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Objective: To investigate the molecular etiology of deafness in the postlingually deafened cochlear implantees and determine whether CI performances are affected by the genetic etiologies Materials and methods: Seventy-four postlingually deafened patients who had undergone CI between January 2010 and March 2017 at Seoul National University Hospital and Seoul National University Bundang Hospital were included in the study. Among them, thirty-nine patients were consented to molecular genetic testing(MGT). Molecular genetic etiologies were assessed by Sanger sequencing in patients with a characteristic phenotypic marker. The rest of patients were tested with either panel sequencing or whole exome sequencing. Patients underwent MGT were allocated to the following groups depending on whether the genetic etiology was disclosed or not; "Genetically diagnosed(GD)", "Genetically undiagnosed(GUD)". Patients who did not undergo MGT and who had a shorter deaf duration than 6 years were identified as controls. Speech perception performance was assessed using K-CID sentence score, pre- and post-operative 3, 6, and 12months. Non-parametric testing was performed using Kruskal- Wallis test with post-hoc testing using Mann-Whitney U test with Bonferroni's correction. P<0.05 was considered significant. Results: Among the thirty-nine postlingually deafened cochlear implantees who underwent MGT, 20 patients (51%) turned out to have a conclusive Mendelian genetic etiology, leaving the other 19 patients (49%) undiagnosed. Such an extreme molecular etiologic heterogeneity as to involve 13 deafness genes was noted for this cohort. To interest, about half of the postlingually deafened genetic cases were due to autosomal recessive variants which were previously thought to causes mainly prelingual deafness. The most frequent causative gene was TMC1 (DFNA36) (3 cases), followed by the next tier of genes (2 cases each) (ACTG1, CDH23, COCH, SLC26A4, TMPRSS3) and the genes that were detected only once (ATP1A3, GJB2, ILDR1, MYO7A, NF2, OTOR and SERPNB6). All of these genes are expressed in membranous labyrinth(ML), except TMPRSS3 which is expressed abundantly in spiral ganglion neurons(SGN). The median ages of the GD, GUD and control groups were all younger than 55 years and the median deaf durations of the GD, GUD and control groups were all shorter than 5 years. Post-operative Spondee, PB word score and K-CID scores at 3months, 6months and 12months of the three groups overall did not show statistically significant differences, all reaching about at least 70% for K-CID scores at 1 year. Rising trends in Spondee word scores and KCID scores of GD group at 3 months after CI tend to show slightly heavier, albeit statistically insignificant, than those of GUD group. Among the GD groups, there was no significant difference of speech perception performance between the groups of genes expressing in the SGN and genes expressed in the ML. Although most of the genetically diagnosed cases showed relatively good speech perception performances, two patients who had ACTG1 mutation and each one of the patients who had SLC26A4, CDH23, TMC1, TMPRSS3 and OTOR mutations had post-operative K-CID scores below interquartile range of control group. Among them, two patients with ACTG1 mutation and one of the patients with TMC1 mutation who had deaf durations over 10 years showed KCID scores under 50% a year after CI. Conclusion: Our genetic diagnosis rate was 51% in postlingually deafened cochlear implantees and a wide variety of causative genes have been found. Cochlear implantees who were genetically diagnosed showed speech perception performances comparable to the control group, even in the genes expressed in SGN. However, even with the same causative mutation, those with significantly longer deaf duration are associated with relatively worse performance, mandating prompt implantation, if indicated. [ABSTRACT FROM AUTHOR]

Objectives: Auditory neuropathy spectrum disorder (ANSD) is a disorder, in which the transmission of sound signal from the inner ear to the auditory nerve/ brain cortex is impaired, while the outer hair cells function normally. Previously, our group reported that anatomically intact, prelingual-onset, ANSD in Koreans is mainly due to mutations in OTOF (DFNB9). Since our previous report, we further recruited anatomically intact, prelingualonset ANSD subjects and we disclosed a mutational and phenotypic spectrum of OTOF-related ANSD in the Korean population. Materials and Methods: Six patients with ANSD were recruited from two referral hospitals. Genetic diagnosis was made through the screening panel, targeted exome sequencing, or whole exome sequencing. Together with five previously documented DFNB9 patients, a total of 11 patients' genotypic and phenotypic analysis was made. Results: Genetic diagnosis identified three novel variants of OTOF in our cohorts: a nonsense variant, p.Tyr1064Ter, a missense variant, p.Gly1845Glu, and a splice site variant, c.4227+5G>C. Regarding the contribution of each OTOF variants in Korean ANSD, p.Arg1939Gln was most commonly identified among the 22 alleles in 11 DFNB9 subjects, with its frequency in our cohort calculated to be 36.4%, followed by p.Glu841Lys (13.6%), p.Leu1011Pro (9.1%) and p.Arg1856Trp (9.1%). Although ABR results of our patients consistently did not show responses to sound, ASSR results demonstrated relatively diverse spectrum of hearing status including significant residual hearing and asymmetric hearing. Ten of 11 patients received cochlear implantation for auditory rehabilitation, showing favorable outcomes with more rapid improvement on early-CI group (age at CI ≤ 18 mo.) than late-CI group. Conclusions: Here, we report three novel variants of OTOF, related with ANSD and confirmed the significant contribution of a recurring predominant variant (p.Arg1939Gln) of OTOF to Korean ANSD in our cohorts which is, to date, the largest OTOF-related ANSD cohort in Korea. Additionally, relatively diverse auditory spectrum of DFNB9 was observed in the ASSR results of our patients. Clinically, given the genotypic spectrum of our cohorts, we suggest the four major alleles of OTOF: p.Arg1939Gln, p.Glu841Lys, p.Leu1011Pro and p.Arg1856Trp as included in a screening panel to facilitate the molecular genetic diagnosis of Korean OTOF-related ANSD, further prompting the early CI for timely development of auditory perceptive ability. [ABSTRACT FROM AUTHOR]