Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family

Wolfram syndrome (MIM 222300) is characterized by juvenile-onset diabetes m ellitus and optic atrophy. Previous linkage analyses in the United States a nd UK families have indicated that the gene for Wolfram syndrome (WFS) is l ocalized on the short arm of chromosome 4. We herein confirm the linkage of the WFS locus to D4S3023 on 4p with a two-point LOD score of 3.42 in a lar ge Japanese family with Wolfram syndrome. Multipoint linkage analysis revea led the maximum LOD score of 4.82 between D4S3023 and D4S394. We also evalu ated putative health risks in carriers by multiple logistic analysis with i ndependent variables, age, gender, and numbers of affected haplotypes and w ith dependent variables, such as hearing loss, diabetes mellitus, polyuria, incontinence, psychological illness, and visual acuity. The results showed that the putative disease haplotype increased a risk of hearing loss (odds ratio =35.68, 95% confidence interval =4.12-308.95) and diabetes mellitus (odds ratio =7.57, 95% confidence interval =2.03-28.23) independently. This is the first report of an increased health risk of illness in carriers, ot her than for psychiatric disease.