{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:19:03Z","timestamp":1784027943705,"version":"3.55.0"},"reference-count":14,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,10,9]],"date-time":"2020-10-09T00:00:00Z","timestamp":1602201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["UM1 HG008900"],"award-info":[{"award-number":["UM1 HG008900"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["R01 HG009141"],"award-info":[{"award-number":["R01 HG009141"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["U54HD090255"],"award-info":[{"award-number":["U54HD090255"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Inherited optic neuropathies (IONs) are neurodegenerative disorders characterized by optic atrophy with or without extraocular manifestations. Optic atrophy\u201010 (OPA10) is an autosomal recessive ION recently reported to be caused by mutations in <jats:italic>RTN4IP1<\/jats:italic>, which encodes reticulon 4 interacting protein 1 (RTN4IP1), a mitochondrial ubiquinol oxydo\u2010reductase. Here we report novel compound heterozygous mutations in <jats:italic>RTN4IP1<\/jats:italic> in a male proband with developmental delay, epilepsy, optic atrophy, ataxia, and choreoathetosis. Workup was notable for transiently elevated lactate and lactate\u2010to\u2010pyruvate ratio, brain magnetic resonance imaging with optic atrophy and T2 signal abnormalities, and a nondiagnostic initial genetic workup, including chromosomal microarray and mitochondrial panel testing. Exome sequencing identified a paternally inherited missense variant (c.263T&gt;G, p.Val88Gly) predicted to be deleterious and a maternally inherited deletion encompassing <jats:italic>RTN4IP1<\/jats:italic>. To our knowledge, this is the first report of a non\u2010single nucleotide pathogenic variant associated with OPA10. This case highlights the expanding phenotypic spectrum of OPA10, the association between \u201csyndromic\u201d cases and severe <jats:italic>RTN4IP1<\/jats:italic> mutations, and the importance of nonbiased genetic testing, such as ES, to analyze multiple genes and variants types, in patients suspected of having genetic disease.<\/jats:p>","DOI":"10.1002\/ajmg.a.61910","type":"journal-article","created":{"date-parts":[[2020,10,10]],"date-time":"2020-10-10T06:52:23Z","timestamp":1602312743000},"page":"203-207","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Exome sequencing identifies novel missense and deletion variants in <scp><i>RTN4IP1<\/i><\/scp> associated with optic atrophy, global developmental delay, epilepsy, ataxia, and choreoathetosis"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2482-5328","authenticated-orcid":false,"given":"Alissa M.","family":"D'Gama","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children's Hospital  Boston Massachusetts USA"},{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleina","family":"England","sequence":"additional","affiliation":[{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A.","family":"Madden","sequence":"additional","affiliation":[{"name":"The Manton Center for Orphan Disease Research, Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahai","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences City University of Hong Kong  Hong Kong Hong Kong SAR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine R.","family":"Chao","sequence":"additional","affiliation":[{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8162-5031","authenticated-orcid":false,"given":"Monica H.","family":"Wojcik","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children's Hospital  Boston Massachusetts USA"},{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alcy R.","family":"Torres","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Department of Pediatrics, Boston Medical Center Boston University School of Medicine  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1593-6149","authenticated-orcid":false,"given":"Wen\u2010Hann","family":"Tan","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard T.","family":"Berry","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay P.","family":"Prabhu","sequence":"additional","affiliation":[{"name":"Neuroradiology Division, Department of Radiology, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj B.","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children's Hospital  Boston Massachusetts USA"},{"name":"The Broad Institute of MIT and Harvard  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,10,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00234-012-1006-z"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.09.012"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.2065"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046688"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.07.002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.176601"},{"key":"e_1_2_9_11_1","unstructured":"NHLBI Exome Variant Server (EVS)(2012). 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