{"entity": "publication", "iuid": "cc2f6e9d03384fbbaa52dc9055e4ff12", "timestamp": "2026-08-21T13:03:49.198Z", "links": {"self": {"href": "https://publications.scilifelab.se/publication/cc2f6e9d03384fbbaa52dc9055e4ff12.json"}, "display": {"href": "https://publications.scilifelab.se/publication/cc2f6e9d03384fbbaa52dc9055e4ff12"}}, "title": "Long-read genome sequencing enhances diagnostics of pediatric neurological disorders.", "authors": [{"family": "Ek", "given": "Marlene", "initials": "M"}, {"family": "Kvarnung", "given": "Malin", "initials": "M"}, {"family": "Ten Berk de Boer", "given": "Esmee", "initials": "E"}, {"family": "La Fleur", "given": "Linn\u00e9a", "initials": "L"}, {"family": "Lj\u00f6stad", "given": "Lena", "initials": "L"}, {"family": "Lyander", "given": "Anna", "initials": "A"}, {"family": "Faergeman", "given": "S\u00f8ren Lejsted", "initials": "SL"}, {"family": "Drue", "given": "Simon Opstrup", "initials": "SO"}, {"family": "Thonberg", "given": "H\u00e5kan", "initials": "H"}, {"family": "Nordgren", "given": "Ann", "initials": "A"}, {"family": "Soller", "given": "Maria Johansson", "initials": "MJ"}, {"family": "Wirta", "given": "Valtteri", "initials": "V"}, {"family": "Eisfeldt", "given": "Jesper", "initials": "J"}, {"family": "Lindstrand", "given": "Anna", "initials": "A"}], "type": "journal article", "published": "2026-01-09", "journal": {"title": "Genome Med", "issn": "1756-994X", "volume": "18", "issue": "1", "pages": "12", "issn-l": "1756-994X"}, "abstract": "Singleton short-read genome sequencing (GS) is increasingly used as a first-line genetic test for childhood neurological disorders (such as intellectual disability, neurodevelopmental delay, motor delay, and hypotonia) with diagnostic yields from 26 to 35%, typically involving a mix of single nucleotide variants and small insertions/deletions (SNV/INDELs), structural variants (SVs), and short tandem repeats (STRs). 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.\n\nWe prospectively included 100 children and adolescents (\u2264 20 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.\n\nThe long-read GS generated an average of 111 GB data per sample, with a median read-length of 5 kb and average N50 of 16 kb; resulting in an average coverage of 34X. Short-read and long-read GS identified the same 29% diagnostic yield, including SNV/INDELs (n = 18), SVs (n = 9), STRs (n = 1), and uniparental disomy (n = 1). Long-read GS provided additional diagnostic value in 13 cases involving 17 distinct variants, including phasing of SMN1 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 de novo 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 FMR1 expansion.\n\nIn 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.", "doi": "10.1186/s13073-025-01596-5", "pmid": "41514368", "labels": {"Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12838436"}, {"db": "pii", "key": "10.1186/s13073-025-01596-5"}], "notes": [], "created": "2026-08-20T14:12:42.223Z", "modified": "2026-08-20T14:12:42.226Z"}