WLS-related Zaki syndrome: New clinical features and evidence for p.(Tyr478Cys) variant as a possible mutational hotspot.

INTRODUCTION: The Wnt ligand secretion mediator is encoded by WLS, and biallelic variants in this gene have been associated with an ultra-rare syndrome known as Zaki syndrome (ZKS). This study presents the fourteenth documented case of ZKS globally and reviews the clinical and genetic information of previously identified ZKS patients. METHODS: A 17-year-old female from Iran underwent whole-exome sequencing due to a range of phenotypic symptoms suggestive of a unique syndrome. Sanger sequencing was employed to validate the candidate variant and to investigate its segregation among family members. RESULTS: The patient was found to be homozygous for NM_024911.7: c.1433A>G, p.(Tyr478Cys) located in exon 11 of WLS. She represents the fifth ZKS patient identified with this variant, indicating a possible mutational hotspot. Furthermore, our patient exhibited distinct clinical characteristics compared to previously reported cases, including hyperphagia, congenital blindness, clinodactyly, and early pubertal development. A comparison of all reported ZKS patients suggests that this syndrome displays a recognizable pattern of developmental delay, intellectual disability, postnatal microcephaly, facial dysmorphism, skeletal and ocular anomalies, and short stature. Nevertheless, challenges persist in diagnosing ZKS due to poorly defined genotype-phenotype correlations. CONCLUSION: The clinical characteristics observed in our patient expand the phenotypic spectrum of ZKS. Additionally, the p.(Tyr478Cys) variant may represent a potential mutational hotspot within WLS.