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Background: Mutations in MPZL2, the characteristic genetic etiology of autosomal recessive deafness loci 111 (DFNB111), cause non-syndromic and moderate sensorineural hearing loss., Methods: In this study, we analyzed the phenotype and genotype of eight pedigrees consisting of 10 hearing loss patients with bi-allelic pathogenic or likely pathogenic variants in MPZL2. These patients were identified from a 3272 Chinese patient cohort who underwent genetic testing., Results: Apart from symmetrical and moderate sensorineural hearing loss, the MPZL2-related phenotype was characterized by progressive hearing loss with variation in the onset age (congenital defect to onset at the young adult stage). We determined that in the Chinese population, the genetic load of MPZL2 defects was 0.24% (8/3272) in patients diagnosed with hearing loss and 7.02% (8/114) in patients diagnosed with hereditary moderate sensorineural hearing loss caused by STRC, OTOA, OTOG, OTOGL, TECTA, MPZL2 and others. Three known MPZL2 variants (c.220C > T (p.Gln74*), c.68delC (p.Pro23Leufs*2), c.463delG (p.Ala155Leufs*10)) and a novel start loss variant (c.3G > T (p.Met1?)) were identified. MPZL2 c.220C > T was identified as the hotspot variant in the Chinese population and even in East Asia compared with c.72delA (p.Ile24Metfs*22) in European and West Asia through allele frequency., Conclusions: We concluded that apart from moderate HL, progressive HL is another character of MPZL2-related HL. No specified variant was verified for the progression of HL, the penetrance and expressivity cannot be determined yet. A novel MPZL2 variant at the start codon was identified, enriching the variant spectrum of MPZL2. The hotspot variants of MPZL2 vary in different ethnicities. This study provides valuable data for the diagnosis, prognosis evaluation and genetic counseling of patients with moderate sensorineural hearing loss related to MPZL2., (© 2024. The Author(s).)

The 2018 Hearing Loss Expert Panel (HL-EP)-specific guidelines specified from the universal 2015 ACMG/AMP guidelines are proposed to be used in genetic HL, which prompted this study. A genetic HL cohort comprising 135 unrelated probands with available exome sequencing data was established. Overall, 169 variants were prioritized as candidates and interpreted using the 2015 ACMG/AMP and 2018 HL-EP guidelines. Changes in rule application and variant classification between the guidelines were compared. The concordance rate of variant classification of each variant between the guidelines was 71.60%, with significant difference. The proportion of pathogenic variants increased from 13.02% (2015) to 29.59% (2018). Variant classifications of autosomal recessive (AR) variants that previously belonged to VUS or likely pathogenic in the 2015 guidelines were changed toward pathogenic in the 2018 guidelines more frequently than those of autosomal dominant variants (29.17% vs. 6.38%, P = 0.005). Stratification of the PM3 and PP1 rules in the 2018 guidelines led to more substantial escalation than that in the 2015 guidelines. We compared the disease-specific guidelines (2018) with the universal guidelines (2015) using real-world data. Owing to the sophistication of case-level data, the HL-specific guidelines have more explicitly classified AR variants toward "likely pathogenic" or "pathogenic", serving as potential references for other recessive genetic diseases., (© 2022. The Author(s).)

Background: Down-sloping sensorineural hearing loss (SNHL) in people in their teens and 20s hampers efficient learning and communication and in-depth social interactions. Nonetheless, its aetiology remains largely unclear, with the exception of some potential causative genes, none of which stands out especially in people in their teens and 20s. Here, we examined the role and genotype-phenotype correlation of lipoxygenase homology domain 1 ( LOXHD1 ) in down-sloping SNHL through a cohort study., Methods: Based on the Seoul National University Bundang Hospital (SNUBH) genetic deafness cohort, in which the patients show varying degrees of deafness and different onset ages (n=1055), we have established the 'SNUBH Teenager-Young Adult Down-sloping SNHL' cohort (10-35 years old) (n=47), all of whom underwent exome sequencing. Three-dimensional molecular modelling, minigene splicing assay and short tandem repeat marker genotyping were performed, and medical records were reviewed., Results: LOXHD1 accounted for 33.3% of all genetically diagnosed cases of down-sloping SNHL (n=18) and 12.8% of cases in the whole down-sloping SNHL cohort (n=47) of young adults. We identified a potential common founder allele, as well as an interesting genotype-phenotype correlation. We also showed that transcript 6 is necessary and probably sufficient for normal hearing., Conclusions: LOXHD1 exceeds other genes in its contribution to down-sloping SNHL in young adults, rising as a signature causative gene, and shows a potential but interesting genotype-phenotype correlation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Loss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP 2 ), an obligatory phospholipid for maintaining KCNQ channel activity, confers differential pharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP 2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP 2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP 2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP 2 effectively downregulated the hyperactive WT-p.G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP 2 level and KCNQ-regulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2., (© 2021. The Author(s).)

