title: Diagnosis of mitochondrial disorders by concomitant next-generation sequencing of the exome and mitochondrial genome.
abstract: Mitochondrial diseases are notoriously difficult to diagnose due to extreme locus and allelic heterogeneity, with both nuclear and mitochondrial genomes potentially liable. Using exome sequencing we demonstrate the ability to rapidly and cost effectively evaluate both the nuclear and mitochondrial genomes to obtain a molecular diagnosis for four patients with three distinct mitochondrial disorders. One patient was found to have Leigh syndrome due to a mutation in MT-ATP6, two affected siblings were discovered to be compound heterozygous for mutations in the NDUFV1 gene, which causes mitochondrial complex I deficiency, and one patient was found to have coenzyme Q10 deficiency due to compound heterozygous mutations in COQ2. In all cases conventional diagnostic testing failed to identify a molecular diagnosis. We suggest that additional studies should be conducted to evaluate exome sequencing as a primary diagnostic test for mitochondrial diseases, including those due to mtDNA mutations.
authors: Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA. dldinwiddie@salud.unm.edu
authors: Darrell L
authors: DL
authors: Dinwiddie
authors: Laurie D
authors: LD
authors: Smith
authors: Neil A
authors: NA
authors: Miller
authors: Andrea M
authors: AM
authors: Atherton
authors: Emily G
authors: EG
authors: Farrow
authors: Meghan E
authors: ME
authors: Strenk
authors: Sarah E
authors: SE
authors: Soden
authors: Carol J
authors: CJ
authors: Saunders
authors: Stephen F
authors: SF
authors: Kingsmore
mesh_terms: D001259:Ataxia / Q000175:diagnosis / Q000235:genetics; D002675:Child, Preschool; D042967:Electron Transport Complex I / Q000172:deficiency / Q000235:genetics; D059472:Exome; D005260:Female; D014644:Genetic Variation; D054629:Genome, Mitochondrial; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007888:Leigh Disease / Q000175:diagnosis / Q000235:genetics; D008928:Mitochondria / Q000235:genetics; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics; D025202:Molecular Diagnostic Techniques; D018908:Muscle Weakness / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D014451:Ubiquinone / Q000172:deficiency / Q000235:genetics
chemical_list: D014451:Ubiquinone; D042967:Electron Transport Complex I
keywords: CoQ10 deficiency; Exome; Homoplasmy; Inborn error of metabolism; Lactic academia; Leigh syndrome; MT-ATP6; Mitochondrial complex I; Mitochondrial genome; Molecular diagnostics; Next-generation sequencing
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