Phenotypic variability and mutation hotspot in COX15-related Leigh syndrome

Daniel Halperin, Max Drabkin, Ohad Wormser, Yuval Yogev, Vadim Dolgin, Zamir Shorer, Libe Gradstein, Ilan Shelef, Hagit Flusser, Ohad S. Birk

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3 Scopus citations


COX15 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-exome 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 COX15 mutations. Interestingly, of the previously reported five cases of COX15-mutated patients, all of different ethnic origins, three had a p.R217W mutation. We highlight p.R217W as a hotspot mutation in COX15 and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date.

Original languageEnglish
Pages (from-to)1506-1512
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Issue number6
StatePublished - 1 Jun 2020


  • COX15
  • Leigh syndrome
  • mutation hotspot


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