Background: Understanding the characteristics of residual hearing at low frequencies and its natural course in relation to molecular genetic etiology may be important in developing rehabilitation strategies. Thus, we aimed to explore the characteristics and natural course of residual hearing at low frequencies associated with the two most frequent deafness genes: GJB2 and SLC26A4., Methods: Initially, 53 GJB2 and 65 SLC26A4 subjects were enrolled, respectively. Only those whose audiograms exhibited hearing thresholds ≤70 dB at 250 and 500 Hz, and who had at least 1-year follow-up period between the first and last audiograms, were included. Collectively, the clinical characteristics of 14 ears from eight subjects with GJB2 variants, and 31 ears from 22 subjects with SLC26A4 variants fulfilled the strict criteria. In this study, a dropout rate refers to an incidence of dropping out of the cohort by cochlear implant surgery due to severe hearing deterioration., Results: Among the ears with complete serial audiogram data set, significant residual hearing at low frequencies at the time of inclusion was observed in 18.8% of those with GJB2 variants (15 out of 80 ears) and 42.6% of those with SLC26A4 variants (46 out of 108 ears), revealing a difference between two deafness genes. Subsequently, ears with SLC26A4 variants (11 of 46 ears, 23.9%) turned out to have a higher dropout rate for cochlear implantation due to hearing deterioration within the first year than those with GJB2 variants (1 of 15, 6.7%), albeit with no statistical significance. Throughout the follow-up period (mean: 37.2 ± 6.8, range: 12 to 80 months), deterioration of residual hearing at low frequencies at 250 Hz (dB HL/y) and 500 Hz (dB HL/y) of those with GJB2 variants exhibited 3.1 ± 1.3 (range: 0 to 15) and 5.2 ± 1.6 (range: 0 to 20), respectively, suggesting the deterioration of residual hearing in GJB2 variants was rather slow and gradual. Specifically, GJB2 p.Leu79Cysfs*3 show less remarkable residual hearing at low frequencies, but then a relatively stable nature. In contrast, SLC26A4 variants demonstrated a significantly higher dropout rate due to severe hearing deterioration requiring cochlear implantation compared with the GJB2 variants. This trend was observed not only in the first-year follow-up period but also in the follow-up periods thereafter. The p.His723Arg;c.919-2A>G genotype of SLC26A4, in particular, was associated with a high propensity for sudden hearing deterioration, as indicated by the dropout rate, which was as high as 46.2% for cochlear implantation due to hearing deterioration during the first year follow-up period. Furthermore, the dropout rate for cochlear implantation was observed in 7.1% of those with GJB2 variants (one out of 14 ears) and 30.3% of those with SLC26A4 variants (10 out of 33 ears) throughout the entire follow-up period., Conclusions: Our results suggest that there is a difference with respect to the progressive nature of residual hearing at low frequencies between the two most common genes responsible for hearing loss, which may provide clinical implications of having individualized rehabilitation and timely intervention., Competing Interests: The authors have no conflicts of interest to declare, (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Recent advances in molecular genetic testing (MGT) have improved identification of genetic aetiology of candidates for cochlear implantation (CI). However, whether genetic information increases CI outcome predictability in post-lingual deafness remains unclear. Therefore, we evaluated the outcomes of CI with respect to genetic aetiology and clinical predictors by comparing the data of study subjects; those with an identified genetic aetiology (GD group), and those without identifiable variants (GUD group). First, we identified the genetic aetiology in 21 of 40 subjects and also observed genetic etiologic heterogeneity. The GD group demonstrated significantly greater improvement in speech perception scores over a 1-year period than did the GUD group. Further, inverse correlation between deafness duration and the 1-year improvement in speech perception scores was tighter in the GD group than in the GUD group. The weak correlation between deafness duration and CI outcomes in the GUD group might suggest the pathophysiology underlying GUD already significantly involves the cortex, leading to lesser sensitivity to further cortex issues such as deafness duration. Under our MGT protocol, the correlation between deafness duration and CI outcomes were found to rely on the presence of identifiable genetic aetiology, strongly advocating early CI in individual with proven genetic aetiologies.

