Weiss-Kruszka Syndrome: two new case reports of Chinese ancestry and literature review

Abstract The zinc finger protein 462 ( ZNF462) gene, first linked to human disease, Weiss-Kruszka Syndrome (WSKA) in 2019. Pathogenic variants in this gene are associated with a neurodevelopmental disorder characterized by a broad phenotypic spectrum, including developmental delay, intellectual disability, distinctive craniofacial features (such as ptosis, hypertelorism, and a broad nasal tip), hypotonia, and variable congenital anomalies. Additional reported features include corpus callosum abnormalities, skeletal anomalies, and ophthalmologic manifestations. Purpose Here, we presented two newly diagnosed Chinese patients with WSKA from two unrelated families, harboring two novel variants in the ZNF462 gene. Methods Genetic investigation using whole-genome sequencing was performed which identified a de novo pathogenic variant in ZNF462 (NM_021224.6:c.3414del, p.(Glu1139Lysfs*2)) in proband 1 and a heterozygous 4-base pair deletion in ZNF462 (NM_021224.6:c.4460_4463del) in proband 2. Results In addition to one previous case reporting structural malformation of pituitary gland with endocrine dysfunction, we present another Chinese patient molecularly confirmed as WSKA, having hypoplastic pituitary gland and rarely reported clinical manifestations of olfactory dysfunction and hypoplastic olfactory bulbs, with small olfactory grooves and non-identifiable olfactory bulbs. Conclusion Our case report further contributes to the growing understanding of the genotypic and phenotypic variability of ZNF462 -related disorder and highlight the importance of this gene in diagnostic evaluations of individuals with unexplained neurodevelopmental delays and dysmorphic features. Our patients help to further delineate the phenotype, genotype and potential therapeutic management strategies for WSKA.