A clinical research team from the LKS Faculty of Medicine, the University of Hong Kong (HKUMed), and international genetic researchers led a global research study using multi-omics analysis and identified a novel gene, DDX39B, for a rare disease. Genetic mutations in this gene impact brain function, leading to developmental delay and hypotonia (diminished muscle tone), which are symptoms of a rare neurodevelopmental syndrome. After the discovery of this disease-causing gene, the team found that DDX39B variants are associated with six cases worldwide. This groundbreaking study showcases the immense potential of advanced multi-omics technology for understanding rare diseases with previously unknown genetic causes, contributing significantly towards future diagnoses, prevention strategies and treatment plans. The findings were published in the journal Brain.

Background

Dr Brian Chung Hon-yin, Clinical Associate Professor in the Department of Paediatrics and Adolescent Medicine at the School of Clinical Medicine, HKUMed, leads a research team dedicated to investigating rare diseases. Their previous studies found that approximately 1 in 67 individuals in Hong Kong, constituting about 1.5% of the local population, are affected by these uncommon conditions. The team estimated that each rare disease patient in Hong Kong incurs a substantial socio-economic burden of approximately HK$490,000 per year. Their research found that these patients and their caregivers experience significantly lower health-related quality of life (QoL) compared to the general population of Hong Kong, as well as those suffering from other chronic diseases. Dr Chung emphasised that early genetic diagnosis plays a pivotal role in significantly reducing disease-related costs and the risk of financial hardship. Dr Chung, who is a Commissioner for the Lancet Commission on Rare Diseases, and his team are calling for greater awareness of, and attention to, the importance of rare diseases from both the Hong Kong and international community.

Research method and findings

The HKUMed research team undertook this study in 2022 involving a local toddler who had exhibited hypotonia from birth, causing difficulties in feeding. Later, motor and speech delays were also observed, but the root cause of these symptoms remained undiagnosed. The team acquired blood samples from the patient and utilised multi-omics technologies, including RNA sequencing (RNA-seq) and proteomics, to prioritise the patient’s genetic variant profile to identify disease-causing mutations. Through RNA-seq, the researchers analysed transcriptomic features and identified abnormal RNA splicing signatures, indicating that the mutation in the DDX39B gene is a genetic cause of this rare neurodevelopmental syndrome. In one of the experiments, the team discovered that zebrafish with DDX39B gene deletion exhibited symptoms such as small head size and short body length, which are strikingly similar to the symptoms observed in human patients. This suggests that the genetic mutation may cause similar symptoms in different species.

Whole transcriptome analysis of Proband C

(A-C) Volcano plot of aberrant splicing events detectd by three splicing metrics (psi3 for alternative splicing donors, psi5 for alternative splicing acceptors, and theta for aberrant splicing efficiencies) of FRASER in DROP. Red dots are significant aberrant splicing events with false discovery rate ≤ 0.05 (horizontal cut-off line) and magnititue ≥ 0.2 (vertical cut-off line). (D) Distrubution plot of the number of aberrant splicing event in indivduals of the internal RNA-seq samples (n=28) and GTEx controls (n=58). Proband C is a significant outlier comparing to the internal samples and external controls. (E) Pathway enrichment analysis by PANTHER. Three of the GO term for cell component are related to nucleus.

This groundbreaking discovery represents a significant breakthrough in the field of rare disease research. The HKUMed team, in collaboration with other genetic researchers across the globe, identified six patients in Hong Kong, the United States, the United Kingdom and Ireland who have variations in the DDX39B gene. The patients all exhibited symptoms of hypotonia, along with varying degrees of short stature, developmental delay and epilepsy.

Dr Brian Chung remarked, ‘This is a world-first discovery of this novel neurodevelopmental syndrome. These patients have lived with an undiagnosed situation for years, and now we can finally understand the cause of their condition. By providing crucial information to the patients and their families, the research helps reduce clinical uncertainties and alleviate parental anxiety, bringing a measure of comfort to those affected and their families. I hope this study opens a new research direction for the medical community, leading to the development of targeted diagnostic and treatment plans in the future. This will enable more patients with similar conditions to receive appropriate support and care they need.’

Significance of the study

Multi-omics encompasses genomics, epigenomics, transcriptomics, proteomics and metabolomics. By using clinically available tissues such as blood, multi-omics can cover a wide range of human diseases in a single analysis, thereby aiding the development of novel screening, diagnostic, preventive and therapeutic strategies. Dr Brian Chung pointed out that this research, which combines transcriptomics and genomics, enhanced the overall diagnostic rate.

He stated, ‘This multi-omics approach not only deepens our understanding of rare diseases but also reveals the potential genetic factors causing these conditions. It lays the foundation for devising innovative treatment strategies tailored to specific genetic characteristics, which could improve the clinical treatment outcomes of patients in Hong Kong and around the world.’

‘Having identified the DDX39B gene mutation, our next step is to broaden our research scope,’ Dr Chung continued. ‘We plan to delve deeper into studies associated with other genes related to the transcription-export (TREX) complex to better understand their impact on human health and diseases. We established an international consortium with our global partners to collectively explore common potential mechanisms underlying a variety of neurodevelopmental disorders and focus on diseases with overlapping pathophysiological features. This approach aims to enhance diagnostic accuracy and develop targeted treatment strategies for patients.’

Source – The University of Hong Kong