In brief

Advances in next-generation sequencing promise to accelerate the diagnosis of suspected genetic disorders from decades to a few years.

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Ending the diagnostic odyssey

20 Oct 2021

Asian patients with suspected but undiagnosed rare genetic diseases could get answers sooner thanks to next-generation sequencing technologies.

For patients with undiagnosed conditions, waiting can be the hardest part. This is especially true for difficult-to-diagnose genetic disorders, when test after test yields little to no information about the nature of their conditions.

“When families have genetic diseases, it is usually very agonizing not to know what the exact diagnosis is,” said Roger Foo, Principal Investigator at A*STAR’s Genome Institute of Singapore (GIS). Weeks of waiting for a diagnosis can easily stretch into years and even decades, a diagnostic odyssey that delays patients’ access to treatments for their conditions.

In such cases, diagnostic clues lie in the patients’ genes and can be unlocked using next-generation sequencing (NGS) technologies. However, while such genetic tests to ‘read’ patients’ genomes are widely available to individuals elsewhere in the world, these advances are far less accessible to Asian patients, particularly in resource-limited settings.

In their study, Foo and the study’s corresponding author Saumya Jamuar, a senior consultant at KK Women’s and Children’s Hospital, explored the clinical utility of NGS for shortening diagnostic times in an Asian setting, in a cohort of Singaporean patients with suspected (but unconfirmed) genetic disorders. These 275 patients were recruited from the Singapore Undiagnosed Disease Program.

Genomic DNA from the patients and their families was extracted, sequenced and then analyzed for variants, signature differences in gene sequences that point to the presence of a genetic condition. Variants that were deemed likely pathogenic led to a positive molecular diagnosis.

The team’s analysis showed that NGS contributed to a diagnostic yield of 37.2 percent, meaning that for every 100 people with symptoms of a genetic disorder, 37 of them would receive a definitive diagnosis. “Diagnostic yield is how often a confirmed genetic diagnosis can be made when someone suspected of the disease is subjected to the test,” Foo explained.

Foo and colleagues demonstrated how these results dramatically shortened the path to diagnoses. For example, five study participants born before the advent of NGS technologies waited over 20 years for a diagnosis. However, ten patients with more immediate access to sequencing tests were diagnosed within 1–2 years.

Quicker diagnoses also helped improve patients’ quality of care: in 27 percent of cases, a positive molecular diagnosis led to changes in treatment and management; in 100 percent of cases, genetic counseling was adjusted.

Besides being transformative for patients, NGS studies are contributing much-needed genetic data on variants among Asian populations, information that has been extremely under-represented in existing genetic databases. Consequently, Foo and other experts are advocating for NGS to become routine for diagnosing Singaporeans with suspected genetic diseases. “We look forward to clearing reimbursement protocols for these tests in due course,” he adds.

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS), Institute of Molecular and Cell Biology (IMCB) and Skin Research Institute of Singapore (SRIS).

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Bhatia, N.S., Lim, J.Y., Bonnard, C., Kuan, J.L., Brett, M. et al. Singapore Undiagnosed Disease Program: Genomic analysis aids diagnosis and clinical management. Archives of Disease in Childhood 106, 31–37 (2020) | article

About the Researcher

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Roger Foo

Principal Investigator

Genome Institute of Singapore
Roger Foo received his MD from the National University of Singapore and underwent higher specialist training at the University of Cambridge, where he focused on gene expression control and epigenetics, using NGS systems to analyze patient heart muscle samples. When he returned home to Singapore, Foo advocated for the use of NGS in clinics and also helped establish the Singapore Undiagnosed Research Program for Kids. He is also a Principal Investigator at A*STAR’s Genome Institute of Singapore, where his research interests revolve around the cardiac epigenome, molecular epigenetics and the stress-gene response.

This article was made for A*STAR Research by Wildtype Media Group