No abstract

Intraoperative monitoring of CM thresholds may be valuable for identifying the exact point of time at which residual hearing is affected in CI patients. Opening of the cochlea itself seems to be unrelated to hearing loss. A significant proportion of patients may have hearing loss caused by secondary effects rather than a direct trauma.

From the first identified non-syndromic hearing loss gene in 1995, to those discovered in present day, the field of human genetics has witnessed an unparalleled revolution that includes the completion of the Human Genome Project in 2003 to the $1000 genome in 2014. This review highlights the classical and cutting-edge strategies for non-syndromic hearing loss gene identification that have been used throughout the twenty year history with a special emphasis on how the innovative breakthroughs in next generation sequencing technology have forever changed candidate gene approaches. The simplified approach afforded by next generation sequencing technology provides a second chance for the many linked loci in large and well characterized families that have been identified by linkage analysis but have presently failed to identify a causative gene. It also discusses some complexities that may restrict eventual candidate gene discovery and calls for novel approaches to answer some of the questions that make this simple Mendelian disorder so intriguing.

Increasing attention has been directed toward assessing mutational fallout of stereocilin (STRC), the gene underlying DFNB16. A major challenge is due to a closely linked pseudogene with 99.6% coding sequence identity. In 94 GJB2/GJB6-mutation negative individuals with non-syndromic sensorineural hearing loss (NSHL), we identified two homozygous and six heterozygous deletions, encompassing the STRC region by microarray and/or quantitative polymerase chain reaction (qPCR) analysis. To detect smaller mutations, we developed a Sanger sequencing method for pseudogene exclusion. Three heterozygous deletion carriers exhibited hemizygous mutations predicted as negatively impacting the protein. In 30 NSHL individuals without deletion, we detected one with compound heterozygous and two with heterozygous pathogenic mutations. Of 36 total patients undergoing STRC sequencing, two showed the c.3893A>G variant in conjunction with a heterozygous deletion or mutation and three exhibited the variant in a heterozygous state. Although this variant affects a highly conserved amino acid and is predicted as deleterious, comparable minor allele frequencies (MAFs) (around 10%) in NSHL individuals and controls and homozygous variant carriers without NSHL argue against its pathogenicity. Collectively, six (6%) of 94 NSHL individuals were diagnosed with homozygous or compound heterozygous mutations causing DFNB16 and five (5%) as heterozygous mutation carriers. Besides GJB2/GJB6 (DFNB1), STRC is a major contributor to congenital hearing impairment.

Isolated cochlear outer hair cells undergo rapid, force-generating length changes in response to electrical stimulation. The cellular mechanism responsible for electromotility and its structural substrate is not yet known. Salicylates reduce and block electromotility in vitro. Therefore, we exposed isolated outer hair cells from the guinea pig cochlea to various doses of sodium salicylate and evaluated both ultrastructural changes and responses to electrical stimulation. Following salicylate superfusion, the subsurface cisternae showed dilatation, vesiculation and a deviation from their normal, unfenestrated, axial orientation below the plasma membrane. These changes were time and dose dependent and reversible over a time course of about 30 min. Electromotility was blocked and showed recovery following the same time course as the salicylate-induced reversible structural changes. These results indicate that intact, unfenestrated subsurface cisternae are required for the optimal generation of electrically-induced motility in mammalian outer hair cells.

Purpose:Targeted next-generation sequencing provides a remarkable opportunity to identify variants in known disease genes, particularly in extremely heterogeneous disorders such as nonsyndromic hearing loss. The present study attempts to shed light on the complexity of hearing impairment.Methods:Using one of two next-generation sequencing panels containing either 80 or 129 deafness genes, we screened 30 individuals with nonsyndromic hearing loss (from 23 unrelated families) and analyzed 9 normal-hearing controls.Results:Overall, we found an average of 3.7 variants (in 80 genes) with deleterious prediction outcome, including a number of novel variants, in individuals with nonsyndromic hearing loss and 1.4 in controls. By next-generation sequencing alone, 12 of 23 (52%) probands were diagnosed with monogenic forms of nonsyndromic hearing loss; one individual displayed a DNA sequence mutation together with a microdeletion. Two (9%) probands have Usher syndrome. In the undiagnosed individuals (10/23; 43%) we detected a significant enrichment of potentially pathogenic variants as compared to controls.Conclusion:Next-generation sequencing combined with microarrays provides the diagnosis for approximately half of the GJB2 mutation–negative individuals. Usher syndrome was found to be more frequent in the study cohort than anticipated. The conditions in a proportion of individuals with nonsyndromic hearing loss, particularly in the undiagnosed group, may have been caused or modified by an accumulation of unfavorable variants across multiple genes.

The consensus opinion was that brainstem trauma is a primary factor in the variability of outcomes in NF2 patients. The significant co-factors in outcomes implied that ABI surgery should be accomplished with great care to minimize physical and venous trauma to the brainstem. It is clear that high levels of speech recognition, including high levels of open-set speech recognition, are possible with the ABI even in patients with NF2 and large tumors.

No abstract