Exome sequencing of a patient with suspected mitochondrial disease reveals a likely multigenic etiology.

TitleExome sequencing of a patient with suspected mitochondrial disease reveals a likely multigenic etiology.
Publication TypeJournal Article
Year of Publication2013
AuthorsCraigen, WJ, Graham, BH, Wong, L-J, Scaglia, F, Lewis, RAlan, Bonnen, PE
JournalBMC Med Genet
Date Published2013 Aug 16
KeywordsAdult, Computational Biology, DNA Helicases, Exome, Genetic Diseases, X-Linked, Genetic Loci, Homozygote, Humans, Male, Mitochondrial Diseases, Multifunctional Enzymes, Mutation, Missense, Nephrolithiasis, Oculocerebrorenal Syndrome, Pedigree, Phenotype, Phosphoric Monoester Hydrolases, RNA Helicases, RNA, Ribosomal, 16S, Sequence Analysis, DNA, Spinocerebellar Ataxias, Spinocerebellar Degenerations

BACKGROUND: The clinical features of mitochondrial disease are complex and highly variable, leading to challenges in establishing a specific diagnosis. Despite being one of the most commonly occurring inherited genetic diseases with an incidence of 1/5000, ~90% of these complex patients remain without a DNA-based diagnosis. We report our efforts to identify the pathogenetic cause for a patient with typical features of mitochondrial disease including infantile cataracts, CPEO, ptosis, progressive distal muscle weakness, and ataxia who carried a diagnosis of mitochondrial disease for over a decade.METHODS: Whole exome sequencing and bioinformatic analysis of these data were conducted on the proband.RESULTS: Exome sequencing studies showed a homozygous splice site mutation in SETX, which is known to cause Spinocerebellar Ataxia, Autosomal Recessive 1 (SCAR1). Additionally a missense mutation was identified in a highly conserved position of the OCRL gene, which causes Lowe Syndrome and Dent Disease 2.CONCLUSIONS: This patient's complex phenotype reflects a complex genetic etiology in which no single gene explained the complete clinical presentation. These genetic studies reveal that this patient does not have mitochondrial disease but rather a genocopy caused by more than one mutant locus. This study demonstrates the benefit of exome sequencing in providing molecular diagnosis to individuals with complex clinical presentations.

Alternate JournalBMC Med Genet
PubMed ID23947751
PubMed Central IDPMC3751849

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