Surgical and Audiologic Comparison Between Sophono and Bone-Anchored Hearing Aids Implantation.

OBJECTIVES: Bone-anchored hearing aids (BAHA) occasionally cause soft tissue problems due to abutment. Because Sophono does not have abutment penetrating skin, it is thought that Sophono has no soft tissue problem relating to abutment. On the other hand, transcutaneous device's output is reported to be 10 to 15 dB lower than percutaneous device. Therefore, in this study, Sophono and BAHA were compared to each other from surgical and audiological points of view. METHODS: We retrospectively reviewed the medical records of 9 Sophono patients and 10 BAHA patients. In BAHA cases, single vertical incision without skin thinning technique was done. We compared Sophono to BAHA by operation time, wound healing time, postoperative complications, postoperative hearing gain after switch on, and postoperative air-bone gap. RESULTS: The mean operation time was 60 minutes for Sophono and 25 minutes for BAHA. The wound healing time was 14 days for Sophono and 28 days for BAHA. No major intraoperative complication was observed. Skin problem was not observed in the 2 devices for the follow-up period. Postoperative hearing gain of bilateral aural atresia patients was 39.4 dB for BAHA (n=4) and 25.5 dB for Sophono (n=5). However, the difference was not statistically significant. In all patients included in this study, the difference of air-bone gap between two groups was 16.6 dB at 0.5 kHz and 18.2 dB at 4 kHz. BAHA was statistically significantly better than Sophono. CONCLUSION: Considering the audiologic outcome, BAHA users were thought to have more audiologic benefit than Sophono users. However, Sophono had advantages over BAHA with abutment in cosmetic outcome. Sophono needed no daily skin maintenance and soft tissue complication due to abutment would not happen in Sophono. Therefore, a full explanation about each device is necessary before deciding implantation.

Identification of CDH23 mutations in Korean families with hearing loss by whole-exome sequencing.

BACKGROUND: Patient genetic heterogeneity renders it difficult to discover disease-cause genes. Whole-exome sequencing is a powerful new strategy that can be used to this end. The purpose of the present study was to identify a hitherto unknown mutation causing autosomal recessive nonsyndromic hearing loss (ARNSHL) in Korean families. METHODS: We performed whole-exome sequencing in 16 individuals from 13 unrelated small families with ARNSHL. After filtering out population-specific polymorphisms, we focused on known deafness genes. Pathogenic effects of the detected mutations on protein structure or function were predicted via in silico analysis. RESULTS: We identified compound heterozygous CDH23 mutations in hearing-loss genes of two families. These include two previously reported pathological mutations, p.Pro240Leu and p.Glu1595Lys, as well as one novel mutation, p.Asn342Ser. The p.Pro240Leu mutation was found in both families. We also identified 26 non-synonymous variants in CDH23 coding exons from 16 hearing-loss patients and 30 Korean exomes. CONCLUSION: The present study is the first to show that CDH23 mutations cause hearing loss in Koreans. Although the precise contribution made by such mutations needs to be determined using a larger patient cohort, our data indicate that mutations in the CDH23 gene are one of the most important causes of non-syndromic hearing loss in East Asians. Further exome sequencing will identify common mutations or polymorphisms and contribute to the molecular diagnosis of, and development of new therapies for, hereditary hearing loss.

Intrafamilial phenotypic variability in families with biallelic SLC26A4 mutations.

OBJECTIVES/HYPOTHESIS: Enlarged vestibular aqueduct (EVA) and hearing loss are known to be caused by SLC26A4 mutations, but large phenotypic variability exists among patients with biallelic SLC26A4 mutations. Intrafamilial phenotypic variability was analyzed in multiplex EVA families carrying biallelic SLC26A4 mutations to identify the contribution of SLC26A4 mutations and other genetic or environmental factors influencing the clinical manifestations. STUDY DESIGN: Retrospective case series. METHODS: Eleven multiplex Korean families with EVA and hearing loss that carry biallelic mutations of the SLC26A4 gene were included. Genetic analysis for SLC26A4 and other genes including FOXI1, FOXI1-DBD, and KCNJ10 was performed. The auditory and other phenotypes were compared among siblings with the same SLC26A4 mutations. RESULTS: The difference in the auditory phenotypes was identified between siblings in approximately half of the EVA families. Families with SLC26A4 mutations other than H723R homozygous mutations demonstrated more phenotypic variability, especially in those carrying IVS7-2A>G splice site mutation. Cochlear malformation was a consistent finding among siblings with the same SLC26A4 mutations. No mutation was identified in the FOXI1, FOXI1-DBD, and KCNJ10 genes in the tested families. CONCLUSIONS: The possibility of variability concerning auditory phenotype should be considered even within family members carrying the same SLC26A4 mutations when providing genetic counseling to multiplex EVA families. Mutations in the currently known genes associated with EVA other than SLC26A4 were not found to be responsible for the intrafamilial phenotypic variability. Modifier genes or environmental factors other than the currently known genes seem to play a role in the phenotypic expressions of EVA patients.

Limitations of hearing screening in newborns with PDS mutations.

