{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:41:19Z","timestamp":1792813279977,"version":"4.5.0"},"reference-count":28,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82450115"],"award-info":[{"award-number":["82450115"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82330037"],"award-info":[{"award-number":["82330037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Intragenic structural variants of\n SLC20A2<\/jats:italic>\n remain poorly characterized in primary brain calcification (PBC).\n <\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n \n The aim was to identify and characterize intragenic\n SLC20A2<\/jats:italic>\n structural variants in PBC.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n One familial PBC pedigree and two sporadic patients underwent whole\u2010genome sequencing and copy\u2010number analysis, followed by polymerase chain reaction (PCR) and Sanger validation. Long\u2010read sequencing (LRS) resolved complex architecture. Transcript and protein effects were assessed by reverse transcription (RT)\u2010PCR, RT\u2010quantitative PCR, and western blotting.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We identified three intragenic\n SLC20A2<\/jats:italic>\n structural variants: exon 2\u20133 and exon 5 tandem duplications in F1 and F3, respectively, and a complex exon 2\u20133 inverted insertion in F2. F1 and F3 showed aberrant, frameshift\u2010generating transcripts, and F3 showed reduced\n SLC20A2<\/jats:italic>\n mRNA and protein. Accordingly, the F1 and F3 variants were classified as pathogenic, whereas the F2 variant remained of uncertain significance.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our study expands the spectrum of intragenic\n SLC20A2<\/jats:italic>\n structural variation in PBC and highlights the value of copy number variation analysis and LRS in genetically unresolved individuals. \u00a9 2026 International Parkinson and Movement Disorder Society.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mds.70576","type":"journal-article","created":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:18:57Z","timestamp":1792811937000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\n SLC20A2<\/i>\n <\/scp>\n Intragenic Structural Variants as a Cause of Primary Brain Calcification"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2227-8162","authenticated-orcid":false,"given":"Wen\u2010Hao","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan\u2010Dan","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6883-3226","authenticated-orcid":false,"given":"Ze\u2010Hong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Fang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Geriatrics The Second Affiliated Hospital of Fujian Medical University Quanzhou Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2944-1614","authenticated-orcid":false,"given":"Xin\u2010Xin","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine Center The First Affiliated Hospital, Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Kun","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7948-6108","authenticated-orcid":false,"given":"Xiang\u2010Ping","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2010Zhen","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-4404","authenticated-orcid":false,"given":"Xue\u2010Wen","family":"Cheng","sequence":"additional","affiliation":[{"name":"Lin Gang Laboratory Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9655-9735","authenticated-orcid":false,"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4425-5294","authenticated-orcid":false,"given":"Wan\u2010Jin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1890-9640","authenticated-orcid":false,"given":"Jin\u2010Lan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Neurology The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture Enshi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2020-752X","authenticated-orcid":false,"given":"Yi\u2010Heng","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fujian Institute of Neurology the First Affiliated Hospital, Fujian Medical University Fuzhou China"},{"name":"Department of Rare Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University Fuzhou China"},{"name":"Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1093\/brain\/awz095","article-title":"Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype","volume":"142","author":"Grangeon L","year":"2019","journal-title":"Brain"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"3270","DOI":"10.1007\/s00415-023-11650-0","article-title":"The clinical and genetic spectrum of primary familial brain calcification","volume":"270","author":"Carecchio M","year":"2023","journal-title":"J Neurol"},{"key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1001\/jamaneurol.2014.3889","article-title":"Primary familial brain calcification with known gene mutations: a systematic review and challenges of phenotypic characterization","volume":"72","author":"Tadic V","year":"2015","journal-title":"JAMA Neurol"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1002\/ajmg.b.32605","article-title":"Estimation of minimal disease prevalence from population genomic data: application to primary familial brain calcification","volume":"177","author":"Nicolas G","year":"2018","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/ng.1077","article-title":"Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis","volume":"44","author":"Wang C","year":"2012","journal-title":"Nat Genet"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/ng.3289","article-title":"Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export","volume":"47","author":"Legati A","year":"2015","journal-title":"Nat Genet"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/ng.2723","article-title":"Mutations in the gene encoding PDGF\u2010B cause brain calcifications in humans and mice","volume":"45","author":"Keller A","year":"2013","journal-title":"Nat Genet"},{"key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1212\/WNL.0b013e31827ccf34","article-title":"Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification","volume":"80","author":"Nicolas