Biallelic WDR91 variants cause a neurodevelopmental disorder through impaired endosomal maturation and autophagy dysregulation

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Abstract Biallelic variants in genes regulating endosomal, lysosomal and autophagy pathways are increasingly implicated in severe neurodevelopmental disorders, yet the contribution of the Rab7 effector WDR91 to human disease remains incompletely defined. We report a child with a severe neurodevelopmental disorder characterized by progressive microcephaly, microlissencephaly, corpus callosum hypoplasia, and early-onset epilepsy, harboring compound heterozygous WDR91 variants: a truncating variant (p.Gln215*) and a missense variant (p.Tyr15Asn). Functional analyses show that p.Gln215* abolishes WDR91 expression, whereas p.Tyr15Asn reduces protein abundance through increased degradation. Reduced WDR91 expression was confirmed in primary patient-derived cells. In silico analyses suggest that p.Tyr15Asn induces a localized change within an N-terminal degron-containing region, potentially affecting protein stability. In cellular models, both variants impair early-to-late endosomal maturation and alter WDR91 localization to Rab7-positive compartments. WDR91 deficiency is further associated with transcriptional and functional evidence of autophagy dysregulation. While the p.Tyr15Asn variant partially restores autophagic flux under overexpression conditions, patient-derived cells display impaired autophagic turnover, consistent with a context-dependent functional and partial loss of function effect of this variant. Together, these findings provide functional evidence supporting the pathogenicity of WDR91 variants and implicate combined defects in endosomal maturation and autophagy in WDR91-related neurodevelopmental disease.

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