Yumiko Kobayashi

Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns.

AbstractMutations in the GJB2 (connexin 26, Cx26) gene are the major cause of nonsyndromic hearing impairment in many populations. Genetic testing offers opportunities to determine the cause of deafness and predict the course of hearing, enabling the prognostication of language development. In the current study, we compared severity of hearing impairment in 60 patients associated with biallelic GJB2 mutations and assessed the correlation of genotypes and phenotypes. Within a spectrum of GJB2 mutations found in the Japanese population, the phenotype of the most prevalent mutation, 235delC, was found to show more severe hearing impairment than that of V37I, which is the second most frequent mutation. The results of the present study, taken together with phenotypes caused by other types of mutations, support the general rule that phenotypes caused by the truncating GJB2 mutations are more severe than those caused by missense mutations. The present in vitro study further confirmed that differences in phenotypes could be explained by the protein expression pattern.

Massively Parallel DNA Sequencing Facilitates Diagnosis of Patients with Usher Syndrome Type 1

Usher syndrome is an autosomal recessive disorder manifesting hearing loss, retinitis pigmentosa and vestibular dysfunction, and having three clinical subtypes. Usher syndrome type 1 is the most severe subtype due to its profound hearing loss, lack of vestibular responses, and retinitis pigmentosa that appears in prepuberty. Six of the corresponding genes have been identified, making early diagnosis through DNA testing possible, with many immediate and several long-term advantages for patients and their families. However, the conventional genetic techniques, such as direct sequence analysis, are both time-consuming and expensive. Targeted exon sequencing of selected genes using the massively parallel DNA sequencing technology will potentially enable us to systematically tackle previously intractable monogenic disorders and improve molecular diagnosis. Using this technique combined with direct sequence analysis, we screened 17 unrelated Usher syndrome type 1 patients and detected probable pathogenic variants in the 16 of them (94.1%) who carried at least one mutation. Seven patients had the MYO7A mutation (41.2%), which is the most common type in Japanese. Most of the mutations were detected by only the massively parallel DNA sequencing. We report here four patients, who had probable pathogenic mutations in two different Usher syndrome type 1 genes, and one case of MYO7A/PCDH15 digenic inheritance. This is the first report of Usher syndrome mutation analysis using massively parallel DNA sequencing and the frequency of Usher syndrome type 1 genes in Japanese. Mutation screening using this technique has the power to quickly identify mutations of many causative genes while maintaining cost-benefit performance. In addition, the simultaneous mutation analysis of large numbers of genes is useful for detecting mutations in different genes that are possibly disease modifiers or of digenic inheritance.

Mutations in the MYO15A Gene Are a Significant Cause of Nonsyndromic Hearing Loss Massively Parallel DNA Sequencing–Based Analysis

Objectives: Screening for MYO15A mutations was carried out using a large cohort to clarify the frequency and clinical characteristics of patients with MYO15A (DFNB3) mutations in a hearing loss population. Methods: Genetic analysis of 63 previously reported deafness genes based on massively parallel DNA sequencing (MPS) in 1120 Japanese hearing loss patients from 53 otorhinolaryngology departments was performed. Detailed clinical features of the patients with MYO15A mutations were then collected and analyzed. Results: Eleven patients from 10 families were found to have compound heterozygosity for MYO15A. Audiograms showed profound or high frequency hearing loss, with some patients showing progressive hearing loss. Age at onset was found to vary from 0 to 14 years, which seemed to be associated with the mutation. Four children underwent bilateral cochlear implantation for congenital hearing loss, with all showing good results. Conclusion: Mutations in the MYO15A gene are a notable cause of nonsyndromic hearing loss. MPS technology successfully detected mutations in relatively rare deafness genes such as MYO15A.

Mutations in LOXHD1 gene cause various types and severities of hearing loss

Objective: We present 2 families that were identified with novel mutations in LOXHD1 as a cause of nonprogressive hearing loss. Methods: One thousand three hundred fourteen (1314) Japanese subjects with sensorineural hearing loss from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic cause of hearing loss. Results: Two patients in 1 family affected with homozygous mutation c.879+1G>A in LOXHD1 showed profound congenital hearing loss, whereas 2 patients in another family with compound heterozygous mutations, c.5869G>T (p.E1957X) and c.4480C>T (p.R1494X), showed moderate to severe hearing loss. Conclusion: Mutations in LOXHD1 are extremely rare, and these cases are the first identified in a Japanese population. The genotype-phenotype correlation in LOXHD1 is still unclear. The differences in phenotypes in each patient might be the result of the nature of the mutations or the location on the gene, or be influenced by a genetic modifier.

