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

Lookup NU author(s): Professor Robert Taylor, Dr Angela Pyle, Dr Helen GriffinORCiD, Dr Jennifer Duff, Dr Langping He, Tania Smertenko, Dr Charlotte Alston, Vivienne Neeve, Dr Andrew Best, John Yarham, Dr Andrew Morris, Professor Grainne Gorman, Dr Vankateswara Ramesh, Emeritus Professor Doug Turnbull, Dr Mauro Santibanez Koref, Professor Bobby McFarlandORCiD, Professor Rita HorvathORCiD, Professor Patrick Chinnery


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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.RESULTS Presumptive causal variants were identified in 28 patients (53%; 95% CI, 39%-67%) and possible causal variants were identified in 4 (8%; 95% CI, 2%-18%). Together these accounted for 32 patients (60% 95% CI, 46%-74%) and involved 18 different genes. These included recurrent mutations in RMND1, AARS2, and MTO1, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (VARS2, GARS, FLAD1, and PTCD1). Distinguishing clinical features included deafness and renal involvement associated with RMND1 and cardiomyopathy with AARS2 and MTO1. However, atypical clinical features were present in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with TRMU mutations and no cardiomyopathy with founder SCO2 mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%; 95% CI, 26%-54%).CONCLUSIONS AND RELEVANCE Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods.

Publication metadata

Author(s): Taylor RW, Pyle A, Griffin H, Blakely EL, Duff J, He LP, Smertenko T, Alston CL, Neeve VC, Best A, Yarham JW, Kirschner J, Schara U, Talim B, Topaloglu H, Baric I, Holinski-Feder E, Abicht A, Czermin B, Kleinle S, Morris AAM, Vassallo G, Gorman GS, Ramesh V, Turnbull DM, Santibanez-Koref M, McFarland R, Horvath R, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Journal of the American Medical Association

Year: 2014

Volume: 312

Issue: 1

Pages: 68-77

Print publication date: 02/07/2014

Acceptance date: 01/01/1900

ISSN (print): 0098-7484

ISSN (electronic): 1538-3598

Publisher: American Medical Association


DOI: 10.1001/jama.2014.7184


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Funder referenceFunder name
Newcastle University
NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
101876/Z/13/ZWellcome Trust Senior Fellow in Clinical Science
096919Z/11/ZWellcome Trust Centre for Mitochondrial Research
309548European Research Council
G1000848UK Medical Research Council
G0601943UK Medical Research Council Centre for Translational Muscle Diseases
G0800674Mitochondrial Disease Patient Cohort