VPS25 gene changes linked to fatal brain disorder

Researchers at King Abdullah University of Science and Technology (KAUST) and King Faisal Specialist Hospital and Research Center (KFSHRC) have identified changes in the gene VPS25 as the cause of a previously unknown, fatal brain disorder that begins before birth. The study, published in Genome Medicine, connected five unrelated families across Saudi Arabia, Europe, and North America who experienced similar patterns of severe neurological illness in their children. By bringing together clinical observations and laboratory data from these distinct families, the team recognized the condition as a distinct genetic disorder rather than a collection of isolated, unexplained cases. This discovery provides a specific genetic cause for a condition that had previously left families without answers or a clear diagnosis.

The disorder affects brain development from the earliest stages of life, resulting in significant structural abnormalities and severe neurological problems. Affected children can experience seizures, profound developmental difficulties, and major changes in the structure of the brain. For some families, the condition has resulted in the loss of more than one child, often without parents knowing what caused the tragedy or whether it could happen again. The identification of VPS25 as the shared genetic factor offers a definitive explanation for these shared symptoms, transforming a period of uncertainty into a recognized medical condition.

The research team utilized a collaborative approach that combined clinical documentation with advanced genomic analysis. Clinicians at KFSHRC worked directly with affected families to document their symptoms and investigate the possible genetic cause, while researchers at KAUST carried out laboratory studies to understand what was happening inside affected cells. This close collaboration allowed the teams to build a much clearer picture of the newly identified disorder by integrating clinical experience with scientific evidence. The integration of these two perspectives was essential for recognizing the pattern that linked the five families.

Three of the five families in the study were initially 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. Professor Fowzan Alkuraya, clinical genetics lead on the study who is affiliated with both KFSHRC and KAUST, noted that when a condition is this rare, one family alone may not be enough to reveal what is happening. Bringing together clinical experience with genomic data from Saudi Arabia and connecting it with cases internationally allowed the researchers to see a pattern that had previously been invisible.

Comparing cases of children from the five families and conducting 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, providing new insight into how the condition develops and affecting early brain development.

The study included brain imaging of children from the five families, which showed the brain abnormalities shared across the families. The pregnancy ultrasound and MRI scans revealed a missing corpus callosum, the band of fibres connecting the two halves of the brain, and enlarged fluid-filled spaces known as ventricles. These structural changes were consistent across the different families, supporting the conclusion that they shared a common genetic cause. The imaging data provided a visual confirmation of the severe developmental impact of the VPS25 changes on the brain.

Professor Jasmeen Merzaban, co-lead of the study at KAUST, stated that knowing this disease has a rare genetic cause can bring comfort to families who have lived for years with uncertainty about their tragic losses. The identification of the cause also enables clinicians around the world to recognize similar cases and detect the disease through genetic testing during pregnancy. For affected families, identifying the cause can support genetic counselling and help inform decisions about future pregnancies. This practical application of the research offers a path forward for families facing the risk of recurrence.

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. The study provides a new tool for diagnosis, allowing doctors to test for VPS25 changes in children presenting with unexplained brain abnormalities.

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. The study highlights the importance of building genomic resources, which can help find answers to diseases that might otherwise remain unexplained. As more cases are identified, the understanding of the disorder will continue to evolve.

The study illustrates how the combination of clinical observation, genomic data, and laboratory research can uncover the causes of rare diseases.

The work of the research team highlights the critical role of genomic programs in identifying rare diseases. By connecting cases across different countries, the researchers were able to overcome the limitations of studying a single family.

The formal peer-reviewed study, published on September 14, 2026, in Genome Medicine under the title “Recessive variants in ESCRT-II component VPS25 alter vesicular transport and small extracellular vesicle processing in lethal neonatal encephalopathy,” represents an experimental investigation centered on human subjects and cellular mechanisms. Led by Isaioglou and colleagues, the research evaluated five unrelated families located across Saudi Arabia, North America, and Europe. By conducting detailed laboratory investigations on cells from affected individuals alongside clinical evaluations, the investigators established that mutations in the VPS25 gene impair the fundamental processes responsible for maintaining nerve cells.

In their cellular analyses, the researchers at KAUST examined the specific cellular disruptions triggered by these genetic alterations. In healthy cells, VPS25 supports nerve cell maintenance, but the affected cases revealed severe disruptions in essential biological operations. Specifically, these genetic changes altered both the overall number and the internal cargo of the tiny packages released by cells. Laboratory testing demonstrated that the packages released by affected cells lacked critical proteins that are normally required to protect and sustain nerve cells, offering a biological explanation for the devastating neural damage observed in affected infants.

Structural brain imaging across the cohort provided clear visual evidence of the condition’s impact during fetal development. Both pregnancy ultrasound examinations and magnetic resonance imaging documented consistent brain malformations in children from the five families. Most prominently, the scans revealed a missing corpus callosum, the band of fibres connecting the two halves of the brain, alongside noticeably enlarged fluid-filled spaces known as ventricles. These prenatal and neonatal imaging findings confirm that the severe structural abnormalities take shape prior to birth, matching the clinical presentation of early seizures and profound developmental difficulties.

To identify these rare cases, the investigative team linked regional genomic databases with broader international clinical cohorts. Three of the families were initially identified through specialized genomic programs in Saudi Arabia, which clinicians at KFSHRC then connected with matching pediatric cases documented in North America and Europe. This international coordination proved decisive, as studying any single family in isolation would not have provided sufficient evidence to distinguish the pattern. The discovery establishes the first direct link between VPS25 variants and human pathology, creating a reliable diagnostic target that enables physicians to identify the condition during pregnancy and assist families through informed genetic counselling.

Subject of Research: Identification of VPS25 gene changes as the cause of a previously unknown fatal neonatal brain disorder

Article Title: Science solves genetic mystery behind fatal brain disorder in babies and children

Article References: Science solves genetic mystery behind fatal brain disorder in babies and children. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: VPS25 gene, neonatal encephalopathy, brain development, genetic disorder, KAUST, KFSHRC, Genome Medicine, corpus callosum, ventricles, genetic counselling, ESCRT-II, vesicular transport, Saudi Arabia, rare disease, brain imaging, genomic programs, nerve cells, protein transport, clinical genetics, international collaboration