G","year":"2013","journal-title":"Neurology"},{"key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1093\/brain\/awz392","article-title":"Biallelic loss\u2010of\u2010function mutations in JAM2 cause primary familial brain calcification","volume":"143","author":"Cen Z","year":"2020","journal-title":"Brain"},{"key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.neuron.2018.05.037","article-title":"Biallelic mutations in MYORG cause autosomal recessive primary familial brain calcification","volume":"98","author":"Yao X\u2010P","year":"2018","journal-title":"Neuron"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41421-022-00475-2","article-title":"Loss of function of CMPK2 causes mitochondria deficiency and brain calcification","volume":"8","author":"Zhao M","year":"2022","journal-title":"Cell Discov"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1038\/s41467-024-46354-0","article-title":"Biallelic NAA60 variants with impaired N\u2010terminal acetylation capacity cause autosomal recessive primary familial brain calcifications","volume":"15","author":"Chelban V","year":"2024","journal-title":"Nat Commun"},{"key":"e_1_2_9_14_1","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1002\/mds.70058","article-title":"RRP12\n variants are associated with autosomal recessive brain calcifications","volume":"40","author":"Monfrini E","year":"2025","journal-title":"Mov Disord"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1002\/mds.30207","article-title":"The genetic and phenotypic Spectrum of primary brain calcification in a large cohort from China","volume":"40","author":"Lin Z","year":"2025","journal-title":"Mov Disord"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.1093\/brain\/awt255","article-title":"Phenotypic spectrum of probable and genetically\u2010confirmed idiopathic basal ganglia calcification","volume":"136","author":"Nicolas G","year":"2013","journal-title":"Brain"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1186\/s13059-019-1828-7","article-title":"Structural variant calling: the long and the short of it","volume":"20","author":"Mahmoud M","year":"2019","journal-title":"Genome Biol"},{"key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/s41576-019-0180-9","article-title":"Structural variation in the sequencing era","volume":"21","author":"Ho SS","year":"2020","journal-title":"Nat Rev Genet"},{"key":"e_1_2_9_19_1","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/s41592-018-0001-7","article-title":"Accurate detection of complex structural variations using single\u2010molecule sequencing","volume":"15","author":"Sedlazeck FJ","year":"2018","journal-title":"Nat Methods"},{"key":"e_1_2_9_20_1","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1038\/s41467-025-57695-9","article-title":"Long read sequencing enhances pathogenic and novel variation discovery in patients with rare diseases","volume":"16","author":"Sinha S","year":"2025","journal-title":"Nat Commun"},{"key":"e_1_2_9_21_1","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.tig.2023.04.006","article-title":"Genomics in the long\u2010read sequencing era","volume":"39","author":"Van Dijk EL","year":"2023","journal-title":"Trends Genet"},{"key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41436-019-0686-8","article-title":"Technical standards for the interpretation and reporting of constitutional copy\u2010number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the clinical genome resource (ClinGen)","volume":"22","author":"Riggs ER","year":"2020","journal-title":"Genet Med"},{"key":"e_1_2_9_23_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting splicing from primary sequence with deep learning","volume":"176","author":"Jaganathan K","year":"2019","journal-title":"Cell"},{"key":"e_1_2_9_24_1","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.3390\/genes16111279","article-title":"PMP22\u2010related neuropathies: a systematic review","volume":"16","author":"Cesaroni CA","year":"2025","journal-title":"Genes (Basel)"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s13073-024-01411-7","article-title":"Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression","volume":"16","author":"Pehlivan D","year":"2024","journal-title":"Genome Med"},{"key":"e_1_2_9_26_1","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/nrg.2015.25","article-title":"Mechanisms underlying structural variant formation in genomic disorders","volume":"17","author":"Carvalho CMB","year":"2016","journal-title":"Nat Rev Genet"},{"key":"e_1_2_9_27_1","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.cell.2007.11.037","article-title":"A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders","volume":"131","author":"Lee JA","year":"2007","journal-title":"Cell"},{"key":"e_1_2_9_28_1","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrg2593","article-title":"Mechanisms of change in gene copy number","volume":"10","author":"Hastings PJ","year":"2009","journal-title":"Nat Rev Genet"},{"key":"e_1_2_9_29_1","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1093\/hmg\/ddu533","article-title":"Correlation between frequency of non\u2010allelic homologous recombination and homology properties: evidence from homology\u2010mediated CNV mutations in the human genome","volume":"24","author":"Peng Z","year":"2015","journal-title":"Hum Mol Genet"}],"container-title":["Movement Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.70576","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mds.70576","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.70576","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:19:03Z","timestamp":1792811943000},"score":1,"resource":{"primary":{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/10.1002\/mds.70576"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,23]]},"references-count":28,"alternative-id":["10.1002\/mds.70576"],"URL":"https:\/\/doi.org\/10.1002\/mds.70576","archive":["Portico"],"relation":{},"ISSN":["0885-3185","1531-8257"],"issn-type":[{"value":"0885-3185","type":"print"},{"value":"1531-8257","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,23]]},"assertion":[{"value":"2026-07-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"mds.70576"}}