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Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication.

ABSTRACT: Severe to profound sensorineural hearing loss (SNHL) requires cochlear implantation (CI) for auditory rehabilitation. Etiologic diagnoses can contribute to candidacy selection and decision-making regarding the timing of successful CI. However, few studies have been performed to address the etiologic spectrum of severe SNHL in the population where there is no consanguineous marriage and the majority of SNHL cases are sporadic in small sized families. The authors sought to comprehensively understand the etiologies of Korean cochlear implantees by incorporating the targeted resequencing of 204 candidate deafness genes (TRS-204) and a phenotype-driven candidate gene approach.Ninety-three that consented to molecular genetic testing and underwent at least one molecular genetic test were included. Patients with a characteristic Phenotypic marker were subject to Sanger sequencing to detect variants in corresponding candidate genes. The rest of patients without any prominent phenotype were tested on GJB2. Next, TRS-204 was applied in GJB2-negative cases without any phenotypic marker. In addition, the sibling recurrence-risk of SNHL among families with non-diagnostic genotypes after TRS-204 was performed to gain insight of etiologies in non-diagnostic cases.Overall, we could find causative variants in 51 (54.8%) of the 93 cochlear implantees. Thirty (32.3%) probands could be diagnosed by direct Sanger sequencing of candidate genes selected by their phenotypes. GJB2 sequencing added 10 subjects to the group with a diagnostic genotype. TRS-204 could detect a causative variant from additional 11 cases (11.8%). We could not detect any pathogenic deletion or duplication on 204 target genes. The sibling recurrence-risk of SNHL among 42 genetically undiagnosed families with 0.03 (1/38) was significantly lower than among genetically diagnosed recessive families with 0.19 (7/37).Despite that the majority of severe or more degree of SNHL occurs sporadically in Koreans, at least 54.8% of such cases that were willing to join the genetic study in the Korean population are monogenic Mendelian disorders with convincing causative variants. This study also indicates that a substantial portion of unsolved cases after applying our current protocol are predicted to have non-genetic or complex etiology rather than a Mendelian genetic disorder involving new genes beyond the 204 target genes.

SUBMITTER: Park JH

PROVIDER: S-EPMC4243193 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication.

Park Joo Hyun JH Kim Nayoung K D NK Kim Ah Reum AR Rhee Jihye J Oh Seung Ha SH Koo Ja-Won JW Nam Jae-Yong JY Park Woong-Yang WY Choi Byung Yoon BY

Orphanet journal of rare diseases 20141106

<h4>Background</h4>Severe to profound sensorineural hearing loss (SNHL) requires cochlear implantation (CI) for auditory rehabilitation. Etiologic diagnoses can contribute to candidacy selection and decision-making regarding the timing of successful CI. However, few studies have been performed to address the etiologic spectrum of severe SNHL in the population where there is no consanguineous marriage and the majority of SNHL cases are sporadic in small sized families. The authors sought to compr ...[more]

PMID: 25373420

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Project description:OBJECTIVES:We, herein, report two novel USH2A variants from two unrelated Korean families and their clinical phenotypes, with attention to severe or more than severe sensorineural hearing loss (SNHL). METHODS:Two postlingually deafened subjects (SB237-461, M/46 and SB354-692, F/34) with more than severe SNHL and also with suspicion of Usher syndrome type II (USH2) were enrolled. A comprehensive audiological and ophthalmological assessments were evaluated. We conducted the whole exome sequencing and subsequent pathogenicity prediction analysis. RESULTS:We identified the following variants of USH2A from the two probands manifesting more than severe SNHL and retinitis pigmentosa (RP): compound heterozygosity for a nonsense (c.8176C>T: p.R2723X) and a missense variant (c.1823G>A: p.C608Y) in SB237, and compound heterozygosity for two frameshift variants (c.14835delT: p.S4945fs & c.13112_13115delAAAT: p.G4371fs) in SB354. Based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, two novel variants, c.1823G>A: p.C608Y and c.14835delT: p.Ser4945fs, can be classified as "uncertain significance" and "pathogenic," respectively. The audiogram exhibited more than severe SNHL and a down-sloping configuration, necessitating cochlear implantation. The ophthalmic examinations revealed typical features of RP. Interestingly, one proband (SB 354-692) carrying two truncating compound heterozygous variants exhibited more severe hearing loss than the other proband (SB 237-461), carrying one truncation with one missense variant. CONCLUSION:Our results provide insight on the expansion of audiological spectrum encompassing more than severe SNHL in Korean subjects harboring USH2A variants, suggesting that USH2A should also be included in the candidate gene of cochlear implantation. A specific combination of USH2A variants causing truncating proteins in both alleles could demonstrate more severe audiological phenotype than that of USH2A variants carrying one truncating mutation and one missense mutation, suggesting a possible genotype-phenotype correlation. The understanding of audiological complexity associated with USH2A will be helpful for genetic counseling and treatment starategy.

Project description:BackgroundHearing loss increases the risk of poor outcomes across a range of life domains. Where hearing loss is severe or profound, audiological interventions and rehabilitation have limited impact. Hearing dogs offer an alternative, or additional, intervention. They live permanently with recipients, providing sound support and companionship.MethodsA single-centre, randomised controlled trial (RCT) evaluated the impacts of a hearing dog on mental well-being, anxiety, depression, problems associated with hearing loss (responding to sounds, fearfulness/social isolation), and perceived dependency on others. Participants were applicants to the UK charity 'Hearing Dogs for Deaf People'. Eligibility criteria were as follows: first-time applicant; applying for a hearing dog (as opposed to other support provided by the charity). Participants were randomised 1:1 to the following: receive a hearing dog sooner than usual [HD], or within the usual application timeframe (wait-list [WL] comparator). The primary outcome was mental well-being (Short Warwick-Edinburgh Mental Well-Being Scale) 6 months (T1) after HD received a hearing dog. The cost-effectiveness analysis took a health and social care perspective.ResultsIn total, 165 participants were randomised (HD n = 83, WL n = 82). A total of 112 (67.9%) were included in the primary analysis (HD n = 55, WL n = 57). At T1, mental well-being was significantly higher in the HD arm (adjusted mean difference 2.53, 95% CI 1.27 to 3.79, p < 0.001). Significant improvements in anxiety, depression, functioning, fearfulness/social isolation, and perceived dependency, favouring the HD arm, were also observed. On average, HD participants had used fewer statutory health and social care resources. In a scenario whereby costs of provision were borne by the public sector, hearing dogs do not appear to be value for money. If the public sector made a partial contribution, it is possible that hearing dogs would be cost-effective from a public sector perspective.ConclusionsHearing dogs appear to benefit recipients across a number of life domains, at least in the short term. Within the current funding model (costs entirely borne by the charity), hearing dogs are cost-effective from the public sector perspective. Whilst it would not be cost-effective to fully fund the provision of hearing dogs by the public sector, a partial contribution could be explored.Trial registrationThe trial was retrospectively registered with the International Standard Randomised Controlled Trial Number (ISRCTN) registry on 28.1.2019: ISRCTN36452009 .

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Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication.

Publications

Exploration of molecular genetic etiology for Korean cochlear implantees with severe to profound hearing loss and its implication.

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