{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:23:28Z","timestamp":1775175808656,"version":"3.50.1"},"reference-count":18,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T00:00:00Z","timestamp":1647388800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Heterozygous <jats:italic>KMT2B<\/jats:italic> variants are a common cause of dystonia. A novel synonymous <jats:italic>KMT2B<\/jats:italic> variant, c.5073C&gt;T (p.Gly1691=) was identified in an individual with childhood\u2010onset progressive dystonia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The splicing impact of c.5073C&gt;T was assessed using an in vitro exon\u2010trapping assay. The genomic region of <jats:italic>KMT2B<\/jats:italic> exons 23\u201326 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat <jats:italic>Ins2<\/jats:italic> gene. The c.5073C&gt;T variant was then introduced through site\u2010directed mutagenesis. The <jats:italic>KMT2B<\/jats:italic> wild\u2010type and c.5073C&gt;T plasmids were transfected separately into HeLa cells and RNA was extracted 48\u00a0hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR amplified using primers annealing to the flanking rat <jats:italic>Ins2<\/jats:italic> sequences.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sanger sequencing of the PCR products revealed that c.5073C&gt;T caused a novel splice donor site and therefore a 5\u2010bp deletion of <jats:italic>KMT2B<\/jats:italic> exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>To our knowledge, this is the first report of a <jats:italic>KMT2B<\/jats:italic> synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for <jats:italic>KMT2B<\/jats:italic>\u2010related dystonia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1923","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T07:47:47Z","timestamp":1647416867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A novel synonymous <scp><i>KMT2B<\/i><\/scp> variant in a patient with dystonia causes aberrant splicing"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-0551","authenticated-orcid":false,"given":"Bianca R.","family":"Grosz","sequence":"first","affiliation":[{"name":"Northcott Neuroscience Laboratory ANZAC Research Institute  Concord New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Tisch","sequence":"additional","affiliation":[{"name":"Department of Neurology St Vincent's Hospital  Darlinghurst New South Wales Australia"},{"name":"School of Medicine University of New South Wales  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel C.","family":"Tchan","sequence":"additional","affiliation":[{"name":"Clinical Genomics St Vincent's Hospital  Darlinghurst New South Wales Australia"},{"name":"Department of Genetic Medicine Westmead Hospital  Westmead New South Wales Australia"},{"name":"Sydney Medical School, Faculty of Medicine and Health University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor S. C.","family":"Fung","sequence":"additional","affiliation":[{"name":"Sydney Medical School, Faculty of Medicine and Health University of Sydney  Sydney New South Wales Australia"},{"name":"Movement Disorders Unit, Neurology Department Westmead Hospital  Westmead New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Darveniza","sequence":"additional","affiliation":[{"name":"Department of Neurology St Vincent's Hospital  Darlinghurst New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5354-9134","authenticated-orcid":false,"given":"Avi","family":"Fellner","sequence":"additional","affiliation":[{"name":"Kinghorn Centre for Clinical Genomics Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"},{"name":"Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital  Petah Tikva Israel"},{"name":"Department of Neurology, Rabin Medical Center Beilinson Hospital  Petah Tikva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manju A.","family":"Kurian","sequence":"additional","affiliation":[{"name":"Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison","family":"McLean","sequence":"additional","affiliation":[{"name":"Clinical Genomics St Vincent's Hospital  Darlinghurst New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan E.","family":"Tomlinson","sequence":"additional","affiliation":[{"name":"Department of Neurology St Vincent's Hospital  Darlinghurst New South Wales Australia"},{"name":"Sydney Medical School, Faculty of Medicine and Health University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renee","family":"Smyth","sequence":"additional","affiliation":[{"name":"Clinical Genomics St Vincent's Hospital  Darlinghurst New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Devery","sequence":"additional","affiliation":[{"name":"Clinical Genomics St Vincent's Hospital  Darlinghurst New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathy H. 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