Evaluating the diagnostgic impact and cost of rapid whole-exome sequencing for rare genetic diseases in Hong Kong

Abstract

Background: Most rare diseases have a genetic component and are often chronically debilitating. Our recent publication revealed that 1 in 67 people in Hong Kong (HK) has rare disease (1.5% of the population). Local clinicians need to send samples to overseas laboratories as clinical whole exome sequencing (WES) is not available. The turnaround time (TAT) typically takes 2-4 months from test request to final reporting, making it impractical for urgent cases. Rapid WES (rWES) can provide timely molecular diagnosis and has the potential to initiate or alter medical or surgical management (clinical utility) promptly and profoundly. This may avoid unnecessary investigations and hospitalization, prevent mortality, and save costs in the healthcare system. Method: Patients with suspected monogenic disorders who i) were critically ill in intensive care unit (NICU/ PICU) urging for a diagnosis; or ii) would benefit from a timely diagnosis to support decision in clinical management; or iii) required prenatal diagnosis for an on-going pregnancy; or iv) were referred by clinicians; were prospectively recruited from Queen Mary Hospital. We aimed to achieve a rapid TAT of 14 days. Diagnostic and clinical utility of rWES were assessed. Related costs were evaluated when matched controls with standard of care genetic testing in the same setting were available for comparison. Cost analysis is on-going and is completed in four patients where matched controls were available. Results: rWES was offered to 80 families from 2016 to 2019, of which 34% (27/80) were recruited from ICUs. The overall diagnostic yield was 33% (26/80), with a median TAT of 11 days (range: 4-86 days). Clinical management changed in 88% of diagnosed patients (23/26), including surgical and interventional procedures to be performed or contraindicated (31%), referral to specialists (31%), surveillance (27%), and palliative care and termination of pregnancies (19%). In those four patients where matched controls were available, it was estimated that the length of stay was reduced by 566 days; total healthcare cost from avoidance of planned surgical and interventional procedures and reduced length of stay was estimated to save at least UK£583,399 (HK$5,833,990). Conclusion: This study illustrates that rWES in HK is feasible, has high diagnostic and clinical utility, is cost saving, and is comparable to international standards. Cost analysis for rWES is challenging as each rare disease is individually rare and a control diagnosed by conventional methods is even rarer. In addition, each genetic condition has unique clinical features and may not be obvious in neonatal period. rWES merits consideration as a routine clinical diagnostic test in the HK public healthcare system.