{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T15:31:24Z","timestamp":1789486284935,"version":"build-2803163510"},"reference-count":11,"publisher":"Walter de Gruyter GmbH","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,24]]},"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n \n Hereditary transthyretin amyloidosis (ATTRv) is a rare autosomal dominant disorder caused by pathogenic variants in the\n TTR<\/jats:italic>\n gene, with marked clinical heterogeneity and frequent underdiagnosis. Genetic confirmation is essential for patient management but is traditionally based on Sanger sequencing or short-read next-generation sequencing (NGS), which are time-consuming or costly. We evaluated the clinical utility of a long-read sequencing strategy using Oxford Nanopore Technologies (ONT) for comprehensive\n TTR<\/jats:italic>\n gene analysis.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We developed an optimized long-range PCR (6,941\u202fbp) followed by ONT MinION sequencing workflow covering the entire\n TTR<\/jats:italic>\n gene. Analytical performance was evaluated in two independent diagnostic laboratories using a total of 89 previously characterized samples (64 from laboratory #1 and 25 from laboratory #2). The method was subsequently implemented for routine clinical testing in 445 additional patients referred for suspected ATTRv amyloidosis. Performance metrics, variant detection rates, turnaround time, and concordance with short-read NGS were assessed.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n All previously identified pathogenic or likely pathogenic\n TTR<\/jats:italic>\n variants were correctly detected, and no false-positive calls. As expected, the most frequent variants were p.(Val142Ile) and p.(Val50Met). Results were fully concordant with short-read NGS. Flowcell washing and reuse considerably lowered reagent costs without compromising an accurate\n TTR<\/jats:italic>\n genotyping. Implementation of the ONT workflow reduced turnaround time compared with Illumina-based targeted panels.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Long-read ONT sequencing of the\n TTR<\/jats:italic>\n gene provides a robust, rapid, and economical alternative to conventional methods for genetic diagnosis of ATTRv amyloidosis. The approach we developed is well suited for routine clinical laboratories and supports systematic screening of\n TTR<\/jats:italic>\n variants in patients with suspected\u00a0ATTR.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1515\/cclm-2026-0553","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:18:01Z","timestamp":1779207481000},"page":"1939-1946","source":"Crossref","is-referenced-by-count":0,"title":["Long-read Oxford Nanopore sequencing enables rapid, cost-effective, and comprehensive\n TTR<\/i>\n genetic testing for hereditary transthyretin amyloidosis"],"prefix":"10.1515","volume":"64","author":[{"given":"Gilles","family":"Millat","sequence":"first","affiliation":[{"name":"UF Cardiog\u00e9n\u00e9tique Mol\u00e9culaire, LBMMS, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon , Lyon , France"},{"name":"Institut NeuroMyoG\u00e8ne, Laboratoire Physiopathologie et G\u00e9n\u00e9tique du Neurone et du Muscle, CNRS UMR 5261\u00a0\u2013\u00a0INSERM U1315, Universit\u00e9 de Lyon\u00a0\u2013\u00a0Universit\u00e9 Claude Bernard Lyon 1 , Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kahia","family":"Messaoudi","sequence":"additional","affiliation":[{"name":"Constitutional Genetics Laboratory, Amiens University Hospital , Amiens , France"},{"name":"UR4666 HEMATIM, Universit\u00e9 de Picardie Jules Verne , Amiens , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Chanavat","sequence":"additional","affiliation":[{"name":"UF Cardiog\u00e9n\u00e9tique Mol\u00e9culaire, LBMMS, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon , Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin","family":"Testard","sequence":"additional","affiliation":[{"name":"Cellule de Bioinformatique, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon , Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Lucain","sequence":"additional","affiliation":[{"name":"UF Cardiog\u00e9n\u00e9tique Mol\u00e9culaire, LBMMS, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon , Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Cazeneuve","sequence":"additional","affiliation":[{"name":"UF Cardiog\u00e9n\u00e9tique Mol\u00e9culaire, LBMMS, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon , Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Jedraszak","sequence":"additional","affiliation":[{"name":"Constitutional Genetics Laboratory, Amiens University Hospital , Amiens , France"},{"name":"UR4666 HEMATIM, Universit\u00e9 de Picardie Jules Verne , Amiens , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Janin","sequence":"additional","affiliation":[{"name":"UF Cardiog\u00e9n\u00e9tique Mol\u00e9culaire, LBMMS, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon , Lyon , France"},{"name":"Institut NeuroMyoG\u00e8ne, Laboratoire Physiopathologie et G\u00e9n\u00e9tique du Neurone et du Muscle, CNRS UMR 5261\u00a0\u2013\u00a0INSERM U1315, Universit\u00e9 de