Comprehensive Genetic Evaluation in Patients with Special Reference to Late-Onset Sensorineural Hearing Loss.

Hearing loss (HL) is a common and multi-complex etiological deficit that can occur at any age and can be caused by genetic variants, aging, toxic drugs, noise, injury, viral infection, and other factors. Recently, a high incidence of genetic etiologies in congenital HL has been reported, and the usefulness of genetic testing has been widely accepted in congenital-onset or early-onset HL. In contrast, there have been few comprehensive reports on the relationship between late-onset HL and genetic causes. In this study, we performed next-generation sequencing analysis for 91 HL patients mainly consisting of late-onset HL patients. As a result, we identified 23 possibly disease-causing variants from 29 probands, affording a diagnostic rate for this study of 31.9%. The highest diagnostic rate was observed in the congenital/early-onset group (42.9%), followed by the juvenile/young adult-onset group (31.7%), and the middle-aged/aged-onset group (21.4%). The diagnostic ratio decreased with age; however, genetic etiologies were involved to a considerable degree even in late-onset HL. In particular, the responsible gene variants were found in 19 (55.9%) of 34 patients with a familial history and progressive HL. Therefore, this phenotype is considered to be a good candidate for genetic evaluation based on this diagnostic panel.

Comprehensive analysis of syndromic hearing loss patients in Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.

WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis.

A heterozygous mutation in the Wolfram syndrome type 1 gene (WFS1) causes autosomal dominant nonsyndromic hereditary hearing loss, DFNA6/14/38, or Wolfram-like syndrome. To date, more than 40 different mutations have been reported to be responsible for DFNA6/14/38. In the present study, WFS1 variants were screened in a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA6/14/38 and Wolfram-like syndrome. Massively parallel DNA sequencing of 68 target genes was performed in 2,549 unrelated Japanese HL patients to identify genomic variations responsible for HL. The detailed clinical features in patients with WFS1 variants were collected from medical charts and analyzed. We successfully identified 13 WFS1 variants in 19 probands: eight of the 13 variants were previously reported mutations, including three mutations (p.A684V, p.K836N, and p.E864K) known to cause Wolfram-like syndrome, and five were novel mutations. Variants were detected in 15 probands (2.5%) in 602 families with presumably autosomal dominant or mitochondrial HL, and in four probands (0.7%) in 559 sporadic cases; however, no variants were detected in the other 1,388 probands with autosomal recessive or unknown family history. Among the 30 individuals possessing variants, marked variations were observed in the onset of HL as well as in the presence of progressive HL and tinnitus. Vestibular symptoms, which had been rarely reported, were present in 7 out of 30 (23%) of the affected individuals. The most prevalent audiometric configuration was low-frequency type; however, some individuals had high-frequency HL. Haplotype analysis in three mutations (p.A716T, p.K836T, and p.E864K) suggested that the mutations occurred at these mutation hot spots. The present study provided new insights into the audiovestibular phenotypes in patients with WFS1 mutations.

Guiding principles of sublingual immunotherapy for allergic rhinitis in Japanese patients.

OBJECTIVE: Sublingual immunotherapy (SLIT) appears to offer practical advantages for the treatment of allergic rhinitis (AR). Based on a review of the scientific literature, we present recommendations as guiding principles to administer SLIT safely. METHODS: Clinical questions concerning SLIT were prepared. Literature published between January 2003 and December 2012 was searched from PubMed, the Cochrane Library, and Japana Centra Revuo Medicina. Qualified studies were analyzed and the results were evaluated, consolidated, and codified. We answered 17 clinical questions and, based on this, presented evidence-based recommendations. RESULTS: Sublingual immunotherapy improved symptoms (e.g., quality of life [QOL]) and reduced medication scores in seasonal AR and perennial AR. Most SLIT-induced adverse effects were local oral reactions, although systemic adverse effects such as gastrointestinal symptoms, urticaria, and asthma are occasionally reported. There have been no reports of lethal anaphylactic reactions by SLIT. When SLIT is continued for 3-4 years, its effect persists long after discontinuation. CONCLUSION: A correct diagnosis of AR and sufficient informed consent from patients are required before initiating SLIT. Sublingual immunotherapy should be continued for 3 years or longer. The initial administration of SLIT during the uptitration of an allergen vaccine and the general condition of patients are critical for the safe performance of SLIT.

Novel mutation in GRXCR1 at DFNB25 lead to progressive hearing loss and dizziness.

OBJECTIVE: We identified 2 patients in 1 family who had novel mutations in GRXCR1, which caused progressive hearing loss. METHODS: One thousand one hundred twenty Japanese hearing loss patients with sensorineural hearing loss from unrelated families were enrolled in this study. Targeted genomic enrichment with massively parallel sequencing of all known nonsyndromic hearing loss genes was used to identify the genetic causes of hearing loss. RESULTS: In this study, 2 affected individuals with compound heterozygous mutations-c.439C>T (p.R147C) and c.784C>T (p.R262X)-in GRXCR1 were identified. The proband had moderate to severe hearing loss and suffered from dizziness with bilateral canal paralysis. CONCLUSION: Our cases are the first identified in the Japanese population and are consistent with previously reported cases. The frequency of mutations in GRXCR1 seems to be extremely rare. This study underscores the importance of using comprehensive genetic testing for hearing loss. Furthermore, longitudinal audiologic assessment and precise vestibular testing are necessary for a better understanding of the mechanisms of hearing loss and vestibular dysfunction caused by GRXCR1 mutations.

A case of cochlear nerve deficiency without profound sensorineural hearing loss.

OBJECTIVE: To describe a case of cochlear nerve deficiency (CND) with unique otologic findings. PATIENT: A 6-year-old girl. MAIN OUTCOME MEASURES: Magnetic resonance imaging, pure tone audiometry, distortion product otoacoustic emissions, and auditory brainstem response. RESULTS: The patient showed moderate sensorineural hearing impairment limited to high frequency in the right ear on pure tone audiometry. The auditory brainstem response was absent on the right; however, distortion product otoacoustic emissions were detected on both sides. The right cochlear nerve at the level of the fundus was absent on 3-dimensional constructive interference in steady state magnetic resonance imaging. CONCLUSION: Most cases of CND show deafness or profound hearing loss, but the patient in this case had only moderate hearing loss. This finding provides evidence that auditory thresholds are variable in patients with CND. Therefore, careful evaluation is needed in diagnosis of patients with hearing loss.