Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 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 associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent 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 appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive 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 families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence 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.

A Dutch kindred was studied with low-frequency sensorineural hearing impairment linked to a new locus on chromosome 4p16 (DFNA14). Of the affected individuals, 21 (aged 11-75 years) were examined and the most recent audiogram was used for cross-sectional analysis of hearing threshold in relation to age. Suitable serial audiograms were available for a longitudinal analysis in nine cases: they had been obtained from the age of six years onwards and covered a follow-up period from 14 to 36 years. The presumably congenital (offset) component of SNHI was extrapolated or estimated from average values and offset thresholds were found of about 45 dB at 0.25-1 kHz, 25 dB at 2 kHz and 10 dB at 4-8 kHz. Significant progression in hearing impairment occurred at all frequencies, but could be attributed to presbyacusis. The combination of congenital, stationary low-frequency SNHI and presbyacusis resulted in an up-sloping audiogram in the first five decades of life, which evolved into a flat-type audiogram in the sixth or seventh decade and a down-sloping audiogram at a more advanced age. With few exceptions, vestibular function was intact.

The tilted (tlt) mouse carries a recessive mutation causing vestibular dysfunction. The defect in tlt homozygous mice is limited to the utricle and saccule of the inner ear, which completely lack otoconia. Genetic mapping of tlt placed it in a region orthologous with human 4p16.3-p15 that contains two loci, DFNA6 and DFNA14, responsible for autosomal dominant, nonsyndromic hereditary hearing impairment. To identify a possible relationship between tlt in mice and DFNA6 and DFNA14 in humans, we have refined the mouse genetic map, assembled a BAC contig spanning the tlt locus, and developed a comprehensive comparative map between mouse and human. We have determined the position of tlt relative to 17 mouse chromosome 5 genes with orthologous loci in the human 4p16.3-p15 region. This analysis identified an inversion between the mouse and human genomes that places tlt and DFNA6/14 in close proximity.

Previously we confirmed linkage of autosomal dominantly inherited low-frequency sensorineural hearing impairment (LFSNHI) in a German family to the genetic locus DFNA6/DFNA14 on chromosome 4p16.3 close to the markers D4S432 and D4S431. Analysis of data from the Human Genome Project, showed that WFS1 is located in this region. Mutations in WFS1 are known to be responsible for Wolfram syndrome (DIDMOAD, MIM #606201), which follows an autosomal recessive trait. Studies in low-frequency hearing loss families showed that mutations in WFS1 were responsible for the phenotype. In all affected family members analysed, we detected a missense mutation in WFS1 (K705N) and therefore confirm the finding that the majority of mutations responsible for LFSNHI are missense mutations which localise to the C-terminal domain of the protein.

Non-syndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 reported gene localisations. We have identified a large Dutch family with autosomal dominant non-syndromic sensorineural hearing impairment. In most patients, the onset of hearing impairment is in the first or second decade of life, with a slow decline in the following decades, which stops short of profound deafness. The hearing loss is bilateral, symmetrical, and only affects low and mid frequencies up to 2000 Hz. In view of the phenotypic similarities of this family with an American family that has been linked to chromosome 4p16.3 (DFNA6), we investigated linkage to the DFNA6 region. Lod score calculations confirmed linkage to this region with two point lod scores above 6. However, as haplotype analysis indicated that the genetic defect in this family is located in a 5.6 cM candidate region that does not overlap the DFNA6 region, the new locus has been named DFNA14.

Nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) comprises a group (DFNA1, DFNA6, DFNA14, and DFNA38) of hearing disorders affecting only frequencies below 2000 Hz, and is often associated with tinnitus. An LFSNHL locus has recently been assigned to chromosome 4p16, and mutations in WFS1, the causative gene for Wolfram syndrome, have been found to cause LFSNHL in families with DFNA6, DFNA14, or DFNA38. We performed a genome-wide 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 ( P = 1.00) at the D4S2983 locus on 4p16. Haplotype analysis revealed that the disease locus mapped to between D4S2366 and D4S2983. Mutation analysis revealed a novel missense mutation (K634T) in WFS1. We thus concluded that the LFSNHL in this family was caused by the WFS1 mutation. The mutation observed (K634T) was located in the hydrophobic, extracytoplasmic, juxta-transmembrane region of the WFS1 protein, wolframin, and was hitherto undescribed. This unique mutation site in our patients is likely related to their milder phenotype (lacking tinnitus) compared with those of six previous DFNA6/14 patients with WFS1mutations. It is likely that a genotype-phenotype correlation is also applicable in the case of DFNA6/14/38.

