Exome sequencing of a patient with suspected mitochondrial disease reveals a likely multigenic etiology.
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
William J
WJ
Craigen
Brett H
BH
Graham
Lee-Jun
LJ
Wong
Fernando
F
Scaglia
Richard Alan
RA
Lewis
Penelope E
PE
Bonnen
D000328:Adult; D019295:Computational Biology; D004265:DNA Helicases; D059472:Exome; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D056426:Genetic Loci; D006720:Homozygote; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics*; D064251:Multifunctional Enzymes; D020125:Mutation, Missense; D053040:Nephrolithiasis / Q000235:genetics; D009800:Oculocerebrorenal Syndrome / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D020365:RNA Helicases / Q000235:genetics*; D012336:RNA, Ribosomal, 16S / Q000302:isolation & purification; D017422:Sequence Analysis, DNA / Q000379:methods*; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics
D064251:Multifunctional Enzymes; D012336:RNA, Ribosomal, 16S; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases