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While animal models have indicated a link between SIDT2 deficiency and lysosomal storage disorders, no human cases have been reported. Here, we report a child with biallelic <jats:italic>SIDT2<\/jats:italic> missense variants (p.Arg529Trp, p.Arg678Trp), who developed progressive neurological decline with cerebellar atrophy and Parkinsonian features. Functional studies revealed that the affected individual\u2019s variants disrupted the ability of SIDT2 to interact with RNA. Fibroblasts from the affected individual showed impaired autophagy, characterised by abnormal accumulation of autophagy markers. In mouse models, Sidt2 was found to be highly expressed in the brain, particularly in the hippocampus and cerebellum. Sidt2 loss-of-function in mice resulted in not only impaired autophagy in the brain but also neurological dysfunction, including motor incoordination and eventual seizures. These findings suggest that SIDT2 deficiency contributes to both autophagic dysfunction and neurodegenerative processes, providing insight into a potential role in human neurological disease.<\/jats:p>","DOI":"10.1136\/jmg-2025-110654","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T06:50:22Z","timestamp":1750402222000},"page":"592-599","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Biallelic <i>SIDT2<\/i> loss-of-function in a child with cerebellar ataxia and lysosomal dysfunction mimics impairment of <i>SIDT2<\/i> in mice"],"prefix":"10.1136","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2696-9170","authenticated-orcid":false,"given":"Tan","family":"Nguyen","sequence":"first","affiliation":[{"name":"Pathology, University of California San Francisco, San Francisco, California, USA"},{"name":"Walter and Eliza Hall Institute of Medical Research, Melbourne, 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