Zaki syndrome: Researchers identify unknown childhood genetic disorder

A study published in The New England Journal of Medicine details how researchers discovered a previously unknown genetic disorder that affects prenatal development in children and identified a potential cure.

Joseph G. Gleeson, MD, the Rady Professor of Neuroscience at the University of California San Diego School of Medicine and director of neuroscience at Rady Children’s Institute for Genomic Medicine, said in an interview with Healio that he and his colleagues had observed children around the world with DNA mutations in the Wnt-less, or WLS, gene but did not realize that they comprised the same syndrome until comparing clinical notes.

“We deal a lot with patients and families that come to us with medical problems,” Gleeson said. “This started with a large family that we had been asked to look at, where there were five children with the same condition. And we found the cause was a mutation in a gene no one had ever studied, no one had ever linked to human disease before.”

Searching a database of more than 20,000 families with children with neurodevelopmental disorders, the researchers identified 10 people from five unrelated families that had homozygous mutations in WLS.

They called the disorder Zaki syndrome, after co-author Maha S. Zaki, MD, PhD, of the National Research Center in Cairo, who first noticed it. The syndrome affects prenatal development of several organs of the body, including eyes, brain, hands, kidneys and heart, and can result in lifelong disabilities.

“Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects,” they wrote.

The researchers generated stem cells and mouse models for Zaki syndrome and treated the condition with a drug called CHIR99021, which boosts Wnt signaling. In each mouse model, they found CHIR99021 boosted Wnt signals and restored development. The mouse embryos grew body parts that had been missing, and organs resumed normal growth.

“I think it's going to really start to change the way that physicians and scientists think about these structural disorders because now we can think about them as being potentially treatable, if we can diagnose them early enough,” Gleeson said.

He added that it might be “just a matter of time” until CHIR99021 can be used to treat Zaki syndrome regularly.

“We have to have hope for conditions where people think there should be no hope,” Gleeson said. “And I can't tell you the number of families that have come to me and said, ‘My doctor told me that I should take my baby home and wait for it to die’ or, ‘There's no hope for any of these conditions.’ What we're trying to do is really push that and say, ‘Well, no, that's not the case.’ If we can have early diagnosis, we can really think about treatment. And it's really up to the medical field and the whole medical enterprise to rethink pediatric conditions, especially these like structural disorders of the body.”

References:

Chai G, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2033911.