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


METHODS
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.


CONCLUSIONS
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.
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Daniel S
DS
Lieber
Scott B
SB
Vafai
Laura C
LC
Horton
Nancy G
NG
Slate
Shangtao
S
Liu
Mark L
ML
Borowsky
Sarah E
SE
Calvo
Jeremy D
JD
Schmahmann
Vamsi K
VK
Mootha
D001284:Atrophy; D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000737:chemistry; D003937:Diagnosis, Differential; D059472:Exome; D005091:Exons; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics; D020125:Mutation, Missense; D014929:Wolfram Syndrome / Q000175:diagnosis* / Q000235:genetics
D004272:DNA, Mitochondrial; D008565:Membrane Proteins; C114987:wolframin protein