{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T21:42:55Z","timestamp":1787175775787,"version":"build-2736575974"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Biogen Japan Ltd"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease. Most patients with SMA have a mutation in the\n                      <jats:italic>survival motor neuron 1<\/jats:italic>\n                      (\n                      <jats:italic>SMN1<\/jats:italic>\n                      ) gene on chromosome 5q. With current genetic testing,\n                      <jats:italic>SMN1<\/jats:italic>\n                      copy number is determined; a diagnosis is reached when the copy number is zero. When the\n                      <jats:italic>SMN1<\/jats:italic>\n                      copy number is 1, exons and intron\/exon boundaries of the allele are examined for single-nucleotide variants (SNVs). Genetically undiagnosed cases of SMA exist when 2 copies of\n                      <jats:italic>SMN1<\/jats:italic>\n                      exist or when a SNV is in the deep intron. Furthermore,\n                      <jats:italic>SMN1<\/jats:italic>\n                      is highly homologous to\n                      <jats:italic>SMN2<\/jats:italic>\n                      ; therefore, it is expected that many SNVs have not been elucidated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This retrospective observational study conducted in Japan used pre-collected DNA samples from patients with clinically diagnosed SMA. Enrollment period was January 28, 2020 to September 30, 2021. SNV analysis of\n                      <jats:italic>SMN1<\/jats:italic>\n                      (exon 1\u20138 and intron 1\u20137) was conducted by long-range polymerase chain reaction and next-generation sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      From 336 DNA samples collected from patients, 62 patient samples were included in the SNV analysis. Two patients have been genetically diagnosed (a heterozygous variant in intron 6 with 1 copy of\n                      <jats:italic>SMN1<\/jats:italic>\n                      ; a homozygous missense mutation in exon 3 with 2 copies of\n                      <jats:italic>SMN1<\/jats:italic>\n                      ). Three SNVs in intron 6, c.834+1506A&gt;G (n\u2009=\u20099), c.834+1751G&gt;A (n\u2009=\u20092), and c.835-367C&gt;A (n\u2009=\u20095) were identified; all were numerically, and c.834+1506A&gt;G and c.835-367C&gt;A were significantly, more frequent in patients with 0 copies versus those with\u2009\u2265\u20091 copy of exon 7 in\n                      <jats:italic>SMN1<\/jats:italic>\n                      . We confirmed 3 hybrid\n                      <jats:italic>SMN<\/jats:italic>\n                      gene types in 5 patients that contained\n                      <jats:italic>SMN2<\/jats:italic>\n                      gene sequence (aaTgg) flanked by upstream \u201ct\u201d and downstream \u201cG\u201d\n                      <jats:italic>SMN1<\/jats:italic>\n                      sequence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In this study of patients with clinically diagnosed SMA, 2 cases with genetic\n                      <jats:italic>SMN<\/jats:italic>\n                      types were identified that would not have been identified through current genetic testing, which examines\n                      <jats:italic>SMN1<\/jats:italic>\n                      deletions only. Furthermore, for 1 patient with a homozygous\n                      <jats:italic>SMN1<\/jats:italic>\n                      missense mutation, SMA was not suspected by the current copy number screening method. This study demonstrated the importance of performing full-length sequencing for clinically diagnosed SMA to complement current screening methods.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>Trial registration<\/jats:italic>\n                      : University Hospital Medical Information Network Clinical Trials Registry (Number: UMIN000040095).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-025-03568-9","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T04:33:02Z","timestamp":1738902782000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genomic analysis of the SMN1 gene region in patients with clinically diagnosed spinal muscular atrophy: a retrospective observational study"],"prefix":"10.1186","volume":"20","author":[{"given":"Tamaki","family":"Kato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamoru","family":"Yokomura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Osawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"Matsuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Kubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taihei","family":"Homma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2632-0873","authenticated-orcid":false,"given":"Kayoko","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"3568_CR1","doi-asserted-by":"publisher","first-page":"7896","DOI":"10.3390\/ijms22157896","volume":"22","author":"MER Butchbach","year":"2021","unstructured":"Butchbach MER. 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Written informed consent form was obtained by patients prior to data collection. This study was conducted in accordance with the protocol, the Declaration of Helsinki, and all relevant regulations and guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"TK, MY, YO, KM, and YK have no conflicts of interest to declare. TH is an employee of\u00a0Biogen Japan Ltd and owns shares in Biogen USA. KS has received research funds from Biogen Japan Ltd., and received lecture fees from Biogen Japan Ltd, Novartis AG, and Chugai Pharmaceutical Co. Ltd.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"55"}}