Deafness, Autosomal Dominant 6

A number sign (#) is used with this entry because DFNA6 (DFNA14, DFNA38), a form of low frequency sensorineural hearing loss (LFSNHL), is caused by heterozygous mutation in the WFS1 gene (606201) on chromosome 4p16.

Description

Low frequency sensorineural hearing loss is an unusual type of hearing loss in which frequencies of 2,000 Hz and below are predominantly affected. 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 (summary by Bespalova et al., 2001).

Clinical Features

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.

Mapping

By linkage analysis with microsatellite polymorphic markers in a family with autosomal dominant progressive low frequency sensorineural hearing loss ('the Vanderbilt family'), Lesperance et al. (1995) demonstrated linkage with marker D4S126 at 4p16.3, a gene-rich region containing the Huntington disease gene (HTT; 613004); maximum lod = 3.64 at theta = 0.

Van Camp et al. (1999) noted phenotypic similarity between their large Dutch family with LFSHL and the American family reported by Lesperance et al. (1995), which showed linkage to 4p16.3 (DFNA6). By linkage analysis, they found that deafness in the Dutch family was also linked to this region, with 2-point lod scores greater than 6. Haplotype analysis showed that the candidate regions for the 2 families did not overlap. The candidate region for the Dutch family is a 5.6-cM segment bounded by markers D4S3023 and D4S3007, 1.3 CM proximal to the DFNA6 region.

Brodwolf et al. (2001) described a 3-generation family with an autosomal dominant low to mid frequency hearing loss and mapped the disorder to the candidate region for DFNA6 and DFNA14 on chromosome 4p16.3.

Molecular Genetics

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.

Animal Model

Genes for 2 types of abnormal cochleovestibular function in mice, 'tilted' (tlt) and 'Bronx waltzer' (bv), map to chromosome 5 in a region that shows homology of synteny to human 4p16.3. The defect in tlt homozygous mice is limited to the utricle and saccule of the inner ear, which completely lack otoconia. To identify a possible relationship between tlt in mice and DFNA6 and DFNA14 in humans, Hurle et al. (2001) refined the mouse genetic map, assembled a BAC contig spanning the tlt locus, and developed a comprehensive comparative map between mouse and human. They determined the position of tlt relative to 17 mouse chromosome 5 genes with orthologous loci in the human 4p16.3-p15 region. This analysis showed that an inversion had occurred between the mouse and human genomes that placed tlt and DFNA6/14 in close proximity.