Aim: The Hong Kong Genome Project (HKGP) is the first large-scale genome sequencing (GS) project in the Hong Kong Special Administrative Region. The Hong Kong Genome Institute (HKGI) is entrusted with the task of implementing the HKGP. With the aim to sequence 45,000-50,000 genomes in five years, it is the project’s goal to provide participants with more precise diagnosis and personalised treatment, and to drive the application and integration of genomic medicine into routine clinical care.

Methods: The HKGI Laboratory’s hardware and software components were customised to tailor to the needs of the project. Sample handling and storage protocol, DNA extraction, and PCR-free GS workflow were developed and optimised. Quality control indicators and metrics for assessing the quality of samples, sequencing libraries and sequencing data were established.

Results: The Laboratory is designed to facilitate a unidirectional GS workflow to minimise the risk of contamination. The Sample Manager system handles laboratory data generated from the HKGP samples and biobank. The Laboratory handles and analyses approximately 350-500 samples per week, the majority of which are whole blood. During the first 24 months since the launch of the HKGP, 12,937 participants and their family members (6,680 genomes) have been recruited and sequenced. The sequencing capacity of the Laboratory has been further enhanced to include the latest technologies, such as long-read sequencing and multi-omics in order to meet the target of the HKGP.

Conclusion: HKGI Laboratory established a robust GS workflow for the HKGP. The clinical utility of GS will bring precision medicine into routine clinical practice.

Development of new high throughput array-based techniques and, more recently, next-generation sequencing (NGS) technologies have revolutionized our capability to accurately characterize single nucleotide polymorphisms (SNPs) throughout the genome. These advances have facilitated large-scale genome-wide association studies (GWAS), which have served as fundamental elements in establishing links between SNPs and the susceptibility to several complex diseases, including those related to the immune system. Nevertheless, the molecular mechanisms underlying the development of most of these disorders are still poorly defined. Decoding the functionality of SNPs becomes increasingly challenging due to the predominant presence of these risk variants in non-coding regions of the genome. Among them, long non-coding RNAs (lncRNAs) are enriched in disease-associated SNPs. lncRNAs are involved in governing the control of gene expression both during transcription and at the post-transcriptional level. The existence of SNPs within the sequences of lncRNAs has the potential to alter their expression, structure, or function. This, in turn, can influence their regulatory roles and consequently contribute to the onset or progression of various diseases. In this review, we describe the implication of SNPs located in lncRNAs in the development of different immune-related diseases and highlight the potential of these molecules in the development of emerging RNA-based therapies.

Chimeric antigen receptor (CAR) NK cells are demonstrating promising activity in clinical trials and possess a favorable safety profile compared to CAR-T cells. The Killer cell Immunoglobulin-like Receptors (KIR) have a critical role in the control of NK cell function, and recently, this family of activating and inhibitory receptors have been targeted to improve CAR-NK function. These strategies include the utilisation of inhibitory KIR to reduce trogocytosis-associated NK cell fratricide, the downregulation of inhibitory KIR on CAR-NK cells to alleviate HLA mediated suppression, the selection of CAR-NK cell donors enriched for activating KIR, and the use of activating KIR intracellular domains within novel CAR constructs. These pre-clinical studies demonstrate the potential utility of targeting the KIR to improve CAR-NK cell efficacy and patient outcomes.

Mutations in mitochondrial DNA can cause mitochondrial diseases. This review focuses on the main functions of mitochondria and the effect of mutations in mtDNA on the processes of mitophagy, mitodynamics and mitochondrial biogenesis. The main mitochondrial diseases associated with specific mutations in mtDNA are reviewed, with an emphasis on atherosclerosis. It is assumed that mtDNA mutations can provoke pathological changes in the intima of the human aorta and activate a specific immune response, ultimately leading to the development of atherosclerosis. Special attention is paid to the methods of targeted therapy of mitochondrial diseases with the use of antioxidants, mitodynamics modifiers, and phototheranostics.

Moebius Syndrome (MBS) is a rare neurodevelopmental disorder characterised by facial paralysis and ocular motility defects. Its origins trace back to the 19th century, with its clinical delineation attributed to German neurologist Paul Möbius. The syndrome presents with a spectrum of variable systemic clinical features, necessitating a multidisciplinary approach to diagnosis and management. The prevalence of MBS has been estimated to range between 1 in 50,000 to 1 in 500,000 individuals, with a universal distribution across ethnicities and genders. The aetiology of MBS is poorly understood but is likely multifactorial, with developmental, genetic, and environmental factors playing roles. Recent research has identified potential genetic contributors, REV3L and PLXND1, but further work is needed to elucidate the genetic landscape of this rare neurodevelopmental disorder. Here we describe the current understanding of the clinical features, aetiology, genetic landscape, and management of MBS, emphasising the importance of early diagnosis and a holistic approach to patient care. We also propose a set of criteria aimed at standardising MBS reporting to enhance information sharing and bolster MBS research initiatives. Collaborative research efforts in the future hold the potential to offer transformative insights and improved outcomes for affected individuals and their families.

Autism spectrum disorder (ASD) is a behaviorally defined syndrome affected by multiple genetic and environmental factors. A wide variety of risk factors for ASD have been identified and many of these affect immune functions. This may not be surprising, since the immune system and the nervous system share common signaling mechanisms and affect each other as a part of the neuroimmune network. The ever-expanding scope of inborn errors of immunity (IEIs) has revealed multiple pathogenic gene variants that manifest overlapping clinical features of common neuropsychiatric diseases, including ASD. These IEIs often cause dysregulated immune activation and resultant chronic inflammation affecting multiple organs. Some IEIs also cause changes in morphogenesis and plasticity of the central nervous system. Such patients often present with a puzzling array of clinical features and some of them may be diagnosed with ASD or other neuropsychiatric conditions. The progress of our understanding of disease mechanisms for IEIs at the molecular levels has led to gene-specific treatment measures in some diseases. In addition, some ASD patients are found to have laboratory findings of neuroinflammation that resemble those seen in IEI patients. This may pave the way for applying specific treatment measures used for IEI patients in such ASD patients. This review focuses on describing IEIs that have overlapping features of ASD. Emphasis is also on IEIs that can be treated by targeting identified disease mechanisms. Such information may be helpful for clinicians who are considering genetic/metabolic workup in ASD patients.