Objective:The major goal of this study was to examine differences in the middle ear mechano-acoustical properties of normal ears and ears with surgically confirmed otosclerosis using conventional and multifrequency tympanometry (MFT) as well as energy reflectance (ER). Second, we sought to compare E

Energy reflectance and tympanometry in normal and otosclerotic ears.

Otosclerosis is a progressive hearing loss characterized by an abnormal bone homeostasis of the otic capsule that leads to stapes fixation. Although its etiology remains unknown, otosclerosis can be considered a complex disease. Transforming growth factor-beta 1 (TGF-beta1) was chosen for a case-control association study, because of several non-genetic indications of involvement in otosclerosis. Single nucleotide polymorphism (SNP) analysis in a large Belgian-Dutch sample set gave significant results (P = 0.0044) for an amino acid changing SNP, T263I. Analysis of an independent French population replicated this association with SNP T263I (P = 0.00019). The results remained significant after multiple testing correction in both populations. Haplotype analysis and the results of an independent effect test using the weighted haplotype (WHAP) computer program in both populations were both compatible with SNP T263I being the only causal variant. The variant I263 is under-represented in otosclerosis patients and hence protective against the disease. Combining the data of both case-control groups for SNP T263I with a Mantel-Haenszel estimate of common odds ratios gave a very significant result (P = 9.2 x 10(-6)). Functional analysis of SNP T263I with a luciferase reporter assay showed that the protective variant I263 of TGF-beta1 is more active than the WT variant T263 (P = 1.6 x 10(-6)). On the basis of very low P-values, replication in an independent population and a functional effect of the protective variant, we conclude that TGF-beta1 influences the susceptibility for otosclerosis, and that the I263 variant is protective against the disease.

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The coding polymorphism T263I in TGF-β1 is associated with otosclerosis in two independent populations

Otosclerosis is a common form of progressive hearing loss, characterized by abnormal bone remodeling in the otic capsule. The etiology of the disease is largely unknown, and both environmental and genetic factors have been implicated. To identify genetic factors involved in otosclerosis, we used a case-control discovery group to complete a genome-wide association (GWA) study with 555,000 single-nucleotide polymorphisms (SNPs), utilizing pooled DNA samples. By individual genotyping of the top 250 SNPs in a stepwise strategy, we were able to identify two highly associated SNPs that replicated in two additional independent populations. We then genotyped 79 tagSNPs to fine map the two genomic regions defined by the associated SNPs. The region with the strongest association signal, pcombined = 6.23 × 10−10, is on chromosome 7q22.1 and spans intron 1 to intron 4 of reelin (RELN), a gene known for its role in neuronal migration. Evidence for allelic heterogeneity was found in this region. Consistent with the GWA data, expression of RELN was confirmed in the inner ear and in stapes footplate specimens. In conclusion, we provide evidence that implicates RELN in the pathogenesis of otosclerosis.

A genome-wide analysis identifies genetic variants in the RELN gene associated with otosclerosis.

The pathophysiology of otosclerosis: Review of current research

Otosclerosis is caused by abnormal bone homeostasis of the otic capsule leading to bony fixation of the stapedial footplate in the oval window. Because the transmission of sound waves from outer to inner ear is disturbed by this fixation, the disease is characterised by conductive hearing impairment.1 In some cases, an additional sensorineural component develops across all frequencies, leading to mixed hearing impairment.2,3 The conductive component of the hearing impairment can be restored by stapes replacing microsurgery; however, the sensorineural component cannot surgically be corrected.4

Otosclerosis has a prevalence of 0.3–0.4% in the Caucasian population.5 The etiology of the disease is unknown, but epidemiological studies indicate the involvement of genetic as well as environmental factors. However, large families segregating otosclerosis are very rare, whereas there are frequent sporadic cases and smaller families with only a few affected members. Based on these findings, otosclerosis can be considered a genetically complex disease, caused by an interaction of genes and environmental factors, but with rare monogenic forms.

To date, three autosomal dominant otosclerosis loci have been reported: OTSC1 on chromosome 15q25–26,6 OTSC2 on chromosome 7q34–36,7 and OTSC3 on chromosome 6p21–22.8 In addition, a fourth locus, OTSC4 , has been reserved by the Human Genome Organisation nomenclature committee, but this has not been published. None of the corresponding genes have been cloned. In this study, we identified a large Dutch family segregating an autosomal dominant otosclerosis. After exclusion of the known loci, a genome-wide screen and linkage analysis in this family revealed the existence of a fifth otosclerosis locus, OTSC5 , localised on chromosome 3q22–24.

### Clinical diagnosis

The family was identified via the Department of Otorhinolaryngology of the University Medical Center St.-Radboud Nijmegen (The Netherlands) (fig 1). Pure-tone audiometry was performed in all persons with air conduction at …

https://jmg.bmj.com/content/jmedgenet/41/6/450.full.pdf

A fifth locus for otosclerosis, OTSC5, maps to chromosome 3q22–24

Clinical otosclerosis (OMIM 166800/605727) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this group. It is caused by abnormal bone homeostasis of the otic capsule with the consequent development of sclerotic foci that invade the stapedio-vestibular joint (oval window) interfering with free motion of the stapes. Impaired ossicular chain mobility results in a conductive hearing loss. 

We identified the first locus for otosclerosis (OTSC1) on chromosome 15 in 1998 and reported a second locus (OTSC2) on chromosome 7 last year. Here we present results of a genome wide linkage study on a large Cypriot family segregating otosclerosis. Results of this study exclude linkage to OTSC1 and OTSC2 and identify a third locus, OTSC3, on chromosome 6p. The defined OTSC3 interval covers the HLA region, consistent with reported associations between HLA-A/HLA-B antigens and otosclerosis.

https://jmg.bmj.com/content/jmedgenet/39/7/473.full.pdf

C. Komodikis

Papers

Linkage of otosclerosis to a third locus (OTSC3) on human chromosome 6p21.3-22.3