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Long-read GS is emerging as an attractive alternative, offering a more comprehensive assessment of the genome, but its utility still needs to be systematically evaluated in a clinical diagnostic setting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We prospectively included 100 children and adolescents (\u2264\u200920 years) with neurological disorders, newly referred for genetic testing. Routine DNA was used for singleton standard clinical short-read GS in parallel with long-read GS (Oxford Nanopore Technologies). In addition to comprehensive variant calling, long-read GS data was also phased and underwent methylation analysis. Variant interpretation was restricted to in-silico gene panels targeting either intellectual disability (1,568 genes) or neuromuscular disorders (1,035 genes) depending on the clinical presentation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The long-read GS generated an average of 111 GB data per sample, with a median read-length of 5\u00a0kb and average N50 of 16\u00a0kb; resulting in an average coverage of 34X. Short-read and long-read GS identified the same 29% diagnostic yield, including SNV\/INDELs (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200918), SVs (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20099), STRs (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20091), and uniparental disomy (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20091). Long-read GS provided additional diagnostic value in 13 cases involving 17 distinct variants, including phasing of\n                      <jats:italic>SMN1<\/jats:italic>\n                      and biallelic SNVs\/INDELs in autosomal recessive genes, accurate determination of STR length and sequence as well as detailed structural characterization of SVs. Of note, an unbalanced translocation, der(14)t(8;14)(p11.2;p23.1), required\n                      <jats:italic>de novo<\/jats:italic>\n                      assembly and T2T-CHM13 alignment to resolve the breakpoint junctions. Furthermore, long-read GS detected disease-associated aberrant methylation patterns in the Prader-Willi region and across an\n                      <jats:italic>FMR1<\/jats:italic>\n                      expansion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In a clinical diagnostic setting, long-read GS proved to be a streamlined, first-line test, capturing the full spectrum of disease-causing variants, reducing the need for follow-up testing and enabling more precise interpretation. While the overall diagnostic yield may be comparable to that of short-read approaches, long-read GS offers significant added value across multiple variant types.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-025-01596-5","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T09:25:17Z","timestamp":1767950717000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Long-read genome sequencing enhances diagnostics of pediatric neurological disorders"],"prefix":"10.1186","volume":"18","author":[{"given":"Marlene","family":"Ek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malin","family":"Kvarnung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmee","family":"Ten Berk de Boer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linn\u00e9a","family":"La Fleur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Lj\u00f6stad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lyander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren Lejsted","family":"Faergeman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon Opstrup","family":"Drue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kan","family":"Thonberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Nordgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Johansson","family":"Soller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valtteri","family":"Wirta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Eisfeldt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lindstrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"issue":"2","key":"1596_CR1","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.ridd.2010.12.018","volume":"32","author":"PK Maulik","year":"2011","unstructured":"Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. 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