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Service Enhancement Presentations

F5.3 Healthcare Advances, Research and Innovations 09:00 Room 421

Clinical Whole Exome/Genome Sequencing (CWE/GS) for Undiagnosed Diseases
1
Lam CW , Law CY 2
1 2
Department of Pathology, The University of Hong Kong, Department of Pathology, Queen Mary Hospital, Hong Kong
Introduction HOSPITAL AUTHORITY CONVENTION 2018
Diagnostic odyssey refers to an unexpected delay between disease onset and time of the final diagnosis. This is mostly due
to diagnostic difficulties owing to the rarity of the condition. To-date, there are about 7,000 rare diseases affecting 300 million
people worldwide. Nevertheless, the diagnosis of these diseases is challenging as most doctors have not been intensively
trained to diagnose rare diseases. In addition, knowledge in advanced laboratory medicine is also required.

Objectives
We had encountered a number of rare diseases in Hong Kong over the past years and there is a strong need to provide
diagnostic service for rare diseases. In this regard, we set up the first Undiagnosed Diseases Programme (UDP) in Hong Kong
which aims to end the diagnostic odyssey. This programme was supported by the S. K. Yee Medical Foundation in 2014.
Methodology
Clinical Whole Exome Sequencing (CWES) and Clinical Whole Genome Sequencing (CWGS) were performed. Bioinformatics
processing was based on our in-house filtering algorithm. The overall clinical interpretation was based on clinical
presentation, laboratory findings, imaging results and pathomechanism.

Results
We had handled >100 cases and the disease entities were highly heterogeneous. Importantly, some conditions were
potentially treatable, for example, Allan-Herndon-Dudley syndrome, benign recurrent intrahepatic cholestasis (BRIC),
coenzyme Q6 deficiency-related nephrotic syndrome, coenzyme Q10 deficiency, osteogenesis imperfecta type VII, steroid-
resistant nephrotic syndrome, X-linked adrenoleukodystrophy, etc. We also discovered novel treatment for GNAO1-related
epilepsy. Using CWES/CWGS, we had discovered novel disease-causing genes, AK9 in congenital myasthenic syndrome
(CMS) and EBF3 in Moebius syndrome. Our works had been presented in the Diagnostic Challenge Session in the American
Society of Human Genetics (ASHG) 2016 annual meeting and also in a public lecture, Rare Diseases of the Newborn -
Detection and Management (available online - https://www.hkpl.gov.hk/mobile/en/extension-activities/event-detail/88251/
rare-diseases-of-the-new-born-detection-and-management).

A new diagnostic algorithm is proposed for diagnosing rare diseases. In the first tier, newborns should receive expanded
newborn screening for treatable inborn errors of metabolism (IEM) in pre-symptomatic phase. In the second tier, NMR-based
urinalysis, a 15-minute test which allows quantitation of >200 urine metabolites should be arranged for patients presented
with acute metabolic decompensation. In the third tier, patients with undiagnosed disease for >three months should undergo
CWES/CWGS. The clinical interpretation of CWES/CWGS is challenging, requiring in-depth understanding in both advanced
laboratory and clinical medicine. The overall CWES/CWGS analysis and interpretation should therefore be handled by
specialists with strong experience in clinical genomics. Tuesday, 8 May 2018

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