atypical case of wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial diseasewolfram综合症的典型案例显示通过有针对性的外显子组测序在疑似患者线粒体疾病.pdfVIP

Lieber et al. BMC Medical Genetics 2012, 13:3 /1471-2350/13/3 CASE REPORT Open Access Atypical case of Wolfram syndrome revealed through targeted exome sequencing in a patient with suspected mitochondrial disease 1,2,3,4† 1,2,3,4,5† 6 1,2 1,2 1,4 Daniel S Lieber , Scott B Vafai , Laura C Horton , Nancy G Slate , Shangtao Liu , Mark L Borowsky , Sarah E Calvo1,2,3,4, Jeremy D Schmahmann6* and Vamsi K Mootha1,2,3,4* Abstract 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 demonstr