Gene behind novel neurodevelopmental syndrome identified in breakthrough discovery

A clinical research team from the University of Hong Kong (HKU) and an international team of genetic researchers have discovered that a rare neurodevelopmental syndrome is caused by mutations in the DDX39B gene.

The study involved a cohort of six individuals aged 3–36 years (age >18 years, 50 percent) from five families in Hong Kong, the US, UK and Ireland with disease-causing de novo missense variants or inherited splice-altering variants in the DDX39B gene. These individuals exhibit hypotonia along with mild to severe developmental delay, mild to severe intellectual disabilities, varying degrees of short stature, skeletal abnormalities, variable dysmorphic features, microencephaly, and gastrointestinal problems including feeding difficulties, and some have history of epilepsy or seizures. [Brain doi.org/10.1093/brain/awaf035]

DDX39B is a highly conserved RNA helicase belonging to the DExD/H box RNA helicase family, a group of highly conserved proteins found in organisms ranging from yeast to humans.  DDX39B is also a core component of the TRanscription-EXport (TREX) super protein complex, subunits of which are shown in recent studies to have an important role in neurodevelopmental disorders. The loss-of-function mechanism of disease with varying effects on protein or RNA interactions for each of the five variants identified in the cohort was demonstrated using multiomics analysis (a combination of in silico analysis, blood transcriptomics and co-immunoprecipitation studies) and Drosophila and zebrafish models.

Multiomics encompasses genomics, epigenomics, transcriptomics, proteomics and metabolomics. By using clinically available tissues such as blood, multiomics can cover a wide range of human diseases in a single analysis, thereby aiding the development of novel screening, diagnostic, preventive and therapeutic strategies

“This is a world-first discovery of this novel neurodevelopmental syndrome,” remarked leader of the research team, Dr Brian Hong-Yin Chung from the Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, HKU. “These patients have lived with an undiagnosed situation for years, and now we can finally understand the cause of their condition.”

“Providing crucial information to the patients and their families 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, enabling more patients with similar conditions to receive the appropriate support and care they need,” added Chung.

Previous studies by the HKU research team found that approximately 1 in 67 individuals in Hong Kong (approximately 1.5 percent of the local population) are affected by these uncommon conditions. The team estimated that each rare disease patient in Hong Kong incurs a substantial socioeconomic burden of approximately HKD 490,000 per year. These patients and their caregivers also have significantly lower health-related quality of life compared with the general population as well as those suffering from other chronic diseases. “Early genetic diagnosis plays a pivotal role in significantly reducing disease-related costs and the risk of financial hardship,” Chung emphasized.