Compound heterozygous variants in WLS gene causes Zaki syndrome

Biallelic Wnt ligand secretion mediator (WLS gene) variants are associated with Zaki syndrome (OMIM: #619648). Here, we report the first case with Zaki syndrome in the Chinese population. Whole‐exome gene sequencing (WES) identified compound heterozygous variants in the WLS gene (c.1427A > G; p.Tyr476Cys and c.415C > T, p.Arg139Cys; NM_001002292) in a 16‐year‐old boy presenting with facial dysmorphism, astigmatism, renal agenesis, and cryptorchidism. In vitro functional characterization showed that the two variants led to decreased WLS production and secretion of WNT3A, eventually affecting the WNT signal. We also found that the decreased mutant WLS expression can be rescued by 4‐Phenylbutyric acid (4‐PBA). We report a novel heterozygous missense variant in WLS (p.Arg139Cys) associated with Zaki syndrome. 3D modeling revealed that the novel variant changed the amino acid side chain and distorted the structure of WLS protein. In vitro functional characterization showed that the variant led to decreased WLS production and secretion of WNT3A, eventually affecting the WNT signal. Interestingly, our results suggested that the 4‐PBA may be a novel therapeutic.