{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:15:55Z","timestamp":1788156955027,"version":"build-2803163510"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Frontotemporal dementia and amyotrophic lateral sclerosis are clinically distinct disorders that share a common genetic etiology, with pathogenic hexanucleotide repeat expansions in the\n                      <jats:italic>C9orf72<\/jats:italic>\n                      gene representing the most frequent genetic cause of both conditions. In this study we aim to determine the frequency of\n                      <jats:italic>C9orf72<\/jats:italic>\n                      repeat expansions in patients with FTD and\/or ALS and their at-risk relatives from central Portugal, and to analyze the distribution and repeat size of intermediate alleles within this cohort investigating their potential pathogenicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Between January 2016 and January 2026,\n                      <jats:italic>C9orf72<\/jats:italic>\n                      repeat expansions were assessed in 610 patients with the clinical presentation within the spectrum of FTD\/ALS and in 63 asymptomatic relatives.\n                      <jats:italic>C9orf72<\/jats:italic>\n                      repeat expansions were identified using a two-step PCR protocol comprising STR-PCR and RP-PCR, followed by repeat-length sizing with a commercial kit. Capillary electrophoresis traces were subsequently analyzed using AmplideX\u00ae PCR\/CE Reporter software. Furthermore, carriers of intermediate alleles underwent comprehensive clinical, fluid-biomarker, and neuropsychological characterization to investigate the potential pathogenicity of these alleles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Pathogenic\n                      <jats:italic>C9orf72<\/jats:italic>\n                      expansions were identified in 11% of patients. The vast majority carried long expansions (&amp;gt;145 repeats), whereas three patients exhibited shorter expansions ranging from 38 to 78 repeats. Intermediate alleles were found in seven subjects with heterogeneous clinical presentations. Clinically, these individuals were indistinguishable from carriers of longer expansions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>C9orf72<\/jats:italic>\n                      hexanucleotide repeat expansions are a major genetic cause of FTD, ALS, and FTD\u2013ALS in this cohort of patients, highlighting the importance of genetic testing for accurate counselling and clinical management. These findings support routine\n                      <jats:italic>C9orf72<\/jats:italic>\n                      testing in all patients with these disorders, particularly those of European ancestry. Our findings also support the emerging view that intermediate C9orf72 repeat expansions may act as a genetic risk factors contributing to a broad spectrum of clinical phenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1913909","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T05:41:00Z","timestamp":1788154860000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The spectrum of C9orf72 repeat lengths in Portuguese frontotemporal dementia and amyotrophic lateral sclerosis patients: from pathogenic expansions to intermediate alleles"],"prefix":"10.3389","volume":"20","author":[{"given":"Maria Ros\u00e1rio","family":"Almeida","sequence":"first","affiliation":[{"name":"CIBB \u2013 Center for Innovative Biomedicine and Biotechnology, University of Coimbra","place":["Coimbra, Portugal"]},{"name":"CNC-UC \u2013 Center for Neuroscience and Cell Biology, University of Coimbra","place":["Coimbra, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"T\u00e1buas-Pereira","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universit\u00e1rio de Coimbra, Unidade Local de Sa\u00fade de Coimbra (ULS-Coimbra)","place":["Coimbra, Portugal"]},{"name":"Faculty of Medicine, University of Coimbra","place":["Coimbra, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabela","family":"Matos","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universit\u00e1rio de Coimbra, Unidade Local de Sa\u00fade de Coimbra (ULS-Coimbra)","place":["Coimbra, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Santos","sequence":"additional","affiliation":[{"name":"CIBB \u2013 Center for Innovative Biomedicine and Biotechnology, University of Coimbra","place":["Coimbra, Portugal"]},{"name":"CNC-UC \u2013 Center for Neuroscience and Cell Biology, University of Coimbra","place":["Coimbra, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Teixeira","sequence":"additional","affiliation":[{"name":"CIBB \u2013 Center for Innovative Biomedicine and Biotechnology, University of Coimbra","place":["Coimbra, Portugal"]},{"name":"CNC-UC \u2013 Center for Neuroscience and Cell Biology, University of Coimbra","place":["Coimbra, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Baldeiras","sequence":"additional","affiliation":[{"name":"CIBB \u2013 Center for Innovative Biomedicine and Biotechnology, University of Coimbra","place":["Coimbra, Portugal"]},{"name":"CNC-UC \u2013 Center for Neuroscience and Cell Biology, University of Coimbra","place":["Coimbra, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"Lima","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Universit\u00e1rio de Coimbra, Unidade Local de Sa\u00fade de Coimbra (ULS-Coimbra)","place":["Coimbra, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Santana","sequence":"additional","affiliation":[{"name":"CNC-UC \u2013 Center for Neuroscience and Cell Biology, University of Coimbra","place":["Coimbra, Portugal"]},{"name":"Department of Neurology, Hospital Universit\u00e1rio de Coimbra, Unidade Local de Sa\u00fade de Coimbra (ULS-Coimbra)","place":["Coimbra, Portugal"]},{"name":"Faculty of Medicine, University of Coimbra","place":["Coimbra, Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2909168","DOI":"10.1155\/2019\/2909168","article-title":"Molecular mechanisms of neurodegeneration related to C9orf72 hexanucleotide repeat expansion","volume":"2019","author":"Babi\u0107 Leko","year":"2019","journal-title":"Behav. 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