{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:52:25Z","timestamp":1790837545542,"version":"4.1.0"},"reference-count":20,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:00:00Z","timestamp":1673481600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["MDA604011"],"award-info":[{"award-number":["MDA604011"]}],"id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002108","name":"Friedreich Ataxia Research Alliance","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100002108","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CureFA Foundation"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,1,4]]},"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat (GAA-TRE) in intron 1 of the <jats:italic>FXN<\/jats:italic> gene. Some patients are compound heterozygous for the GAA-TRE and another <jats:italic>FXN<\/jats:italic> pathogenic variant. Detection of the GAA-TRE in the heterozygous state, occasionally technically challenging, is essential for diagnosing compound heterozygotes and asymptomatic carriers.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>We explored if the FRDA differentially methylated region (FRDA-DMR) in intron 1, which is hypermethylated in <jats:italic>cis<\/jats:italic> with the GAA-TRE, effectively detects heterozygous GAA-TRE.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                     <jats:italic>FXN<\/jats:italic> DNA methylation was assayed by targeted bisulfite deep sequencing using the Illumina platform.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>FRDA-DMR methylation effectively identified a cohort of known heterozygous carriers of the GAA-TRE. In an individual with clinical features of FRDA, commercial testing showed a paternally inherited pathogenic <jats:italic>FXN<\/jats:italic> initiation codon variant but no GAA-TRE. Methylation in the FRDA-DMR effectively identified the proband, his mother and various maternal relatives as heterozygous carriers of the GAA-TRE, thus confirming the diagnosis of FRDA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                     <jats:italic>FXN<\/jats:italic> DNA methylation reliably detects the GAA-TRE in the heterozygous state and offers a robust alternative strategy to diagnose FRDA due to compound heterozygosity and to identify asymptomatic heterozygous carriers of the GAA-TRE.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2022-108742","type":"journal-article","created":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T13:21:11Z","timestamp":1673529671000},"page":"797-800","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["<i>FXN<\/i> gene methylation determines carrier status in Friedreich ataxia"],"prefix":"10.1136","volume":"60","author":[{"given":"Christina","family":"Lam","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn M","family":"Gilliam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Layne N","family":"Rodden","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"},{"name":"Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly A","family":"Schadt","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"Lynch","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6191-6475","authenticated-orcid":false,"given":"Sanjay","family":"Bidichandani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"},{"name":"Department of Biochemistry & Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,1,12]]},"reference":[{"key":"2025101714442409000_60.8.797.1","unstructured":"Bidichandani SI , Delatycki MB . Friedreich Ataxia. In: Adam MP , Everman DB , Mirzaa GM , eds. GeneReviews\u00ae. Seattle (WA): University of Washington, Seattle, 1998: 1993\u20132022. https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1281\/"},{"key":"2025101714442409000_60.8.797.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5254.1423"},{"key":"2025101714442409000_60.8.797.3","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio815"},{"key":"2025101714442409000_60.8.797.4","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm271"},{"key":"2025101714442409000_60.8.797.5","doi-asserted-by":"publisher","DOI":"10.1086\/301680"},{"key":"2025101714442409000_60.8.797.6","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.11.1771"},{"key":"2025101714442409000_60.8.797.7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/jnc.12303","article-title":"Mitochondrial pathophysiology in Friedreich's ataxia","volume":"126 Suppl 1","author":"Gonz\u00e1lez-Cabo","year":"2013","journal-title":"J Neurochem"},{"key":"2025101714442409000_60.8.797.8","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddaa267"},{"key":"2025101714442409000_60.8.797.9","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.752921"},{"key":"2025101714442409000_60.8.797.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-09002-5"},{"key":"2025101714442409000_60.8.797.11","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(199902)45:2<200::AID-ANA10>3.0.CO;2-U"},{"key":"2025101714442409000_60.8.797.12","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24595"},{"key":"2025101714442409000_60.8.797.13","first-page":"554","article-title":"The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia","volume":"59","author":"Filla","year":"1996","journal-title":"Am J Hum Genet"},{"key":"2025101714442409000_60.8.797.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2010.08.001"},{"key":"2025101714442409000_60.8.797.15","doi-asserted-by":"publisher","DOI":"10.1016\/S1525-1578(10)60523-5"},{"key":"2025101714442409000_60.8.797.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2022.04.008"},{"key":"2025101714442409000_60.8.797.17","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2011.834"},{"key":"2025101714442409000_60.8.797.18","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1999)13:4<328::AID-HUMU10>3.0.CO;2-J"},{"key":"2025101714442409000_60.8.797.19","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.18.2175"},{"key":"2025101714442409000_60.8.797.20","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21052"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2022-108742","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T21:44:38Z","timestamp":1760737478000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2022-108742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,12]]},"references-count":20,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,7,21]]},"published-print":{"date-parts":[[2023,8]]}},"alternative-id":["10.1136\/jmg-2022-108742"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2022-108742","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,12]]}}}