Saudi-led research connects cases across three continents to identify a previously unrecognised condition
A previously unexplained brain disorder affecting babies and children is linked to changes in a single gene, following research connecting five unrelated families across Saudi Arabia, Europe and North America.
The discovery gives clinicians a new genetic cause to consider when investigating severe neurological problems that begin early in life. For affected families, it can provide a diagnosis and help inform decisions about future pregnancies.
Researchers in Saudi Arabia at King Abdullah University of Science and Technology (KAUST) and King Faisal Specialist Hospital and Research Centre (KFSHRC), working with international colleagues, have identified variants in the VPS25 gene in children with similar patterns of illness.
The disorder affects brain development before birth and can cause seizures, profound developmental difficulties, low muscle tone and significant structural brain abnormalities. Some families have lost more than one child without knowing the cause or whether the condition could recur.
Published in Genome Medicine, the study brings together clinical and genetic evidence with laboratory investigations into the effects of the variants. It provides the first evidence linking changes in VPS25 to a human disorder.
For Professor Jasmeen Merzaban, co-lead of the study at KAUST, identifying the cause has immediate significance for families living with uncertainty. “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,” she says. “It also enables clinicians around the world to recognise similar cases and detect the disease through genetic testing during pregnancy.”
Connecting rare cases
Finding the shared genetic cause depends on linking families whose experiences might otherwise remain separate. Three of the five families have been identified through genomic programmes in Saudi Arabia, with additional cases connected through international collaboration.
“When a condition is this rare, one family alone may not be enough to reveal what is happening,” says Professor Fowzan Alkuraya, Clinical Genetics Lead on the study, who is affiliated with 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.”
For one mother involved in the research, the diagnosis comes around a decade after her family first experienced the condition. Without an explanation at the time, she questioned whether something during her pregnancy was responsible.
“As a mother, it was deeply painful to watch my daughter suffer without knowing why. I blamed myself a great deal and kept wondering whether I was responsible for what had happened,” she says. “Knowing the cause changed so much. I now understand that I was not to blame and that there was an inherited genetic cause we had known nothing about. It reassured me and gave me hope for the future.”
The researchers now seek additional cases to establish the wider range of symptoms and genetic variants associated with the condition, and to investigate further how changes in VPS25 affect early brain development.
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