Low-frequency Sensorineural Hearing Impairment Research Articles

A nonsynonymous mutation in the WFS1 gene in a Finnish family with age-related hearing impairment

Wolfram syndrome (WS) is caused by recessive mutations in the Wolfram syndrome 1 (WFS1) gene. Sensorineural hearing impairment (HI) is a frequent feature in WS and, furthermore, certain mutations in WFS1 cause nonsyndromic dominantly inherited low-frequency sensorineural HI. These two phenotypes are clinically distinct indicating that WFS1 is a reasonable candidate for genetic studies in patients with other phenotypes of HI. Here we have investigated, whether the variation in WFS1 has a pathogenic role in age-related hearing impairment (ARHI). WFS1 gene was investigated in a population sample of 518 Finnish adults born in 1938–1949 and representing variable hearing phenotypes. Identified variants were evaluated with respect to pathogenic potential. A rare mutation predicted to be pathogenic was found in a family with many members with impaired hearing. Twenty members were recruited to a segregation study and a detailed clinical examination. Heterozygous p.Tyr528His variant segregated completely with late-onset HI in which hearing deteriorated first at high frequencies and progressed to mid and low frequencies later in life. We report the first mutation in the WFS1 gene causing late-onset HI with audiogram configurations typical for ARHI. Monogenic forms of ARHI are rare and our results add WFS1 to the short list of such genes.

Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family

ObjectiveAutosomal dominant non-syndromic low-frequency sensorineural hearing loss (LFSNHL) DFNA6/14/38 is an uncommon type of hearing loss that classically affects low frequencies of 2000 Hz and below, demonstrating an ascending configuration. The current study aimed to investigate the cause of LFSNHL in a five-generation Chinese family. MethodsThe phenotype of the Chinese family was characterized using audiologic testing and pedigree analysis. The combined approach of array screening and whole-exome sequencing was used to identify the disease-causing gene in this family. ResultsThis pedigree, in which the affected subjects presented isolated low-frequency sensorineural hearing impairment with childhood onset, was associated with autosomal dominant inheritance of the c.2591A > G mutation in exon 8 of the Wolframin syndrome 1 (WFS1) gene which was not present in 286 unrelated controls with matched ancestry and is highly conserved across species. In addition, several mutations affecting the Glu864 residue have been previously identified in different populations, suggesting that this site is likely to be a mutational hot spot. ConclusionsWe identified a novel substitution, Glu864Gly, of WFS1 as the causative variant for this pedigree. Our data extend the mutation spectrum of the WFS1 gene in Chinese individuals and may contribute to establishing a better genotype-phenotype correlation for LFSNHL.

Autosomal dominant transmission of diabetes and congenital hearing impairment secondary to a missense mutation in the WFS1 gene

Mutations of the WFS1 gene have been implicated in autosomal dominant diseases, such as low-frequency sensorineural hearing impairment (LFSNHI) and/or diabetes mellitus and/or optic atrophy. The aim was to investigate WFS1 gene sequences in a family with diabetes mellitus and hearing impairment. Three members of a family with a maternally inherited combination of diabetes mellitus and hearing impairment, but no specific mutations in its mitochondrial genome, were investigated for mutations in the WFS1 gene. This pedigree, in which the proband had non-insulin-dependent diabetes mellitus and congenital hearing impairment and his mother a triple combination of diabetes mellitus, hearing impairment and optic atrophy, was found to be associated with autosomal dominant transmission of the E864K mutation of the WFS1 gene. In the light of this confirmatory study, we recommend the systematic analysis of WFS1 gene sequences in patients with parentally inherited diabetes mellitus and deafness (+/- optic atrophy), in particular when diabetogenic mtDNA mutations have been excluded.

Phenotypic characterization of a DFNA6 family showing progressive low-frequency sensorineural hearing impairment

Only three autosomal dominant hearing loss loci (DFNA1, DFNA6/14/38 and DFNA54) have been reported to be associated with predominantly low-frequency (<2kHz) sensorineural hearing impairment (LFSNHI). The DFNA6 locus was previously mapped to chromosome 4p16.3. It was showed that WFS1 is located in this region. This study presents a six-generation family from Hungary with nonsyndromic, post-lingual, bilateral, symmetric, progressive LFSNHI, that discloses positive linkage to the DFNA6 region. Eleven genetically affected family members have LFSNHI. The HI is started before the age of 25 years. The severity of HI varies from mild to moderate, related to age. Progression was mild but significant at all frequencies causing a flat type audiogram. High-resolution temporal bone CT scan showed normal external, middle and inner ear without any osseus malformations in the temporal bone. Studying genotype-phenotype correlations will enhance our understanding of normal and disturbed hearing process.

Phenotypic characterization of a DFNA6 family with low-frequency hearing loss

Hereditary hearing impairment is a heterogeneous sensory defect with approximately two-thirds of all cases being nonsyndromic. Only two loci (DFNA1 and DFNA6/14/38) are associated with low frequency sensorineural nonsyndromic hearing impairment. DFNA6 was mapped to chromosome 4p16. Recessive mutations in the WFS1 gene are responsible for Wolfram syndrome; missense mutations inherited as an autosomal dominant result in low frequency sensorineural hearing impairment (LFSNHI). In this study we analyzed the phenotype of a large Hungarian family with LFSNHI and linkage to DFNA6. The family contains 14 affected persons. In general, these patients show a postlingual, sensorineural, bilateral, symmetric, nonsyndromic low frequency hearing impairment with a slow progression. This impairment is accompanied by normal vision and normal vestibular responses.

Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease.

WFS1 is a novel gene and encodes an 890 amino-acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition, several WFS1 sequence variants have been shown to be significantly associated with diabetes mellitus and this gene has also been implicated in psychiatric diseases. Wolfram syndrome is highly variable in its clinical manifestations, which include diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Wolfram syndrome mutations are spread over the entire coding region, and are typically inactivating, suggesting that a loss of function causes the disease phenotype. In contrast, only non-inactivating mutations have been found in DFNA6/14 families, and these mutations are mainly located in the C-terminal protein domain. In this paper, we provide an overview of the currently known disease-causing and benign allele variants of WFS1 and propose a potential genotype-phenotype correlation for Wolfram syndrome and LFSNHI.

Progression of low-frequency sensorineural hearing loss (DFNA6/14-WFS1).

To assess the audiometric profile and speech recognition characteristics in affected members of 2 families with DFNA6/14 harboring heterozygous mutations in the WFS1 gene that cause an autosomal dominant nonsyndromic sensorineural hearing impairment trait. Family study. Tertiary referral center. Patients Thirteen patients from 2 recently identified Dutch families with DFNA6/14 (Dutch III and IV). Cross-sectional and longitudinal analyses of pure-tone thresholds at octave frequencies of 0.25 to 8 kHz were performed, and speech phoneme recognition scores were assessed. Progression was evaluated by linear regression analysis with and without correction for presbycusis. All individuals showed low-frequency hearing impairment. The 2-kHz frequency was more affected in the Dutch III family than in the Dutch IV family. Progressive hearing loss beyond presbycusis was found in the Dutch IV family and in 3 individuals in the Dutch III family. Annual threshold deterioration was between 0.6 and 1 dB per year at all frequencies. The speech recognition scores in the Dutch III family showed significantly more deterioration at increasing levels of hearing impairment compared with those in the Dutch IV family. Both families showed an autosomal dominant, progressive, low-frequency sensorineural hearing impairment caused by heterozygous WFS1 mutations.

Identification of a novel mutation in WFS1 in a family affected by low-frequency hearing impairment

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.

Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small non-inactivating mutations.

Hereditary hearing impairment is an extremely heterogeneous trait, with more than 70 identified loci. Only two of these loci are associated with an auditory phenotype that predominantly affects the low frequencies (DFNA1 and DFNA6/14). In this study, we have completed mutation screening of the WFS1 gene in eight autosomal dominant families and twelve sporadic cases in which affected persons have low-frequency sensorineural hearing impairment (LFSNHI). Mutations in this gene are known to be responsible for Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), which is an autosomal recessive trait. We have identified seven missense mutations and a single amino acid deletion affecting conserved amino acids in six families and one sporadic case, indicating that mutations in WFS1 are a major cause of inherited but not sporadic low-frequency hearing impairment. Among the ten WFS1 mutations reported in LFSNHI, none is expected to lead to premature protein truncation, and nine cluster in the C-terminal protein domain. In contrast, 64% of the Wolfram syndrome mutations are inactivating. Our results indicate that only non-inactivating mutations in WFS1 are responsible for non-syndromic low-frequency hearing impairment.

Two families with phenotypically different hereditary low frequency hearing impairment: longitudinal data and linkage analysis.

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.

Inherited sensorineural low-frequency hearing impairment: some aspects of phenotype and epidemiology.

This contribution forms part of the HEAR project. It describes some phenotypes of inherited low-frequency sensorineural hearing impairment (LFSHI) and estimates the prevalence of this inherited hearing impairment (HI) based on a clinical series. During a 10-year period (1987-1996), 418 subjects (134 males and 284 females), with a median age of 68 years (range 4-98), had been examined with LFSHI, defined as hearing loss most pronounced in the low frequencies (i.e., 250 and 500 Hz > 20 dB HL with better hearing, i.e., > or =15-dB difference at 1 and/or 2 and/or 4 kHz with an air-bone gap <15 dB for the average of 0.5, 1, and 2 kHz). The 418 subjects comprising 0.6 per cent of the total number of subjects examined (N=69,309) were subdivided into four categories: category I positive genetic subjects (N=69); category II, probably genetic (N=339); category III, uncertain genetic (N=6); and category IV, subjects with contradictory audiological findings (N=4). The phenotype in category I demonstrated a symmetrical LFSHI, with a pattern of progression showing a slow deterioration in the high frequencies (i.e., 2, 4, and 8 kHz as a function of age)--the progression comprising 40-45 dB. In the low frequencies (i.e., 250, 500, and 1,000 Hz), a deterioration of 15-25 dB could be demonstrated from the youngest to the oldest age group. In category II, a symmetrical LFSHI was found in 179 subjects, showing the same pattern of progression as in category I. However, in the age group 20-39 years, a significantly poorer hearing was found in the low frequencies compared to category I, implying that several phenotypes may be present in LFSHI. A subgroup (A) in category II exhibited normal hearing in one ear with LFSHI in the opposite ear with the same pattern of progression as in category I. Three other subgroups with LFSHI and flat/sloping audiogram in the opposite ear and asymmetrical LFSHI also showed the same type of progression in the ear with LFSHI as in category I. A prevalence of 0.18/1,000 (95 per cent CI 0.13-0.22) of LFSHI was estimated based on the background population with a fairly constant prevalence throughout life. It is concluded that inherited nonsyndromal LFSHI is a rare disease and that the many different phenotypes of LFSHI probably are associated with pronounced genetic heterogeneity.