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Pathogenic missense variants in <jats:italic>ITPR1<\/jats:italic> cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine\/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across <jats:italic>ITPR1<\/jats:italic>, standardize the <jats:italic>ITPR1<\/jats:italic> variant nomenclature, and investigate disease progression in relation to cerebellar atrophy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cases were identified using next\u2010generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. <jats:italic>ITPR1<\/jats:italic> alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We report the largest, multinational case series of 46 patients with 28 unique <jats:italic>ITPR1<\/jats:italic> missense variants. Variants clustered in functional domains of the protein, especially in the N\u2010terminal IP<jats:sub>3<\/jats:sub>\u2010binding domain, the carbonic anhydrase 8 (CA8)\u2010binding region, and the C\u2010terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our <jats:italic>ITPR1<\/jats:italic> transcript expression data, greatly facilitated analysis. Genotype\u2013phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This dataset represents the largest cohort of patients with <jats:italic>ITPR1<\/jats:italic> missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. \u00a9 2023 The Authors. <jats:italic>Movement Disorders<\/jats:italic> published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.29651","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T15:19:17Z","timestamp":1700061557000},"page":"141-151","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Detailed Analysis of <scp><i>ITPR1<\/i><\/scp> Missense Variants Guides Diagnostics and Therapeutic Design"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7350-386X","authenticated-orcid":false,"given":"Jussi Pekka","family":"Tolonen","sequence":"first","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford UK"},{"name":"Kavli Institute of Nanoscience Discovery University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3374-8483","authenticated-orcid":false,"given":"Ricardo","family":"Parolin Schnekenberg","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford UK"},{"name":"Oxford Center for Genomic Medicine Oxford University Hospitals National Health Service Foundation Trust, University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"McGowan","sequence":"additional","affiliation":[{"name":"Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Sims","sequence":"additional","affiliation":[{"name":"Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meriel","family":"McEntagart","sequence":"additional","affiliation":[{"name":"South West Regional Genetics Service St. George's University Hospitals  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Elmslie","sequence":"additional","affiliation":[{"name":"South West Regional Genetics Service St. George's University Hospitals  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie","family":"Shears","sequence":"additional","affiliation":[{"name":"Oxford Center for Genomic Medicine Oxford University Hospitals National Health Service Foundation Trust, University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Stewart","sequence":"additional","affiliation":[{"name":"Oxford Center for Genomic Medicine Oxford University Hospitals National Health Service Foundation Trust, University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9252-5933","authenticated-orcid":false,"given":"George K.","family":"Tofaris","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences University of Oxford  Oxford UK"},{"name":"Kavli Institute of Nanoscience Discovery University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabib","family":"Dabir","sequence":"additional","affiliation":[{"name":"Northern Ireland Regional Genetics Service Belfast City Hospital  Belfast UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Morrison","sequence":"additional","affiliation":[{"name":"Patrick G. 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