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

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.Mitochondrial diseases are a clinically heterogeneous set of disorders that are caused by defects in mitochondria, the organelles responsible for producing most of the cellular ATP in humans [1]. Multiple organ-systems are typically affected in these disorders, with neurologic and myopathic features being the most prominent [2]. Common clinical features of mitochondrial disease include skeletal myopathy accompanied by exercise intolerance, cardiomyopathy, sensorimotor peripheral polyneuropathy, sensorineural deafness, optic atrophy, diabetes mellitus, seizures, and ataxia [3]. These disorders can be caused by mutations in the nuclear or mitochondrial genomes, and over 100 loci have been identified to date [4].The clinical and genetic heterogeneity of mitochondrial diseases as well as the technical difficulty of assessing mitochondrial function create a significant diagnostic challenge [5]. One major source of cost and time delays in the clinical evaluation of patients with suspected mitochondrial disease i