OBJECTIVES: SLC26A4 (PDS) mutations are common cause of congenital hearing loss in East Asia. Hearing loss caused by PDS mutations tends to have delayed presentation; thus universal newborn hearing screening (UNHS) can be less effective in these patients. We examined the efficiency of newborn hearing screening test in patients with bi-allelic PDS mutations. METHODS: Forty-three patients with sensorineural hearing loss were recruited. Patients had an enlarged vestibular aqueduct and biallelic PDS mutations. Among them, newborn hearing screening test had been performed on 14. The remaining 29 patients did not undergo newborn hearing screening test. Another 15 patients without a PDS mutation but who had sensorineural hearing loss were also recruited as a comparison group. We reviewed the hearing loss history of the children using medical records and parent interviews. RESULTS: Among 14 patients with PDS mutation, four (28.6%) passed newborn hearing screening test in both ears and six (42.9%) passed in one ear. In contrast, only 2 of 15 (13.3%) children without a PDS mutation passed newborn hearing screening test bilaterally. The age at confirmation of bilateral hearing loss in bilateral "pass" patients with PDS mutation was 31.5 ± 17.9 months, which was significantly delayed compared to the age for bilateral "refer" children (1.75 ± 0.96 months) (p<0.05). CONCLUSION: The UNHS is not an accurate tool for predicting long-term hearing loss in patients with PDS mutations. We recommend that genetic screening be combined with UNHS, particularly in communities with a high prevalence of PDS mutations, to better identify children in need of early habilitation.

A novel synonymous mutation causing complete skipping of exon 16 in the SLC26A4 gene in a Korean family with hearing loss.

INTRODUCTION: Mutations in PDS (or SLC26A4) cause both Pendred syndrome (PS) and DFNB4, two autosomal recessive disorders that share hearing loss as a common feature. PS and DFNB4 are genetically homogeneous disorders caused by bi-allelic SLC26A4 mutations. Here, we report a novel synonymous mutation (c.1803G>A, p.Lys601Lys), that caused aberrant splicing in two Korean family members who were clinically considered to have DFNB4, along with congenital hearing loss and dilated vestibular aqueducts (DVA). METHODS: After extracting DNA from whole blood using standard procedures, the 21 exons and flanking introns of SLC26A4 were amplified with PCR. To evaluate the implication of a novel synonymous mutation (c.1803G>A), we used The Berkeley Drosophila Genome Project (BDGP) (http://www.fruitfly.org/) as a splice site prediction program and performed exon trapping analysis. RESULTS: In molecular analysis of the 21 exons of SCL26A4, we detected a known splicing mutation (c.919-2A>G, heterozygote) and a novel variant (c.1803G>A, heterozygote) in the patients (II-1 and II-2). According to in silico analysis, the novel variant (c.1803G>A) affects canonical splice donor nucleotide positioning. To define the transcript level effects of this novel 1803G>A variant, we performed exon trapping and confirmed that exon 16 is completely skipped in this variant type. CONCLUSION: We report a novel synonymous mutation (c.1803G>A) causing complete exon 16 skipping in the SLC26A4 gene in two Korean family members with hearing loss. This is the first case of a synonymous SNP (c.1803G>A) affecting vestibulocochlear organs through altering splicing accuracy by causing a complete skipping of exon 16. An important issue raised by this study is that synonymous mutations that have been previously ignored in clinical diagnoses must now be considered as potential pathogenic mutations.

Genetic Screening of GJB2 and SLC26A4 in Korean Cochlear Implantees: Experience of Soree Ear Clinic.

OBJECTIVES: Genetic hearing loss is highly heterogeneous and more than 100 genes are predicted to cause this disorder in humans. In spite of this large genetic heterogeneity, mutations in SLC26A4 and GJB2 genes are primarily responsible for the major etiologies of genetic hearing loss among Koreans. The purpose of this study is to investigate the genetic cause of deafness in Korean cochlear implantees by performing a genetic screening of the SLC26A4 and GJB2 genes. METHODS: The study cohort included 421 unrelated Korean patients with sensorineural hearing loss (SNHL) and who had received cochlear implants (CI) at Soree Ear Clinic from July 2002 to December 2010. Among 421 CI patients, we studied 230 cases who had received the genetic screening for SLC26A4 or GJB2 genes. Written informed consent was obtained from all participants. All patients had severe to profound, bilateral hearing loss. For 56 patients who showed enlarged vestibular aqueduct on their computed tomography (CT) scan, we analyzed SLC26A4. For 174 CT negative patients, GJB2 gene was sequenced. RESULTS: For the 56 SLC26A4 patients, 32 (57.1%) had two pathogenic recessive mutations in SLC26A4. A single recessive SLC26A4 mutation was identified in 14 patients (25%). H723R and IVS7-2A>G were the most commonly found mutations, accounting for 60.3% (47/78) and 30.8% (24/78) of the mutated alleles, respectively. For the 174 GJB2 patients, 20 patients (11.5%) had two pathogenic recessive mutations in GJB2. 235delC was the most common mutation, accounting for 43.0% (31/72) of mutant alleles. CONCLUSION: The two major genes, SLC26A4 and GJB2, contribute major causes of deafness in CI patients. Continuous studies are needed to identify new genes that can cause hearing loss to Korean CI patients.