Use of Whole-Exome Sequencing to Determine the Genetic Basis of Multiple Mitochondrial Respiratory Chain Complex Deficiencies

• Autores: Robert W. Taylo, Angela Pyle, Helen Griffin
• Localización: JAMA: the journal of the American Medical Association, ISSN 0098-7484, Vol. 312, Nº. 1, 2014, págs. 68-77
• Idioma: inglés
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• Resumen

  • Importance Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked to human disease.

    Objective To determine the molecular basis of multiple respiratory chain complex deficiencies.

    Design, Setting, and Participants We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012. All had biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed using 62-Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family.