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region, with six pseudogenes located at 13 Mb proximal to the original PKD1. The sequence of these six
[47]
pseudogenes is highly homologous to the PKD1 gene, with a sequence similarity as high as 97.7% , making
the genetic diagnosis of ADPKD challenging when using exome sequencing (ES) or targeted enrichment
approaches. Compared to ES, GS showed a more uniform coverage of the entire PKD1, including the
duplicated region [Figure 5]. Our preliminary data also showed that long-read GS uniformly covered more
of the “dark regions” in the genome, including the duplicated regions of PKD1 that are challenging for
short-read GS [Figure 5]. Our findings have demonstrated the capability of GS in clinical applications. The
genetic diagnosis informed the patient’s clinical management and treatment choices, such as the use of
Tolvaptan to slow down the progression of kidney failure.

DISCUSSION
As of today, HKGI is the only organisation in Hong Kong to provide free end-to-end WGS with a goal to
cater to participants’ diagnostics needs and answer clinical management questions. With the opportunity to
customise the Laboratory’s hardware and software components to tailor its own needs, the design, and
layout of the Laboratory, the monitoring and data management systems were all carefully planned and
crafted to serve the specific needs of the HKGP. While local accreditation programs for medical tests
involving next-generation sequencing are still under development, the design, construction, and outfitting
of the HKGI Laboratory adopt international standards for clinical genomics laboratory for DNA
sequencing. The HKGP biobank has the capacity to house more than 200,000 tubes of sample aliquots
currently, and can be scaled up as the project extends to various focused disease areas. Together with the
genomic database, the HKGP biobank opens new research opportunities in a collaborative environment.

Successful genomics research requires broad public participation and informed collaboration between
researchers and society, which relies on trustworthy sharing, effective management, and appropriate privacy
[47]
and data security protections . Informed consent guidelines, data collection and storage protocols, and
responsible sharing policies will be reviewed, improved, and augmented to provide the best practices in
genomic research. A research environment is developed to facilitate efficient and effective genomic data
sharing and analysis with clinicians and researchers. A well-developed infrastructure that facilitates active
genomic research collaborations enables the integration of scientific discoveries and genomic findings into
clinical practice. Collaboration between researchers and clinicians could promote the development of
standardised protocols for data collection, analysis, and interpretation in genomic medicine. This
infrastructure enhances the accuracy and reliability of genomic testing and enables more effective treatment
decision-making based on individual genetic profiles. Building a biobank with the inclusion of a population
deviated from that of European descent could also drive research and innovation in genetic medicine,
leading to the discovery of new gene therapies and interventions to further improve patient outcomes.

The Laboratory adopted a PCR-free GS library preparation for the HKGP. The advantages of an
amplification-free GS have been demonstrated by many studies [49,50] , including significantly reduced biases
introduced by the DNA polymerase, reduced duplication rates and false positives, and greater sensitivity in
calling indel and copy number variants. In addition, it provides better mapping and more uniform genome
coverage [50,51] , allowing comprehensive detection of a wide range of variants, from single nucleotide variants
to structural variants. Following the evaluation of different commercial kits for GS library preparation, an
enzymatic fragmentation-based approach was selected. It does not only offer greater flexibility in the input
gDNA amount, but also adaptability to liquid handling systems for routine library preparation. The
Laboratory has devoted considerable investment to fine-tuning the library insert size range and final library
yield, specifically the fragmentation and double-sided size selection steps, to achieve longer insert lengths
for better coverage and indel variant detection.