{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T23:03:16Z","timestamp":1791500596804,"version":"4.3.4"},"reference-count":22,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["FOR2488"],"award-info":[{"award-number":["FOR2488"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Collaborative Center for X-linked Dystonia-Parkinsonism at Massachusetts General Hospital"},{"name":"Else-Kr\u00f6ner Fresenius Foundation"},{"DOI":"10.13039\/501100004168","name":"University of L\u00fcbeck","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004168","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain \u223c65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions.<\/jats:p>\n                  <jats:p>Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs.<\/jats:p>\n                  <jats:p>In addition to the canonical pure SINE-VNTR-Alu-5\u2032-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5\u2032-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5\u2032-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n], at median frequencies of 0.425 (IQR: 0.42\u20130.43) and 0.128 (IQR: 0.12\u20130.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = \u22123.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = \u221241.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = \u2212161.09, P = 3.44 \u00d7 10\u22125). When including the XDP-relevant MSH3\/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = \u221292.46430, P = 0.079).<\/jats:p>\n                  <jats:p>We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules.<\/jats:p>","DOI":"10.1093\/brain\/awac160","type":"journal-article","created":{"date-parts":[[2022,4,26]],"date-time":"2022-04-26T15:27:07Z","timestamp":1650986827000},"page":"1075-1082","source":"Crossref","is-referenced-by-count":29,"title":["Mosaic divergent repeat interruptions in XDP influence repeat stability and disease onset"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5317-7369","authenticated-orcid":false,"given":"Joanne","family":"Trinh","sequence":"first","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"L\u00fcth","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susen","family":"Schaake","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn-Hergen","family":"Laabs","sequence":"additional","affiliation":[{"name":"Institute of Medical Biometry and Statistics, University of L\u00fcbeck , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Schl\u00fcter","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"La\u03b2","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Pozojevic","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronnie","family":"Tse","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inke","family":"K\u00f6nig","sequence":"additional","affiliation":[{"name":"Institute of Medical Biometry and Statistics, University of L\u00fcbeck , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland Dominic","family":"Jamora","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, College of Medicine\u2014Philippine General Hospital, University of the Philippines Manila , Manila , Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6387-1389","authenticated-orcid":false,"given":"Raymond L","family":"Rosales","sequence":"additional","affiliation":[{"name":"Department of Neurology and Psychiatry, University of Santo Tomas and the CNS-Metropolitan Medical Center , Manila , Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5969-6899","authenticated-orcid":false,"given":"Norbert","family":"Br\u00fcggemann","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"},{"name":"Department of Neurology, University of L\u00fcbeck , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8322-4226","authenticated-orcid":false,"given":"Gerard","family":"Saranza","sequence":"additional","affiliation":[{"name":"Section of Neurology, Department of Internal Medicine, Chong Hua Hospital , Cebu , Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cid Czarina E","family":"Diesta","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Movement Disorders Clinic, Makati Medical Center , Makati City , Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics at the University Hospital Essen , Essen , Germany"},{"name":"Center for Rare Diseases (Essenser Zentrum f\u00fcr Seltene Erkrankungen\u2014EZSE) at the University Hospital Essen , Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christel","family":"Depienne","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics at the University Hospital Essen , Essen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher E","family":"Pearson","sequence":"additional","affiliation":[{"name":"Program of Genetics and Genome Biology, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning , Toronto , Canada"},{"name":"University of Toronto, Program of Molecular Genetics , Toronto , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Westenberger","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Klein","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics, University of L\u00fcbeck and University Hospital Schleswig-Holstein , L\u00fcbeck , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,27]]},"reference":[{"key":"2023030117482557600_","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/s41436-018-0408-7","article-title":"Insights into genetics, human biology and disease gleaned from family based genomic studies","volume":"21","author":"Posey","year":"2019","journal-title":"Genet Med"},{"key":"2023030117482557600_","first-page":"137","article-title":"Torsion dystonia in Panay, Philippines","volume":"14","author":"Lee","year":"1976","journal-title":"Adv 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