OBJECTIVE

To delineate the phenotype and genotype of an autosomal dominant low-frequency sensorineural nonsyndromic hearing impairment trait in relation to similar traits.

METHODS

Family study, including retrospective case reviews.

METHODS

Tertiary referral center.

METHODS

Hearing impairment was documented in 11 family members in five generations, 8 of whom were alive and participated in this study.

METHODS

Diagnostic.

METHODS

Clinical study: medical and otologic history and examination, retrieval of previous audiograms, pure-tone audiometry, and statistical analysis of audiometric data. Genetic study: linkage analysis of blood samples in 18 clinically affected and nonaffected family members.

RESULTS

Hearing impairment had been present since early childhood, mainly affecting the low frequencies (mean threshold 45 dB HL at 0.25-1 kHz); speech recognition was hardly affected during the first three decades of life. Higher frequencies became involved with increasing age, thus causing a flat-type audiogram at middle age and down-sloping audiograms after age 60 years. Progression was mild but significant at all frequencies (0.5 dB/year at 0.25 kHz to 1.3 dB/year at 8 kHz) and persisted after correction was applied for normal presbyacusis. The trait was linked to chromosome 4p16.3, in a region comprising both the previously located, closely adjacent DFNA6 and the DFNA14 loci for low-frequency hearing impairment.

CONCLUSIONS

A third family (designated Dutch II) was identified with a low-frequency hearing impairment trait showing linkage to chromosome 4p16.3 (DFNA6/14). The progression of hearing impairment beyond presbyacusis in the current study is unprecedented for DFNA6/14 traits.

We have investigated a three-generation family with an autosomal dominant low-mid frequency hearing loss. Audiograms show consistently a hearing threshold of 50+/-20 db hearing loss (HL) between 250 Hz and 1-2 kHz. Normal hearing level was reached between 3 and 6 kHz in all examined children. Adult patients show an additional hearing impairment (HI) in the mid and higher frequencies that seems to differ from presbyacusis. The HI is always bilateral and symmetrical. Genes causing non-syndromic autosomal-dominant deafness with HI in the low and mid frequencies were previously mapped to chromosome 4p16.3 (DFNA6, DFNA14) and chromosome 5q31 (DFNA1). After exclusion of linkage to DFNA1 on chromosome 5, we mapped the candidate gene region to the DFNA14 and DFNA6 loci, between the genetic markers D4S432 and D4S431, located on chromosome 4. This is a further family in which evident linkage of low-mid frequency HI to the candidate region on chromosome 4p16.3 has been found.

Two families with low frequency hearing impairment have been described previously. Family A (Danish) presented a sensorineural hearing impairment most pronounced for frequencies below 2 kHz and a pedigree typical for an autosomal dominant trait with complete penetrance (Königsmark type). Family B, originating from the Faroe Islands, showed conflicting audiological test results, making a valid classification impossible. The pedigree suggested autosomal dominant inheritance with incomplete penetrance. The objectives of the present study are to acquire longitudinal audiometric data, to clarify the mode of transmission, and to localize the mutant gene by reevaluation of the two families. The methods used are evaluation of the family history, audiological examination and linkage analysis. In family A, update of the pedigree fitted the assumption of an autosomal dominant mode of transmission. In six examined subjects audiological data were available from the previous study. The median progression over a 13-21-year period was 13.8 dB HL for the thresholds, averaged across 0.5, 1, 2 and 4 kHz and 17.5 dB HL for the thresholds, averaged across 2 and 4kHz. In family B, the probable mode of transmission is autosomal dominant with reduced penetrance. In this family no progression of the hearing impairment was found. Linkage analysis of family A showed a lod score of 3.53, indicating significant linkage to the loci DFNA6 and DFNA14 on chromosome 4, previously found to be involved in low frequency hearing impairment. Family B was not linked to the region on chromosome 4, further adding to the genetic heterogeneity in low frequency sensorineural hearing impairment.