{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:07:45Z","timestamp":1781237265098,"version":"3.54.1"},"reference-count":36,"publisher":"SAGE Publications","issue":"17-18","license":[{"start":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T00:00:00Z","timestamp":1745193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T00:00:00Z","timestamp":1745193600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:p>\n                    Canavan disease (CD) is a rare autosomal recessive leukodystrophy caused by biallelic pathogenic variants in the\n                    <jats:italic toggle=\"yes\">ASPA<\/jats:italic>\n                    gene. CD is characterized by developmental delay, macrocephaly, and abnormal muscle tone. The biochemical diagnosis is confirmed by increased\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -acetylaspartic acid levels. The phenotypic presentation varies, with 85\u201390% of individuals exhibiting the severe, typical form, while 10\u201315% present with a milder, atypical form. Here we report on five patients with a clinical and biochemically proven diagnosis in whom a second pathogenic variant had not yet been identified. Targeted long-read sequencing of the entire\n                    <jats:italic toggle=\"yes\">ASPA<\/jats:italic>\n                    gene revealed an SVA_E retrotransposable element located in intron 4 that had been missed by standard short-read-based diagnostic procedures. Haplotype analysis of all patients showed linkage of the SVA_E element with a noncoding variant in intron 1. Functional characterization of the SVA_E element suggests that transcripts of the affected allele are prone to highly efficient mRNA degradation processes. These findings enhance the precision of genetic diagnostics and enable improved guidance for families as well as facilitating potential access to targeted therapies.\n                  <\/jats:p>","DOI":"10.1089\/hum.2025.006","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T06:54:51Z","timestamp":1745218491000},"page":"1248-1256","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Deep Intronic SVA_E Retrotransposition as a Novel Factor in Canavan Disease Pathogenesis"],"prefix":"10.1177","volume":"36","author":[{"given":"Melina","family":"Wei\u00df","sequence":"first","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Selig","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Wierczeiko","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Diederich","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Sigel","sequence":"additional","affiliation":[{"name":"University Medical Center Hamburg-Eppendorf, University Children\u2019s Hospital, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Bredow","sequence":"additional","affiliation":[{"name":"University Medical Center Hamburg-Eppendorf, University Children\u2019s Hospital, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian S.","family":"Eichler","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Seyler","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Holth\u00f6fer","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Gerber","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susann","family":"Schweiger","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Germany"},{"name":"Leibniz Institute for Resilience Research, Mainz, Germany"},{"name":"Institute of Molecular Biology (IMB), Mainz, 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,4,21]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320290234"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1385\/JMN:21:3:185"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20334"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-020-01659-3"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23181"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2024.168"},{"key":"e_1_3_6_8_2","volume-title":"GeneReviews\u00ae","author":"Nagy A","year":"1993","unstructured":"Nagy A, , Bley AE, , Eichler F. 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University of Washington, Seattle: Seattle (WA); 1993\u20132025. 1999 Sep 16 [updated 2023 Dec 21]."},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1994.1278"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.04.025"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.MDNA3-0001-2014"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2010.04.001"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01841-4"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1086\/380207"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2024-110056"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj6987"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06457-y"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.29610"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-024-01711-0"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0407-5"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-023-05349-1"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz365"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btad492"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1086\/500307"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22981"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-024-01421-5"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2005.09.085"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.093153.109"},{"issue":"1","key":"e_1_3_6_30_2","first-page":"34","article-title":"Canavan disease: Mutations among Jewish and non-Jewish patients","volume":"55","author":"Kaul R","year":"1994","unstructured":"Kaul R, , Gao GP, , Aloya M, et al. 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