Discovery of New Gene Linked to Neurodevelopmental Syndrome Enhances Treatment Options

A team of researchers from the LKS Faculty of Medicine at the University of Hong Kong, in collaboration with international genetic experts, has made a significant discovery in the realm of neurodevelopmental disorders. Their study, employing advanced multi-omics techniques, has identified a previously unknown gene, DDX39B, that is associated with a rare neurodevelopmental syndrome.

This gene's mutations have been found to affect brain functionality, resulting in developmental delays and hypotonia, a condition characterized by reduced muscle tone. Following the identification of DDX39B as a disease-causing gene, researchers linked it to six documented cases worldwide.

The research highlights the potential of multi-omics technology in decoding rare diseases with elusive genetic roots. The findings, now published in the journal Brain, could lead to significant advancements in diagnosing, preventing, and treating such conditions.

Dr. Brian Chung Hon-yin, a Clinical Associate Professor at HKUMed and the lead investigator of this study, has dedicated his efforts to shedding light on rare diseases. Previous studies indicated that approximately one in 67 individuals in Hong Kong--around 1.5% of the population--suffers from these uncommon medical conditions. The socio-economic burden for each patient in Hong Kong is estimated at HK$490,000 annually, reflecting the substantial challenges faced by these individuals and their families.

Dr. Chung emphasized the critical role of early genetic diagnosis in mitigating both the financial and emotional toll on patients and their caregivers. He advocates for increased awareness regarding rare diseases from both local and global communities.

The research team began their investigation in 2022 with a local toddler who was born with hypotonia, which hindered feeding. As the child grew, additional challenges in motor skills and speech became apparent, yet the underlying cause remained unidentified. Blood samples were collected, and through the use of comprehensive multi-omics technologies, including RNA sequencing and proteomics, the team was able to identify genetic variants linked to the child's condition.

The RNA sequencing revealed abnormal patterns in RNA splicing, confirming that mutations in the DDX39B gene are responsible for the rare neurodevelopmental syndrome. Additionally, experiments involving zebrafish, which exhibited similar symptoms to those observed in human patients when the DDX39B gene was deleted, further validated the significance of this genetic mutation.

This groundbreaking discovery not only marks a significant advancement in rare disease research but also provides clarity for six patients identified across Hong Kong, the United States, the United Kingdom, and Ireland, all of whom exhibit symptoms such as hypotonia, short stature, developmental delays, and epilepsy.

Dr. Chung expressed hope that this research would pave the way for improved diagnostic and treatment strategies tailored to the needs of these patients. Understanding the genetic basis of their conditions can alleviate uncertainty and anxiety for families affected by these disorders.

The multi-omics approach utilized in this study encompasses various fields such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics. By analyzing clinically relevant samples, this method enhances the diagnostic rate and provides a comprehensive understanding of the genetic factors contributing to rare diseases.

With the identification of the DDX39B mutation, the research team plans to expand their investigation into other genes linked to the transcription-export (TREX) complex to further explore their implications for human health. An international consortium has been established to investigate shared mechanisms underlying a range of neurodevelopmental disorders, aiming to improve diagnostic accuracy and develop targeted treatment options.