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Sequencing Study Points to Prenatal Development Syndrome, Possible Treatment Strategy

NEW YORK – An international team led by investigators in the US and Singapore has identified a syndrome linked to mutations affecting both copies of the "Wnt ligand secretion mediator"-coding gene called WLS that affects the prenatal development of multiple organ systems.

"Our genetic findings provide evidence of impaired WLS function as a cause for this new condition," co-senior and co-corresponding author Joseph Gleeson, a neurosciences and pediatric brain disease researcher affiliated with the University of California, San Diego and the Rady Children's Institute for Genomic Medicine, and his colleagues wrote in the New England Journal of Medicine on Thursday, adding that results from their mouse model experiments "suggest that pharmacologic intervention could be considered for some structural birth defects during gestation."

The researchers identified the condition — dubbed Zaki syndrome, in honor of co-author Maha Zaki at the National Research Center in Cairo using a combination of linkage analyses, whole-genome sequencing, or exome sequencing on affected children and/or parents from families affected by similar unexplained neurodevelopmental conditions and structural birth defects.

Starting from nearly 20,250 neurodevelopmental disorder-affected families from international databases, they focused in on cases involving microencephaly or structural birth defects and comparable symptoms ranging from sparse hair and eyebrows, heart or kidney problems, and webbed toes to cupped ears and facial dysmorphic features.

By digging into the linkage and sequence data, the team identified 10 affected individuals with homozygous pathogenic or likely pathogenic WLS alterations that led to lower-than-usual WLS protein levels in primary dermal fibroblast cell experiments. The cases came from five families, including one family that had five children affected by the congenital condition. Consistent with the recessive nature of the condition, three of the five families involved parental consanguinity. 

The researchers noted that tissue, cellular, or developmental abnormalities also turned up in follow-up experiments on WLS-mutant mouse embryonic fibroblast cell lines or in mouse embryos carrying WLS variants found in two of the patients — Wnt signaling shifts that could be rescued in mice using a Wnt agonist compound called CHIR99021 given during the process of embryonic development.

"The results were very surprising because it was assumed that structural birth defects like Zaki syndrome could not be prevented with a drug," first author Guoliang Chai, a researcher at the Capital Medical University in Beijing, who was a post-doctoral researcher at UCSD when the research was performed, said in a statement. "We can see this drug, or drugs like it, eventually being used to prevent birth defects, if the babies can be diagnosed early enough."

Gleeson cautioned that studies of the proposed Wnt agonist treatment have been done strictly in mouse models so far, though the rise in fetal molecular testing and diagnoses may eventually help to uncover human Zaki syndrome cases prenatally, when they may benefit from a preventive treatment similar to that assessed in mice.

"Currently there are not clinical trials planned, but if enough patients are identified we will initiate a clinical trial," Gleeson said in an email, calling it "unethical to not at least consider how the babies might benefit from treatment."

Likewise, the authors noted that the potential use of Wnt agonists such as CHIR99021 after birth has not yet to be explored in Zaki syndrome models, though they suggested that "we do not rule out potential benefit, because we suspect that most future diagnoses of this condition will be made after rather than before birth."