Lyon\u00a0\u2013\u00a0Universit\u00e9 Claude Bernard Lyon 1 , Lyon , France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"2026091512595707890_j_cclm-2026-0553_ref_001","doi-asserted-by":"crossref","unstructured":"Porcari, A, Fontana, M, Gillmore, JD. Transthyretin cardiac amyloidosis. Cardiovasc Res 2023;118:3517\u201335. https:\/\/doi.org\/10.1093\/cvr\/cvac119.","DOI":"10.1093\/cvr\/cvac119"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_002","doi-asserted-by":"crossref","unstructured":"Fargeot, G, Echaniz-Laguna, A, Labeyrie, C, Svahn, J, Camdessanch\u00e9, JP, Cintas, P, et al.. Hereditary transthyretin amyloidosis in middle-aged and elderly patients with idiopathic polyneuropathy: a nationwide prospective study. Amyloid 2024;31:62\u20139. https:\/\/doi.org\/10.1080\/13506129.2023.2270661.","DOI":"10.1080\/13506129.2023.2270661"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_003","doi-asserted-by":"crossref","unstructured":"Schmidt, HH, Waddington-Cruz, M, Botteman, MF, Carter, JA, Chopra, AS, Hopps, M, et al.. Estimating the global prevalence of transthyretin familial amyloid polyneuropathy. Muscle Nerve 2018;57:829\u201337. https:\/\/doi.org\/10.1002\/mus.26034.","DOI":"10.1002\/mus.26034"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_004","doi-asserted-by":"crossref","unstructured":"Delgado, D, Dabbous, F, Shivappa, N, Mazhar, F, Wittbrodt, E, Shridharmurthy, D, et al.. Epidemiology of transthyretin (ATTR) amyloidosis: a systematic literature review. Orphanet J Rare Dis 2025;20:29. https:\/\/doi.org\/10.1186\/s13023-025-03547-0.","DOI":"10.1186\/s13023-025-03547-0"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_005","doi-asserted-by":"crossref","unstructured":"Misra, P, Blancas-Mejia, LM, Ramirez-Alvarado, M. Mechanistic insights into the early events in the aggregation of immunoglobulin light chains. Biochemistry 2019;58:3155\u201368. https:\/\/doi.org\/10.1021\/acs.biochem.9b00311.","DOI":"10.1021\/acs.biochem.9b00311"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_006","doi-asserted-by":"crossref","unstructured":"Kontorovich, AR, Benson, CB, McClellan, A, Belbin, GM, Kenny, EE, Abul-Husn, NS. Evolving knowledge of red flag clinical features associated with TTR p.(Val142Ile) in a diverse electronic health-record-linked biobank. Genet Med 2025;27:101346. https:\/\/doi.org\/10.1016\/j.gim.2024.101346.","DOI":"10.1016\/j.gim.2024.101346"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_007","doi-asserted-by":"crossref","unstructured":"Caponetti, AG, Sguazzotti, M, Accietto, A, Saturi, G, Ponziani, A, Giovannetti, A, et al.. Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral centre. Eur J Prev Cardiol 2024;31:866\u201376. https:\/\/doi.org\/10.1093\/eurjpc\/zwae011.","DOI":"10.1093\/eurjpc\/zwae011"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_008","doi-asserted-by":"crossref","unstructured":"Janin, A, Januel, L, Cazeneuve, C, Delini\u00e8re, A, Chevalier, P, Millat, G. Molecular diagnosis of inherited cardiac diseases in the era of next-generation sequencing: a single center\u2019s experience over 5\u00a0years. Mol Diagn Ther 2021;25:373\u201385. https:\/\/doi.org\/10.1007\/s40291-021-00530-w.","DOI":"10.1007\/s40291-021-00530-w"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_009","doi-asserted-by":"crossref","unstructured":"Chandrashekar, P, Alhuneafat, L, Mannello, M, Al-Rashdan, L, Kim, MM, Dungu, J, et al.. Prevalence and outcomes of p.Val142Ile TTR amyloidosis cardiomyopathy: a systematic review. Circ Genomic Precis Med 2021;14:e003356. https:\/\/doi.org\/10.1161\/CIRCGEN.121.003356.","DOI":"10.1161\/CIRCGEN.121.003356"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_010","doi-asserted-by":"crossref","unstructured":"Dinatolo, F, Procopio, R, Rocca, V, Lo Feudo, E, Dattola, A, D\u2019Antona, L, et al.. Hereditary transthyretin amyloidosis: genetic characterization of the TTR P.Val142Ile variant in a Calabrian kindred. Genes 2025;16:960. https:\/\/doi.org\/10.3390\/genes16080960.","DOI":"10.3390\/genes16080960"},{"key":"2026091512595707890_j_cclm-2026-0553_ref_011","doi-asserted-by":"crossref","unstructured":"Bourfiss, M, van Vugt, M, Alasiri, AI, Ruijsink, B, van Setten, J, Schmidt, AF, et al.. Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population. Circ Genom Precis Med 2022;15:e003704. https:\/\/doi.org\/10.1161\/CIRCGEN.122.003704.","DOI":"10.1161\/CIRCGEN.122.003704"}],"container-title":["Clinical Chemistry and Laboratory Medicine (CCLM)"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/cclm-2026-0553\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/cclm-2026-0553\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:04:19Z","timestamp":1789477459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/cclm-2026-0553\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":11,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,3,13]]},"published-print":{"date-parts":[[2026,8,24]]}},"alternative-id":["10.1515\/cclm-2026-0553"],"URL":"https:\/\/doi.org\/10.1515\/cclm-2026-0553","relation":{},"ISSN":["1434-6621","1437-4331"],"issn-type":[{"value":"1434-6621","type":"print"},{"value":"1437-4331","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]}}}