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Lieber, Daniel Solomon

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Lieber

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Daniel Solomon

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Lieber, Daniel Solomon
Author's Publications: search.filters.isAuthorOfPublication.50287c04-609e-46ae-ae37-7887c016c32c

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    Computational and Experimental Approaches For Evaluating the Genetic Basis of Mitochondrial Disorders
    (2013-10-08) Lieber, Daniel Solomon; Mootha, Vamsi Krishna; Springer, Michael; Walsh, Christopher; Korson, Mark; Hirschorn, Joel; Church, George; Ruvkun, Gary
    Mitochondria are responsible for many fundamental biological pathways and metabolic processes, including aerobic ATP production by the mitochondrial respiratory chain. In humans, mitochondrial dysfunction can lead to severe disorders of energy metabolism, which are collectively referred to as mitochondrial disorders and affect approximately 1:5,000 individuals. These disorders are clinically heterogeneous and can affect multiple organ systems, often within a single individual. Symptoms can include myopathy, exercise intolerance, hearing loss, blindness, stroke, seizures, diabetes, and GI dysmotility. Mutations in over 150 genes in the mitochondrial DNA (mtDNA) and nuclear genome are known to cause mitochondrial diseases and an additional ~1,000 nuclear-encoded mitochondrial proteins have the potential to underlie mitochondrial disorders but have not yet been linked to human disease. As a result, determining a molecular diagnosis for patients with suspected mitochondrial disorders remains a challenge.
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    Atypical Case Of Wolfram Syndrome Revealed Through Targeted Exome Sequencing In A Patient With Suspected Mitochondrial Disease
    (BioMed Central, 2012) Lieber, Daniel Solomon; Vafai, Scott B.; Horton, Laura C; Slate, Nancy G; Liu, Shangtao; Borowsky, Mark L; Calvo, Sarah; Schmahmann, Jeremy; Mootha, Vamsi
    Background: 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. Conclusion: 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.