Researchers at King Abdullah University of Science and Technology (KAUST) and King Faisal Specialist Hospital and Research Centre (KFSHRC), identify a previously unknown cause of a fatal newborn brain disorder, giving long-awaited answers to families whose children were affected by the disease. 

The disorder affects brain development from before birth and can cause severe neurological problems from the earliest stages of life. Affected children can experience seizures, profound developmental difficulties, and significant abnormalities in the structure of the brain. For some families, the condition has resulted in the loss of more than one child, without parents knowing what caused it or whether it could happen again. Published in Genome Medicine, the study brought together five unrelated families across Saudi Arabia, Europe, and North America whose children had experienced similar patterns of illness. By connecting these cases, researchers were able to identify a shared genetic cause and recognize the condition as a previously unknown disorder.  

“Knowing that this disease has a rare genetic cause can bring comfort to families who have lived for years with uncertainty about their tragic losses,” said Professor Jasmeen Merzaban, co-lead of the study at KAUST. “It also enables clinicians around the world to recognize similar cases and detect the disease through genetic testing during pregnancy.” 

Comparing cases of children from the five families and cellular testing, the team discovered changes in the same gene, VPS25, which is responsible for maintaining nerve cells. Research into cell mechanisms in the affected cases showed that critical biological processes were disrupted, changing both the number and contents of tiny packages released by cells. Some of the missing contents of these packages included proteins important for protecting and maintaining nerve cells. 

This is the first evidence linking changes in VPS25 to a human disorder, and the findings offer new insight into how the condition develops, giving clinicians a new gene to consider when investigating children with similar unexplained brain abnormalities. For affected families, identifying the cause can also support genetic counselling and help inform decisions about future pregnancies. 

Finding these answers depended on close collaboration between clinicians and researchers. Clinicians at KFSHRC worked directly with affected families, documenting their symptoms and investigating the possible genetic cause, while researchers at KAUST carried out laboratory studies to understand what was happening inside affected cells. By bringing the clinical and scientific evidence together, the teams were able to build a much clearer picture of the newly identified disorder. 

The researchers connected these findings with genomic data from other families. Three of the five families in the study were identified through genomic programs in Saudi Arabia, before the team connected these cases with additional families in North America and Europe. Together, the cases revealed a pattern that would have been difficult to see from any one family alone.  

“When a condition is this rare, one family alone may not be enough to reveal what is happening,” said Professor Fowzan Alkuraya, clinical genetics lead on the study who is affiliated with both KFSHRC and KAUST. “Bringing together clinical experience with genomic data from Saudi Arabia, and connecting it with cases internationally, allowed us to see a pattern that had previously been invisible. This is why building these genomic resources matters: they can help us find answers to diseases that might otherwise remain unexplained.” 

Researchers hope the discovery will now help identify other families around the world living with the same condition. Finding additional cases will help scientists build a clearer picture of the disorder, improve recognition and diagnosis, and deepen understanding of how changes in VPS25 affect early brain development.