Low frequency sensorineural hearing loss is an unusual type of hearing loss in which frequencies of 2,000 Hz and below are predominantly affected (Bespalova et al., 2001). Many patients have tinnitus, but there are otherwise no associated features ... Low frequency sensorineural hearing loss is an unusual type of hearing loss in which frequencies of 2,000 Hz and below are predominantly affected (Bespalova et al., 2001). Many patients have tinnitus, but there are otherwise no associated features such as vertigo. Because high frequency hearing is generally preserved, LFSNHL patients retain excellent understanding of speech, although presbycusis or noise exposure may cause high frequency loss later in life. LFSNHL worsens over time without progressing to profound deafness; in contrast, low frequency hearing loss linked to DFNA1 (124900), caused by mutations in the DIAPH1 gene (602121), is associated with progression to profound deafness by the fourth decade of life. The Vanderbilt University Hereditary Deafness Study Group (1968) described low frequency deafness of sensorineural type in a large kindred. Speech development, intelligence, vestibular function, and general physical condition were normal. Autosomal dominant inheritance was demonstrated. Above 2,000 cycles per second hearing was normal or near normal. A localized abnormality of the cochlear apex was suggested. Lesperance et al. (1995) later studied this family. Three families reported by Konigsmark et al. (1971) may have represented the same disorder. Van Camp et al. (1999) reported a large Dutch family in which nonsyndromic hearing loss segregated in an autosomal dominant manner. The onset of hearing impairment was typically in the second decade, with a slow decline stopping short of profound deafness. The hearing loss was bilateral, symmetric, and affected low and mid frequencies (up to 2,000 Hz). Hildebrand et al. (2008) reported a 5-generation American family segregating autosomal dominant sensorineural hearing loss associated with a heterozygous mutation in the WFS1 gene (606201.0023) in 6 affected individuals. Two affected females had concurrent Crohn disease (see 266600) and Graves disease (275000), respectively. Hildebrand et al. (2008) noted that polymorphisms in the WFS1 gene (see, e.g., 606201.0021) had been associated with autoimmune disease, and suggested that the autoimmune disease in the 2 family members may be related to variants in the WFS1 gene.
Bespalova et al. (2001) further studied the DFNA6 family of Lesperance et al. (1995) and identified a phenocopy, thus concluding that DFNA6 and DFNA14 are allelic. The DFNA6/14 critical region includes WFS1 (606201), mutations in which are responsible ... Bespalova et al. (2001) further studied the DFNA6 family of Lesperance et al. (1995) and identified a phenocopy, thus concluding that DFNA6 and DFNA14 are allelic. The DFNA6/14 critical region includes WFS1 (606201), mutations in which are responsible for Wolfram syndrome (222300), an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. The authors characterized 5 different heterozygous missense mutations in the WFS1 gene (e.g., 606201.0014) among 6 LFSNHL families, thus concluding that mutations in WFS1 are a common cause of low frequency sensorineural hearing loss. Young et al. (2001) described a 6-generation Canadian family with dominantly inherited progressive hearing loss (DFNA38), in which the phenotype was mapped to 4p16 by linkage analysis. This region contains the WFS1 gene and overlaps the critical region for 2 other loci for deafness, DNFA6 and DFNA14. Affected individuals were heterozygous for a 2146G-A transition in WFS1. The mutation resulted in an ala716-to-thr substitution (606201.0014). Affected individuals lacked additional phenotypic features seen in Wolfram syndrome, with the exception of a child who was homozygous for the mutation and also manifested diabetes mellitus by the age of 3 years. Komatsu et al. (2002) performed a genomewide linkage analysis of a Japanese family in which 20 members were affected with LFSNHL and obtained a maximum lod score of 5.36 at a recombination fraction of 0.05 at the D4S2983 locus on chromosome 4p16. Mutation analysis revealed a lys634-to-thr missense mutation in the WFS1 gene (606201.0018). Fukuoka et al. (2007) analyzed the WFS1 gene in 206 Japanese autosomal dominant and 64 autosomal recessive (sporadic) nonsyndromic hearing loss probands with varying severities of hearing loss and identified 2 different missense mutations in 3 unrelated families (see 606201.0014 and 606201.0020, respectively). All of the mutation-positive patients had dominantly inherited low frequency sensorineural hearing loss. Because both mutations had previously been identified in patients of European ancestry, the authors suggested that the sites are likely to be mutation hotspots.