{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:48:41Z","timestamp":1785473321497,"version":"3.56.0"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["UM1 HG008895"],"award-info":[{"award-number":["UM1 HG008895"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["5U01HG009088\u201002"],"award-info":[{"award-number":["5U01HG009088\u201002"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia Open"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recessive variants in <jats:italic>RARS2<\/jats:italic>, a nuclear gene encoding a mitochondrial protein, were initially reported in pontocerebellar hypoplasia. Subsequently, a recessive <jats:italic>RARS2<\/jats:italic> early\u2010infantile (&lt;12\u00a0weeks) developmental and epileptic encephalopathy was described with hypoglycaemia and lactic acidosis. Here, we describe two unrelated patients with a novel <jats:italic>RARS2<\/jats:italic> phenotype and reanalyse the published <jats:italic>RARS2<\/jats:italic> epilepsy phenotypes and variants. Our novel cases had infantile\u2010onset myoclonic developmental and epileptic encephalopathy, presenting with a progressive movement disorder from 9\u00a0months on a background of normal development. Development plateaued and regressed thereafter, with mild to profound impairment. Multiple drug\u2010resistant generalized and focal seizures occurred with episodes of non\u2010convulsive status epilepticus. Seizure types included absence, atonic, myoclonic, and focal seizures. Electroencephalograms showed diffuse slowing, multifocal, and generalised spike\u2010wave activity, activated by sleep. Both patients had compound heterozygous <jats:italic>RARS2<\/jats:italic> variants with likely impact on splicing and transcription. Remarkably, of the now 52 <jats:italic>RARS2<\/jats:italic> variants reported in 54 patients, our reanalysis found that 44 (85%) have been shown to or are predicted to affect splicing or gene expression leading to protein truncation or nonsense\u2010mediated decay. We expand the <jats:italic>RARS2<\/jats:italic> phenotypic spectrum to include infantile encephalopathy and suggest this gene is enriched for pathogenic variants that disrupt splicing.<\/jats:p>","DOI":"10.1002\/epi4.12553","type":"journal-article","created":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T18:42:44Z","timestamp":1635619364000},"page":"170-180","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Infantile\u2010onset myoclonic developmental and epileptic encephalopathy: A new <i>RARS2<\/i> phenotype"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6242-4306","authenticated-orcid":false,"given":"Guillem","family":"de Valles\u2010Ib\u00e1\u00f1ez","sequence":"first","affiliation":[{"name":"Department of Paediatrics and Child Health University of Otago Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Department of Medicine Epilepsy Research Centre University of Melbourne Austin Health Melbourne Victoria Australia"},{"name":"Murdoch Children\u2019s Research Institute Royal Children\u2019s Hospital Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5132-0774","authenticated-orcid":false,"given":"Melanie","family":"Bahlo","sequence":"additional","affiliation":[{"name":"Population Health and Immunity Division The Walter and Eliza Hall Institute of Medical Research Parkville Victoria Australia"},{"name":"Department of Medical Biology University of Melbourne Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chontelle","family":"King","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health University of Otago Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Coleman","sequence":"additional","affiliation":[{"name":"Department of Medicine Epilepsy Research Centre University of Melbourne Austin Health Melbourne Victoria Australia"},{"name":"Murdoch Children\u2019s Research Institute Royal Children\u2019s Hospital Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E.","family":"Green","sequence":"additional","affiliation":[{"name":"Department of Medicine Epilepsy Research Centre University of Melbourne Austin Health Melbourne Victoria Australia"},{"name":"Murdoch Children\u2019s Research Institute Royal Children\u2019s Hospital Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Goldsmith","sequence":"additional","affiliation":[{"name":"Waikids Paediatric Service Waikato District Health Board Hamilton New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Davis","sequence":"additional","affiliation":[{"name":"Starship Children\u2019s Hospital Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Gill","sequence":"additional","affiliation":[{"name":"T.Y. Nelson Department of Neurology and Neurosurgery The Children's Hospital at Westmead Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Mandelstam","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging Royal Children\u2019s Hospital Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2311-2174","authenticated-orcid":false,"given":"Ingrid E.","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Department of Medicine Epilepsy Research Centre University of Melbourne Austin Health Melbourne Victoria Australia"},{"name":"Murdoch Children\u2019s Research Institute Royal Children\u2019s Hospital Melbourne Victoria Australia"},{"name":"The Florey Institute of Neuroscience and Mental Health Melbourne, Victoria Australia"},{"name":"Departments of Paediatrics University of Melbourne Austin Health and Royal Children's Hospital Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5355-7115","authenticated-orcid":false,"given":"Lynette G.","family":"Sadleir","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health University of Otago Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1086\/521227"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2019.103766"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9413-6"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-012-9487-9"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2013-304308"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33531"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.13358"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2016.02.012"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2016_584"},{"issue":"1","key":"e_1_2_8_11_1","first-page":"1099","article-title":"Distinct magnetic 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