A Novel Mutation of MYO15A Associated with Hearing Loss in a JapaneseFamily

Mutations in the MYO15A gene located on chromosome 17 p11.2, are responsible for non-syndromic autosomal recessive profound hearing loss (DFNB3). Direct sequencing of 96 Japanese families with profound congenital hearing loss revealed one family with a novel homozygous mutation in MYO15A, a T to A transition at the nucleotide of 9413 (c.9413T>A) that encodes the MyTh4 domain of the protein (p. L3138Q). This is the first report of an East Asian hearing loss patient with a MYO15A mutation.

Body balance function of cochlear implant patients with and without sound conditions

OBJECTIVE The relation between well-controlled auditory stimulation through cochlear implant (CI) and the body balance has been sparsely investigated. The purpose of this study was to evaluate the body balance function of CI patients with- and without-sound in anechoic sound-shielded room. METHODS We recorded 8 experienced CI recipients and 8 young normal-hearing volunteers. All subjects were assessed using posturography under 4 conditions: (1) eyes open with-sound, (2) eyes closed with-sound, (3) eyes open without-sound, and (4) eyes closed without-sound. RESULTS The total path length and the total area were significantly larger in the eyes closed condition than in the eyes open condition. In normal hearing subjects, the average displacement of center of pressure (COP) in the mediolateral direction under with-sound condition was not different from that under without-sound condition. In CI recipients, the COP significantly displaced to the CI side after the deprivation of visual cues in without-sound condition. This shift was eliminated in with-sound condition (significant interaction among sound condition, eye condition, and between-group factor). CONCLUSION In CI subjects, sound stimulation improves the abnormal displacement of COP in the mediolateral direction. SIGNIFICANCE A posturographic study under an anechoic condition proved that sound stimulation improves body balance function in CI subjects.

Cochlear implant function in a patient with Jervell and Lange-Nielsen syndrome after defibrillation by countershock

Jervell and Lange-Nielsen syndrome (JLNS), a rare autosomal recessive congenital QT prolongation syndrome, is characterized by cardiac arrhythmias, syncopal episodes, and profound deafness. A cochlear implant (CI) for patients with JLNS is expected to result in hearing improvement. Sometimes, defibrillation is required if a patient experiences lethal arrhythmia. In this paper, we report a pediatric patient with JLNS who received defibrillation after CI surgery in his right ear at the age of 2 years. With intensive care, the post-operative course was uneventful, and the patient acquired satisfactory speech and hearing abilities. Five years after the surgery, he underwent defibrillation because of the incidence of syncopal attack. Thereafter, arrhythmic syncope recurred three times, which necessitated defibrillation therapy. To prevent recurrence of cardiac arrhythmia, he underwent ICD (implantable cardioverter-defibrillator) implantation at the age of 11 years. At present, CI works well and provides good hearing, while syncopal attack is prevented by ICD. From the experience of this case, electronic circuit of CI is thought to tolerate emergency countershock if the speech processor is removed.

A Case of Sick-House Syndrome

Sick-house syndrome is characterized by diverse physical disorders caused by a variety of indoor environmental factors. A 27-year-old female with a history of atopic dermatitis visited our clinic complaining of chemical hypersensitivity of the upper respiratory tract. Exposure to tobacco smoke or perfume made her feel headache, nausea and pain in the throat. She was suspected of having sick-house syndrome because indefinite complaints such as headache and nausea appeared soon after the move to her new house. Blood examination showed no manifestations of allergic diseases or significant elevation of IgE for particular chemical substances. The level of formaldehyde in her house turned out to exceed the concentration recommended by the Ministry of Health, Labor and Welfare of Japan. Ventilating her house for twenty-four hours diminished her complaints immediately. Sick-house syndrome may have some correlation with allergy, for among her family no one except her had a history of allergic disease or of complaints like hers.