{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:56:33Z","timestamp":1781636193015,"version":"3.54.5"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T00:00:00Z","timestamp":1771632000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T00:00:00Z","timestamp":1771632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004721","name":"The University of Tokyo","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004721","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurogenetics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hypomyelinating leukodystrophy 15 (HLD15) results from biallelic pathogenic variants in\n                    <jats:italic>EPRS1<\/jats:italic>\n                    , but exonic deletions have not been reported. We describe a 40-year-old woman with mild intellectual disability, ataxia, dystonia, and MRI showing hypomyelination. Whole-exome sequencing identified a heterozygous missense variant in the prolyl-tRNA synthetase domain of\n                    <jats:italic>EPRS1<\/jats:italic>\n                    (c.3430\u00a0C\u2009&gt;\u2009G; p.Leu1144Val, NM_004446.3), without second variant. Whole-genome sequencing revealed a heterozygous 220-bp deletion spanning exon 15 (c.1743-30_1932del), and segregation analysis confirmed compound heterozygosity. RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele. These findings support loss-of-function for the deletion and classify c.3430\u00a0C\u2009&gt;\u2009G as likely pathogenic under ACMG\/AMP criteria (PM1, PM2, PM3, PP3). This case represents the first exonic deletion reported in\n                    <jats:italic>EPRS1<\/jats:italic>\n                    . The relatively mild, adult-onset phenotype broadens both mutational and clinical spectra of HLD15 and highlights the importance of structural-variant analysis when only a single candidate variant is detected in recessive leukodystrophy.\n                  <\/jats:p>","DOI":"10.1007\/s10048-026-00885-4","type":"journal-article","created":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T03:50:47Z","timestamp":1771645847000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15"],"prefix":"10.1007","volume":"27","author":[{"given":"Akihiko","family":"Mitsutake","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Matsukawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Orimo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunihiro","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonari","family":"Seki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Shiio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Mitsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Ishiura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harushi","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsushi","family":"Toda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,21]]},"reference":[{"key":"885_CR1","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/s41582-020-00432-1","volume":"17","author":"NI Wolf","year":"2021","unstructured":"Wolf NI, Ffrench-Constant C, van der Knaap MS (2021) Hypomyelinating leukodystrophies - unravelling Myelin biology. Nat Rev Neurol 17:88\u2013103","journal-title":"Nat Rev Neurol"},{"key":"885_CR2","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.ajhg.2015.02.012","volume":"96","author":"C Simons","year":"2015","unstructured":"Simons C, Griffin LB, Helman G et al (2015) Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect. Am J Hum Genet 96:675\u2013681","journal-title":"Am J Hum Genet"},{"key":"885_CR3","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1016\/j.ajhg.2013.04.006","volume":"92","author":"RJ Taft","year":"2013","unstructured":"Taft RJ, Vanderver A, Leventer RJ et al (2013) Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am J Hum Genet 92:774\u2013780","journal-title":"Am J Hum Genet"},{"key":"885_CR4","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.ajhg.2018.02.011","volume":"102","author":"MI Mendes","year":"2018","unstructured":"Mendes MI, Gutierrez Salazar M, Guerrero K et al (2018) Bi-allelic mutations in EPRS, encoding the glutamyl-prolyl-aminoacyl-tRNA synthetase, cause a hypomyelinating leukodystrophy. Am J Hum Genet 102:676\u2013684","journal-title":"Am J Hum Genet"},{"key":"885_CR5","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1002\/ana.24167","volume":"76","author":"NI Wolf","year":"2014","unstructured":"Wolf NI, Salomons GS, Rodenburg RJ et al (2014) Mutations in RARS cause hypomyelination. Ann Neurol 76:134\u2013139","journal-title":"Ann Neurol"},{"key":"885_CR6","doi-asserted-by":"publisher","first-page":"4284","DOI":"10.1038\/s41467-024-48549-x","volume":"15","author":"D Khan","year":"2024","unstructured":"Khan D, Ramachandiran I, Vasu K et al (2024) Homozygous EPRS1 missense variant causing hypomyelinating leukodystrophy-15 alters variant-distal mRNA m6A site accessibility. Nat Commun 15:4284","journal-title":"Nat Commun"},{"key":"885_CR7","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754\u20131760","journal-title":"Bioinformatics"},{"key":"885_CR8","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Handsaker B, Wysoker A et al (2009) The sequence Alignment\/Map format and samtools. Bioinformatics 25:2078\u20132079","journal-title":"Bioinformatics"},{"key":"885_CR9","doi-asserted-by":"publisher","first-page":"e1010625","DOI":"10.1371\/journal.pgen.1010625","volume":"19","author":"Y Kawai","year":"2023","unstructured":"Kawai Y, Watanabe Y, Omae Y et al (2023) Exploring the genetic diversity of the Japanese population: insights from a large-scale whole genome sequencing analysis. PLoS Genet 19:e1010625","journal-title":"PLoS Genet"},{"key":"885_CR10","doi-asserted-by":"publisher","first-page":"e10","DOI":"10.5808\/GI.2020.18.1.e10","volume":"18","author":"KR Franke","year":"2020","unstructured":"Franke KR, Crowgey EL (2020) Accelerating next generation sequencing data analysis: an evaluation of optimized best practices for genome analysis toolkit algorithms. Genom Inf 18:e10","journal-title":"Genom Inf"},{"key":"885_CR11","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1093\/bioinformatics\/btv710","volume":"32","author":"X Chen","year":"2016","unstructured":"Chen X, Schulz-Trieglaff O, Shaw R et al (2016) Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32:1220\u20131222","journal-title":"Bioinformatics"},{"key":"885_CR12","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 17:405\u2013424","journal-title":"Genet Med"},{"key":"885_CR13","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1111\/cge.14269","volume":"103","author":"D Jin","year":"2023","unstructured":"Jin D, Wek SA, Cordova RA et al (2023) Aminoacylation-defective bi-allelic mutations in human EPRS1 associated with psychomotor developmental delay, epilepsy, and deafness. Clin Genet 103:358\u2013363","journal-title":"Clin Genet"},{"key":"885_CR14","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.molcel.2008.01.010","volume":"29","author":"J Jia","year":"2008","unstructured":"Jia J, Arif A, Ray PS et al (2008) WHEP domains direct noncanonical function of glutamyl-Prolyl tRNA synthetase in translational control of gene expression. Mol Cell 29:679\u2013690","journal-title":"Mol Cell"},{"key":"885_CR15","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1006\/geno.1994.1059","volume":"19","author":"E Kaiser","year":"1994","unstructured":"Kaiser E, Hu B, Becher S et al (1994) The human EPRS locus (formerly the QARS locus): a gene encoding a class I and a class II aminoacyl-tRNA synthetase. Genomics 19:280\u2013290","journal-title":"Genomics"}],"container-title":["Neurogenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10048-026-00885-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10048-026-00885-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10048-026-00885-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:36:08Z","timestamp":1781634968000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10048-026-00885-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,21]]},"references-count":15,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["885"],"URL":"https:\/\/doi.org\/10.1007\/s10048-026-00885-4","relation":{},"ISSN":["1364-6753"],"issn-type":[{"value":"1364-6753","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,21]]},"assertion":[{"value":"30 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16"}}