Researchers from the Agency for Science, Technology and Research's (A*STAR) Genome Institute of Singapore (GIS), and Rady Children's Institute for Genomic Medicine identified a previously unknown condition affecting children, which they discovered could be prevented by administering a drug during pregnancy.

Through a worldwide collaboration, the researchers identified children from Egypt, India, United Arab Emirates, Brazil, and USA affected by the same condition. Although different doctors were caring for these children, they all showed similar symptoms and had DNA mutations in the same gene.

The condition, which doctors named 'Zaki Syndrome' after one of the physicians who first identified it, impacts the development of several organs of the body including the eyes, brain, digit, kidney, hair, and heart. Using whole genome sequencing, doctors were able to find mutations in a previously mysterious gene called 'WNT-less', abbreviated WLS. The WLS gene controls the level of signaling of a hormone-like protein called WNT (pronounced wint).

Surprisingly, a drug that counteracts the loss of the WLS was able to mostly restore normal development in both pre-clinical trial model and a stem cell model of Zaki syndrome. Moving forward, researchers hope to discover how the drug could be administered to pregnant mothers to help correct the condition in developing fetuses.

We were perplexed by this paediatric condition for many years. We observed children from across the globe with DNA mutations in the WNT-less gene, but did not recognize that they all had the same disease until doctors compared clinical notes. We then realized we were dealing with a new syndrome that can be identified by clinicians, and potentially prevented."

Dr Joseph Gleeson, senior author and pediatric neurogeneticist at Rady Children's Institute for Genomic Medicine and University of California, San Diego

Prof Bruno Reversade, co-senior author, head of the Laboratory of Human Genetics and Therapeutics at GIS, and Research Director at the Institute of Molecular and Cell Biology (IMCB), whose team helped to identify several families and studied the disease symptoms using patients' cells, wondered if such a condition may be amenable to therapeutic intervention. He commented, "While we have shown that it is possible to mimic WNT-deficiency with dedicated drugs, the real challenge was to overcome, and possibly rescue, this congenital disease."

To attempt this, researchers generated stem cells and mouse models for Zaki Syndrome, and treated it with a man-made drug that boosts WNT signaling, which is defective when WNT-less is mutated. In each model, they found that the drug, called CHIR99021, was able to boost WNT signals and restore development. The embryos regrew body parts that were missing (e.g. vertebrae), and organs began growing almost normally.

"The results were very surprising to us because it was previously assumed that structural birth defects like Zaki Syndrome could not be prevented with a drug," said first author Dr Guoliang Chai, a member of the team at Rady Children's Institute for Genomic Medicine, and currently at Capital Medical University in Beijing. "We could eventually see this drug, or drugs like it, being used to prevent birth defects if the fetuses are diagnosed early enough."

Prof Patrick Tan, Executive Director of GIS, said, "Research into rare diseases helps scientists understand more common ailments. The findings from such research sometimes results in unexpected findings that may better inform diagnoses or therapies for patients suffering from these diseases. It always feels rewarding for GIS to be part of such collaborations that contribute to better health and social outcomes for Singapore, and beyond."