that includes everything from ordering the tests to delivering the results and providing the requisite genetic counselling. He says that explaining results is relatively easy when the diagnosis is clear, but much harder in the case of uncertain causes.

To improve the data interpretation process, VGH is currently working with an external AI company to develop an advanced bioinformatics platform. Their vision is to build a comprehensive “precision medicine aid” that not only supports diagnosis of complex inherited diseases, but also includes other functions like pharmacogenomics and carrier screening.

Exomes for epilepsy research at CGMH

Several of Taiwan’s private sector hospitals and clinics are also participating in exome sequencing research too. One example is the Chang Gung Memorial Hospital (CGMH) system, a major hospital network with branches across the country, which has an ongoing project with the National Health Research Institute to sequence exomes from two thousand Taiwanese patients with rare diseases.

Kaohsiung Chang Gung Memorial Hospital, a medical centre in the CGMH system that is located in the southern city of Kaohsiung, also serves as a recruiting centre for the Epi25 collaborative, an international research project focused on epilepsy. Another two thousand exomes have already been gathered through this study and other research projects, according to Dr Meng-Han Tsai, Professor and Director of the Department of Medical Research and the Genomics & Proteomics Core Laboratory at the hospital.

“We used to use gene panels, which were less expensive, but we eventually realised that whole exome or genome sequences were much better,” he reflects. “More than 400 genes can cause epilepsy, and not all epilepsies have a genetic basis, so we need lots of information to understand the root cause.”

A noted expert in the genetics of epilepsy, Dr Tsai often uses his research funding to cover exome sequencing for his patients, as cost is still a barrier for many in the out-of-pocket market. He also notes that many clinicians are not adequately trained in genetic data interpretation, and that it is hard to find good bioinformaticians who support the analytic process, but believes the situation is improving.

The future of exome sequencing in Taiwan

With a dedicated community of clinical geneticists that are actively committed to research and clinical care, Taiwan has a long history of excellence and innovation in rare disease diagnostics [3]. As order volumes for exome sequencing services grow each year, the country is likely to continue driving advances in genomic medicine that will have regional and global impact.

Despite all the progress and potential, however, public sector reimbursement for WES remains limited in Taiwan. While many local hospitals offer competitive pricing and investigators work to secure research funding for sequencing services, cost remains a key barrier for some patients, particularly those from low-resource households.

Unlike other countries in Asia and around the world, Taiwan also has not yet launched any major research studies to explore the role of whole exome or genome sequencing for newborn screening. Some researchers are actively working with health policy makers to explore opportunities for local programmes, but concerns about cost-benefit and bioethics of this approach create headwinds.

The good news is that Taiwan has a strong healthcare system and a robust out-of-pocket market for healthcare technology. Moreover, alternative funding sources for rare disease diagnostics, such as through NGOs like the Taiwan Foundation for Rare Disorders, are also available, though most experts agree that they are insufficient to meet clinical demand.

Overall, when compared to other countries in the Asia Pacific region, Taiwan is doing an excellent job of ensuring its people have access to high-quality diagnostics for rare diseases. While access to WES today remains imperfect, further progress can be expected in the coming years.

This article was written by Will Greene, Healthcare Engagement Lead at Roche Diagnostics Asia Pacific and co-lead on Project Strongbow, an initiative to drive best practices in newborn screening and rare disease diagnostics through educational content and community building. Visit our Newborn Screening page to see more of the articles and videos on this topic. 

Research and writing of the article was supported by Patrick Danoy, APAC Business Manager (Sequencing Sample Prep) at Roche Diagnostics Asia Pacific; Alvin Hsiang, Diagnostic Value Analyst at Roche Diagnostics Taiwan; and Sasa Sha, Diagnostic Value Lead at Roche Diagnostics Taiwan. 

References:

[1] Dimmock, D. et al. (2021) ‘Project Baby Bear: Rapid Precision Care incorporating rwgs in 5 California Children’s hospitals demonstrates improved clinical outcomes and reduced costs of care’, The American Journal of Human Genetics, 108(7), pp. 1231–1238. doi:10.1016/j.ajhg.2021.05.008.

[2] AI_Variant Prioritizer – a smart variant prioritization system. National Taiwan University Hospital. Available at: https://www.ntuh.gov.tw/SH/News.action?q_type=A01&q_itemCode=13057&agroup=a

[3] Chien, Y.-H. and Hwu, W.-L. (2023) ‘The modern face of newborn screening’, Pediatrics & Neonatology, 64. doi:10.1016/j.pedneo.2022.11.001.