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Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease

Daniel S Lieber1234, Scott B Vafai12345, Laura C Horton6, Nancy G Slate12, Shangtao Liu12, Mark L Borowsky14, Sarah E Calvo1234, Jeremy D Schmahmann6* and Vamsi K Mootha1234*

Author Affiliations

1 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA

2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA

3 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA

4 Broad Institute of Harvard and MIT, Cambridge, MA 02141, USA

5 Diabetes Unit and Endocrine Division, Massachusetts General Hospital, Boston, MA 02114, USA

6 Ataxia Unit, Cognitive and Behavioral Neurology Unit, Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston MA 02114, USA

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BMC Medical Genetics 2012, 13:3  doi:10.1186/1471-2350-13-3

Published: 6 January 2012



Mitochondrial diseases comprise a diverse set of clinical disorders that affect multiple organ systems with varying severity and age of onset. Due to their clinical and genetic heterogeneity, these diseases are difficult to diagnose. We have developed a targeted exome sequencing approach to improve our ability to properly diagnose mitochondrial diseases and apply it here to an individual patient. Our method targets mitochondrial DNA (mtDNA) and the exons of 1,600 nuclear genes involved in mitochondrial biology or Mendelian disorders with multi-system phenotypes, thereby allowing for simultaneous evaluation of multiple disease loci.

Case Presentation

Targeted exome sequencing was performed on a patient initially suspected to have a mitochondrial disorder. The patient presented with diabetes mellitus, diffuse brain atrophy, autonomic neuropathy, optic nerve atrophy, and a severe amnestic syndrome. Further work-up revealed multiple heteroplasmic mtDNA deletions as well as profound thiamine deficiency without a clear nutritional cause. Targeted exome sequencing revealed a homozygous c.1672C > T (p.R558C) missense mutation in exon 8 of WFS1 that has previously been reported in a patient with Wolfram syndrome.


This case demonstrates how clinical application of next-generation sequencing technology can enhance the diagnosis of patients suspected to have rare genetic disorders. Furthermore, the finding of unexplained thiamine deficiency in a patient with Wolfram syndrome suggests a potential link between WFS1 biology and thiamine metabolism that has implications for the clinical management of Wolfram syndrome patients.