{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:36:21Z","timestamp":1760236581869,"version":"build-2065373602"},"reference-count":27,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01 AR068429"],"award-info":[{"award-number":["R01 AR068429"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>SLC25A46 (solute carrier family 25 member 46) mutations have been linked to various neurological diseases with recessive inheritance, including Leigh syndrome, optic atrophy, and lethal congenital pontocerebellar hypoplasia. SLC25A46 is expressed in the outer membrane of mitochondria, where it plays a critical role in mitochondrial dynamics. A deceased 7-month-old female infant was suspected to have Leigh syndrome. Clinical exome sequencing was non-diagnostic, but research reanalysis of the sequencing data identified two novel variants in SLC25A46: a missense (c.1039C&gt;T, p.Arg347Cys; NM_138773, hg19) and a donor splice region variant (c.283+5G&gt;A) in intron 1. Both variants were predicted to be damaging. Sanger sequencing of cDNA detected a single missense allele in the patient compared to control, and the SLC25A46 transcript levels were also reduced due to the splice region variant. Additionally, Western blot analysis of whole-cell lysate showed a decrease of SLC25A46 expression in proband fibroblasts, relative to control cells. Further, analysis of mitochondrial morphology revealed evidence of increased fragmentation of the mitochondrial network in proband fibroblasts, compared to control cells. Collectively, our findings suggest that these novel variants in SLC24A46, the donor splice one and the missense variant, are the cause of the neurological phenotype in this proband.<\/jats:p>","DOI":"10.3390\/jpm11121277","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T21:19:08Z","timestamp":1638479948000},"page":"1277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reanalysis of Exome Data Identifies Novel SLC25A46 Variants Associated with Leigh Syndrome"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0069-8512","authenticated-orcid":false,"given":"Qifei","family":"Li","sequence":"first","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School,\r\nBoston, MA 02115, USA"},{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill A.","family":"Madden","sequence":"additional","affiliation":[{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School,\r\nBoston, MA 02115, USA"},{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2198-1296","authenticated-orcid":false,"given":"Jasmine","family":"Lin","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School,\r\nBoston, MA 02115, USA"},{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahai","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, City University of Hong Kong, Kowloon, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha M.","family":"Rosen","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School,\r\nBoston, MA 02115, USA"},{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Schmitz-Abe","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School,\r\nBoston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pankaj B.","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"name":"The Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Harvard Medical School,\r\nBoston, MA 02115, USA"},{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1038\/ng.3354","article-title":"Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder","volume":"47","author":"Abrams","year":"2015","journal-title":"Nat. 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