{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:25:00Z","timestamp":1770290700874,"version":"3.49.0"},"reference-count":3,"publisher":"BMJ","issue":"3","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,1,8]]},"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:p>Biallelic pathogenic variants in <jats:italic>C2orf69<\/jats:italic> cause a fatal autosomal recessive multisystem disorder characterized by recurrent autoinflammation, hypomyelination, progressive neurodegeneration, microcephaly, failure to thrive, liver dysfunction, respiratory chain defects and accumulation of glycogen in skeletal muscle. No missense variants in <jats:italic>C2orf69<\/jats:italic> have been reported to date.<\/jats:p>\n               <jats:p>We report a 6-year-old boy with microcephaly, global developmental delays, lower limb spasticity with hyperreflexia, epilepsy, abnormal brain MRI, failure to thrive, recurrent fevers and transaminitis. Whole-exome sequencing identified a homozygous missense c.320 C&gt;G, p.(Pro107Arg) variant of uncertain significance (VUS) in <jats:italic>C2orf69<\/jats:italic>. Skeletal muscle biopsy showed active and chronic muscle fibre degeneration with deposits of periodic acid\u2013Schiff-positive material in affected tissues, consistent with abnormal glycogen storage. Mitochondrial respiratory assays were normal in muscle tissue. Primary patient fibroblasts showed normal levels of mRNA expression but significantly reduced levels of endogenous C2ORF69 protein and GBE1 by Western blot. We report a patient with a homozygous missense variant in <jats:italic>C2orf69<\/jats:italic>, causing loss of function. Depletion of endogenous GBE1 in affected cells can be considered a biomarker for this disorder and assist in the interpretation of VUS in <jats:italic>C2orf69<\/jats:italic>. This expands the clinical and genetic spectrum of <jats:italic>C2orf69<\/jats:italic>-related disorder.<\/jats:p>","DOI":"10.1136\/jmg-2024-110419","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T13:20:36Z","timestamp":1737638436000},"page":"206-209","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Homozygous missense variant in <i>C2orf69<\/i> causes early-onset neurodegeneration, leukoencephalopathy and autoinflammation"],"prefix":"10.1136","volume":"62","author":[{"given":"Rachel Youjin","family":"Oh","sequence":"first","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Maier","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), Republic of Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Blaser","sequence":"additional","affiliation":[{"name":"Division of Neuroradiology, Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessie","family":"Cameron","sequence":"additional","affiliation":[{"name":"Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada"},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"},{"name":"Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruno","family":"Reversade","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore (GIS), Agency for Science Technology and Research (A*STAR), Republic of Singapore"},{"name":"Department of Physiology, Cardiovascular Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore"},{"name":"Laboratory of Human Genetics & Therapeutics, BESE, KAUST, Thuwal, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0415-4416","authenticated-orcid":false,"given":"Grace","family":"Yoon","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada"},{"name":"Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"2025101713124010000_62.3.206.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.05.003"},{"key":"2025101713124010000_62.3.206.2","doi-asserted-by":"crossref","unstructured":"Lausberg E , Gie\u00dfelmann S , Dewulf JP , et al . C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation. J Clin Invest 2021;131. doi:10.1172\/JCI143078","DOI":"10.1172\/JCI143078"},{"key":"2025101713124010000_62.3.206.3","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.63310"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2024-110419","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T20:12:48Z","timestamp":1760731968000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2024-110419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":3,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2,26]]},"published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1136\/jmg-2024-110419"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2024-110419","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,23]]}}}