Gene expression profiles of the cochlea and vestibular endorgans: localization and function of genes causing deafness.

OBJECTIVES: We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss. METHODS: Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords. RESULTS: Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans. CONCLUSIONS: The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function.

A Japanese family showing high-frequency hearing loss with KCNQ4 and TECTA mutations.

CONCLUSIONS: We describe a Japanese family with high-frequency sensorineural hearing loss (SNHL) harboring a c.211delC mutation in the KCNQ4 gene. Families showing progressive high-frequency SNHL should be investigated for mutations in the KCNQ4 gene. OBJECTIVE: To determine the responsible deafness gene in a Japanese family with dominantly inherited high-frequency SNHL of unknown etiology. METHODS: We performed hearing tests for five members of the family, and the three affected with hearing loss underwent further audiological and vestibular examinations. Genetic analysis was performed to identify any possible causative mutations, as well as analysis of detailed clinical findings to determine the phenotype. RESULTS: The three affected subjects showed high-frequency SNHL. Extensive audiologic evaluation suggested cochlear involvement and progressive hearing loss. As for bilateral caloric testing, two of the three affected subjects showed hyporeflexia with recurrent vestibular symptoms. We identified the c.211delC mutation in the KCNQ4 gene and the c.2967C>A (p.H989Q) mutation in the TECTA gene. Based on the genotype-phenotype correlation, the c.211delC mutation in the KCNQ4 gene was associated with high-frequency SNHL in this family.

Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients.

Target exon resequencing using Massively Parallel DNA Sequencing (MPS) is a new powerful strategy to discover causative genes in rare Mendelian disorders such as deafness. We attempted to identify genomic variations responsible for deafness by massive sequencing of the exons of 112 target candidate genes. By the analysis of 216randomly selected Japanese deafness patients (120 early-onset and 96 late-detected), who had already been evaluated for common genes/mutations by Invader assay and of which 48 had already been diagnosed, we efficiently identified causative mutations and/or mutation candidates in 57 genes. Approximately 86.6% (187/216) of the patients had at least one mutation. Of the 187 patients, in 69 the etiology of the hearing loss was completely explained. To determine which genes have the greatest impact on deafness etiology, the number of mutations was counted, showing that those in GJB2 were exceptionally higher, followed by mutations in SLC26A4, USH2A, GPR98, MYO15A, COL4A5 and CDH23. The present data suggested that targeted exon sequencing of selected genes using the MPS technology followed by the appropriate filtering algorithm will be able to identify rare responsible genes including new candidate genes for individual patients with deafness, and improve molecular diagnosis. In addition, using a large number of patients, the present study clarified the molecular epidemiology of deafness in Japanese. GJB2 is the most prevalent causative gene, and the major (commonly found) gene mutations cause 30-40% of deafness while the remainder of hearing loss is the result of various rare genes/mutations that have been difficult to diagnose by the conventional one-by-one approach. In conclusion, target exon resequencing using MPS technology is a suitable method to discover common and rare causative genes for a highly heterogeneous monogenic disease like hearing loss.

Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

The present study of KCNQ4 mutations was carried out to 1) determine the prevalence by unbiased population-based genetic screening, 2) clarify the mutation spectrum and genotype/phenotype correlations, and 3) summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL) families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287). While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC) showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.

Prevalence of level V metastasis in head and neck squamous cell carcinoma.

CONCLUSION: The results of this study accord with those of past reports about the prevalence of level V metastasis in head and neck squamous cell carcinoma (HNSCC) cases. Because of the low rate of level V metastasis, and from the viewpoint of standard postoperative radiotherapy, selective neck dissection without level V dissection may be possible in cases without clinical evidence of level V metastasis on both the ipsilateral and contralateral sides. In addition, degree of pathological differentiation and pN stage >N2b are suggested risk factors for level V metastasis. OBJECTIVES: The most frequent complication of any type of neck dissection in HNSCC cases with level V metastasis is shoulder dysfunction secondary to traction or ischemic injury to the spinal accessory nerve (SAN). The purpose of this study was to examine procedures to preserve the SAN and avoid level V dissection and shoulder dysfunction due to SAN injury. This study investigated the prevalence of level V metastasis and its associated risk factors at various primary sites in patients with HNSCC. METHODS: Clinical and pathological data were retrospectively reviewed for 162 patients with HNSCC, including those with clinically negative neck (cN0) and clinically positive neck (cN+) in whom level V neck dissection was performed. The prevalence of pathological metastasis to level V lymph nodes on both the ipsilateral and contralateral sides was investigated. Several potentially predictive risk factors for level V metastasis, such as age, sex, primary site, T stage, N stage, degree of pathological differentiation, and lymph node status of levels I-IV, were also evaluated. Statistical analysis was performed using Fisher's exact test. RESULTS: In total, 301 neck dissections (ipsilateral side, n = 162; contralateral side, n = 139) were performed in this study. The most common primary site was the oral cavity (n = 51), followed by the larynx (n = 48), hypopharynx (n = 39), and oropharynx (n = 24). On the ipsilateral side, the overall incidence of pathologically positive neck (pN+) was 63.6% (103/162). The overall prevalence of level V metastasis was 7.4% (12/162), 6.8% (11/162) on the ipsilateral side, and 1.4% (2/139) on the contralateral side. Isolated level V metastasis and bilateral level V metastasis was observed in three patients and one patient, respectively. Metastasis to level V and other levels was observed in eight patients (8/96, 8.3%), and level V involvement on the ipsilateral side alone was observed only in three patients (3/66, 4.5%). There were two cases in which level V was involved when the other levels were also involved (2/22, 9.1%), and there was no case in which the other levels were not involved on the contralateral side. A statistically significant association was found between level V metastasis and pN stage >N2b (p = 0.0035), degree of pathological differentiation (p = 0.0305) on the ipsilateral side, status of neck levels I-IV (p = 0.001), and the number of positive neck levels (p < 0.0001) on the contralateral side.