{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T20:45:08Z","timestamp":1780778708198,"version":"3.54.1"},"reference-count":12,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T00:00:00Z","timestamp":1585612800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"The Legacy Heritage Bio-Medical program of the Israel Science Foundation","award":["1798\/16"],"award-info":[{"award-number":["1798\/16"]}]},{"name":"The Morris Kahn Family Foundation and the National Knowledge Center for Rare \/ Orphan Diseases sponsored by the Israel Ministry of Science, Technology and Space"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>COX15<\/jats:italic> mutations were shown to underlie Leigh syndrome (LS), a progressive subacute necrotizing encephalopathy caused by defects in the mitochondrial respiratory chain. Here, two siblings of consanguineous kindred presented in infancy with a syndrome of hypotonia, nystagmus, psychomotor retardation, and pyramidal signs. Toward the end of their second year, both patients developed progressive quadriparesis, convulsions, and pseudobulbar palsy. Similar to two previously reported cases, one of the two affected siblings had severe hypertrophic obstructive cardiomyopathy, hearing loss, and no visual response. Through linkage analysis and whole\u2010exome sequencing, we identified a homozygous p.R217W mutation in Cytochrome C oxidase assembly protein COX15 homolog. Consistent with the known heterogeneity of mitochondrial diseases in general and that of LS in particular, several phenotypic features were markedly distinguished between the affected siblings and in relation to previous reports of <jats:italic>COX15<\/jats:italic> mutations. Interestingly, of the previously reported five cases of <jats:italic>COX15<\/jats:italic>\u2010mutated patients, all of different ethnic origins, three had a p.R217W mutation. We highlight p.R217W as a hotspot mutation in <jats:italic>COX15<\/jats:italic> and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date.<\/jats:p>","DOI":"10.1002\/ajmg.a.61577","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T08:36:29Z","timestamp":1585643789000},"page":"1506-1512","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Phenotypic variability and mutation hotspot in <scp><i>COX15<\/i><\/scp>\u2010related Leigh syndrome"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1598-989X","authenticated-orcid":false,"given":"Daniel","family":"Halperin","sequence":"first","affiliation":[{"name":"Faculty of Health Sciences, The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev Ben\u2010Gurion University of the Negev  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Drabkin","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev Ben\u2010Gurion University of the Negev  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ohad","family":"Wormser","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev Ben\u2010Gurion University of the Negev  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2218-9938","authenticated-orcid":false,"given":"Yuval","family":"Yogev","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev Ben\u2010Gurion University of the Negev  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Dolgin","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev Ben\u2010Gurion University of the Negev  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zamir","family":"Shorer","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Unit, Division of Pediatrics Soroka University Medical Center, Ben\u2010Gurion University of the Negev  Beer\u2010Sheva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Libe","family":"Gradstein","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Soroka University Medical Center and Clalit Health Services, Ben\u2010Gurion University of the Negev  Beer\u2010Sheva 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Israel"},{"name":"Genetics Institute, Soroka University Medical Center  Beer\u2010Sheva 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