Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1

Dominantly inherited progressive hearing loss DFNA38 is caused by heterozyg osity for a novel mutation in WFS1, the gene for recessively inherited Wolf ram syndrome. Wolfram syndrome is defined by juvenile diabetes mellitus and optic atrophy and may include progressive hearing loss and other neurologi cal symptoms. Heterozygotes for other Wolfram syndrome mutations generally have normal hearing. Dominant deafness defined by DFNA38 is more severe tha n deafness of Wolfram syndrome patients and lacks any syndromic features. I n a six-generation kindred from Newfoundland, Canada, WFS1 Ala716Thr (2146 G -->A) was shared by all deaf members of the family and was specific to de af individuals. The causal relationship between this missense mutation and deafness was supported by two observations based on haplotype and mutation analysis of the kindred. First, a relative homozygous for the mutation was diagnosed at age 3 years with insulin-dependent diabetes mellitus, the cent ral feature of Wolfram syndrome. Second, two relatives with normal hearing had an identical haplotype to that defining DFNA38, with the exception of t he base pair at position 2146. Other rare variants of WFS1 co-inherited wit h deafness in the family could be excluded as disease-causing mutations on the basis of this hearing-associated haplotype. The possibility that 'mild' mutations in WFS1 might be a cause of non-syndromic deafness in the genera l population should be explored.