{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:50:02Z","timestamp":1787320202072,"version":"build-2736575974"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T00:00:00Z","timestamp":1754870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurogenetics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Familial Adult Myoclonic Epilepsy type 3 (FAME3) is a rare autosomal dominant disorder characterized by cortical tremor and epilepsy, caused by a noncoding pentanucleotide repeat expansion (TTTTA\/TTTCA)\n                    <jats:sub>n<\/jats:sub>\n                    in the\n                    <jats:italic>MARCHF6<\/jats:italic>\n                    gene. Conventional genetic testing often fails to detect this expansion due to its repetitive structure and intronic location. We evaluated a 61-year-old woman with refractory myoclonic and generalized tonic-clonic seizures, whose prior genetic testing\u2014including exome and genome sequencing\u2014was non-diagnostic. Using PacBio HiFi long-read whole-genome sequencing and the tandem repeat genotyping tool TRGT, we identified a pathogenic\n                    <jats:italic>MARCHF6<\/jats:italic>\n                    intronic expansion. The proband harbored one allele with 15\n                    <jats:italic>TTTTA<\/jats:italic>\n                    repeats and a second allele with a compound expansion of 661\n                    <jats:italic>TTTTA<\/jats:italic>\n                    and 12\n                    <jats:italic>TTTCA<\/jats:italic>\n                    repeats. Three affected relatives shared similarly expanded alleles, but with increasing repeat size in the latter generations. Importantly, analysis using TRGT-instability revealed repeat mosaicism in all affected individuals, reflected by variability in motif counts across individual sequencing reads. This somatic heterogeneity may contribute to the phenotypic penetrance, variable expressivity and pleiotropism seen in FAME3 disease expression. To our knowledge, this is the first clinical diagnosis of FAME3 using a commercially available long-read sequencing platform, underscoring its diagnostic utility in resolving complex repeat expansion disorders and uncovering biologically relevant mosaicism.\n                  <\/jats:p>","DOI":"10.1007\/s10048-025-00835-6","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T10:18:25Z","timestamp":1754907505000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["First clinical diagnosis of FAME3 via commercial Long-Read sequencing reveals mosaic repeat expansion in MARCHF6 gene"],"prefix":"10.1007","volume":"26","author":[{"given":"B. Lakshitha A.","family":"Perera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Furuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly M.","family":"Ezell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynette","family":"Rives","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Nunley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"McMinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyson","family":"Krokosky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Koziura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Undiagnosed Diseases Network","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rizwan","family":"Hamid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy D.","family":"Cogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Cassini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric R.","family":"Gamazon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Phillips III","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory J.","family":"Tinker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"key":"835_CR1","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1212\/01.wnl.0000260063.46425.7e","volume":"68","author":"JA Carr","year":"2007","unstructured":"Carr JA, van der Walt PE, Nakayama J, Fu Y-H, Corfield V, Brink P, Ptacek L (2007) FAME 3: a novel form of progressive myoclonus and epilepsy. 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E.R.G. is a co-inventor on patents for molecular signatures of cardiovascular phenotypes and metabolic health, use of RNAs as therapeutics and biomarkers in disease, and methods in metabolomics. R.S. was previously an employee of Singular Genomics, a genomics device manufacturer. R.S. holds company stock options from this employment. R.S. has not received compensation from or performed work for this company since July 2022.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosures"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"61"}}