Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting o nly 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be a ssociated with mild tinnitus but is not associated with vertigo. We have pr eviously reported two families with autosomal dominant LFSNHL linked to adj acent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appear s to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region incl udes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessiv e disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL fa milies. Mutations in WFS1 were identified in all LFSNHL families tested, wi th A716T arising independently in two families. None of the mutations was f ound in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the pr evalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.