Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome

Am J Med Genet A. 2007 Jul 15;143A(14):1605-12. doi: 10.1002/ajmg.a.31809.


Mutations in the WFS1 gene have been reported in Wolfram syndrome (WS), an autosomal recessive disorder defined by early onset of diabetes mellitus (DM) and progressive optic atrophy. Because of the low prevalence of this syndrome and the recent identification of the WFS1 gene, few data are available concerning the relationships between clinical and molecular aspects of the disease. Here, we describe 12 patients from 11 families with WS. We report on eight novel (A214fsX285, L293fsX303, P346L, I427S, V503fsX517, R558C, S605fsX711, P838L) and seven previously reported mutations. We also looked for genotype-phenotype correlation both in patients included in this study and 19 additional WS patients that were previously reported. Subsequently, we performed a systematic review and meta-analysis of five published clinical and molecular studies of WFS1 for genotype-phenotype correlation, combined with our current French patient group for a total of 96 patients. The presence of two inactivating mutations was shown to predispose to an earlier age of onset of both DM and optic atrophy. Moreover, the clinical expression of WS was more complete and occurred earlier in patients harboring no missense mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Family Health
  • Female
  • Genotype
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Meta-Analysis as Topic
  • Mutation*
  • Pedigree
  • Phenotype
  • Wolfram Syndrome / genetics*
  • Wolfram Syndrome / pathology


  • Membrane Proteins
  • wolframin protein