We performed targeted re-sequencing to identify the genetic etiology of early-onset postlingual deafness and encountered a frequent TMPRSS3 allele harboring two variants in a cis configuration. We aimed to evaluate the pathogenicity of the allele. Among 88 cochlear implantees with autosomal recessive non-syndromic hearing loss, subjects with GJB2 and SLC26A4 mutations were excluded. Thirty-one probands manifesting early-onset postlingual deafness were sorted. Through targeted re-sequencing, we detected two families with a TMPRSS3 mutant allele containing p.V116M and p.V291L in a cis configuration, p.[p.V116M; p.V291L]. A minor allele frequency was calculated and proteolytic activity was measured. A p.[p.V116M; p.V291L] allele demonstrated a significantly higher frequency compared to normal controls and merited attention due to its high frequency (4.84%, 3/62). The first family showed a novel deleterious splice site variant-c.783-1G>A-in a trans allele, while the other showed homozygosity. The progression to deafness was noted within the first decade, suggesting DFNB10. The proteolytic activity was significantly reduced, confirming the severe pathogenicity. This frequent mutant allele significantly contributes to early-onset postlingual deafness in Koreans. For clinical implication and proper auditory rehabilitation, it is important to pay attention to this allele with a severe pathogenic potential., Competing Interests: The authors declare no conflict of interest.

Background: Pathogenic variants of MYH14 are known to be associated (in either a syndromic or nonsyndromic manner) with hearing loss. Interestingly, all reported cases to date of MYH14-related nonsyndromic hearing loss with detailed phenotypes have demonstrated mild-to-moderate progressive hearing loss with postlingual onset., Methods: In the present study, targeted resequencing (TRS) of known deafness genes was performed to identify the causative variant in two multiplex families segregating autosomal dominant (AD) inherited hearing loss., Results: TRS uncovered two novel variants of MYH14 (c.A572G: p.Asp191Gly in the myosin head domain and c.C73T:p.Gln25* in exon 2) from two multiplex deafness Korean families. Notably, both probands showed phenotypes of congenital or prelingual severe hearing loss. It is remarkably uncommon to encounter such a severe-to-profound, prelingual, AD hearing loss. Given that the first variant, p. Asp191Gly, was the first documented missense allele discovered in the myosin head domain of this gene related to either congenital or prelingual severe nonsyndromic hearing loss, and also that the second variant, p. Gln25*, lead to a null allele, more severe phenotypes from our probands may have been the result of either genotype-phenotype correlation or genetic backgrounds, or both., Conclusions: In the present study, we report that MYH14 can manifest as nonsyndromic prelingual severe sensorineural hearing loss in an AD fashion in Koreans. The results of the present study suggest that further genetic studies of similar patients should consider MYH14 as a causative gene, and cochlear implantation during infant or early childhood should be indicated for those patients with certain MYH14 pathogenic variants., (Copyright © 2017 John Wiley & Sons, Ltd.)

TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA) or as the autosomal-recessive version. The α-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS), we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187) in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257-262CCTTTC>GCT (p. Ser86Cys; p. Pro88del) in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA.

Conclusions: Intraoperative computed tomography (iCT)-guided cochlear implantation is practical and effective for correct electrode placement in the cochlea of patients with congenital inner ear and/or complex middle ear malformation., Objectives: The operation in patients with inner ear and/or complex middle ear malformation including abnormal facial nerve course is difficult. This study evaluated the efficacy of cochlear implantation under the guidance of iCT to insure correct electrode placement., Methods: This was a prospective interventional case series. Ten patients with severe to profound sensorineural hearing loss due to ear malformations were enrolled, and iCT was used to confirm the right placement of electrodes., Results: Intraoperative CT was performed three times in one patient, twice in two, and once in the others. Interruption of the surgical process for each iCT until resumption of surgery was 9.64 ± 0.63 min. iCT revealed incorrectly positioned cochlear implants in two patients, which were immediately corrected. There were no reoperations due to misplacement of electrodes. iCT helped locate the cochlea in the middle ear of one patient with an abnormal facial nerve course. The overall intervention rate based on iCT findings was 30%., Level of Evidence: level 4.

Conclusion: Real-time quantitative polymerase chain reaction (qPCR) with a TaqMan minor groove binding (MGB) probe is useful for large-scale screening for the C1494T mutation. The mitochondrial DNA(mtDNA) C1494T mutation has a low carrier frequency in Chinese patients with nonsyndromic hearing loss., Objective: To develop a simple, rapid, and reliable real-time qPCR assay based on TaqMan technology using a new MGB probe for detecting the mtDNA C1494T mutation directly, and to investigate the carrier frequency in nonsyndromic deaf Chinese subjects., Methods: A TaqMan-MGB probe was constructed. Peripheral blood samples were collected from 3133 nonsyndromic deaf patients and genomic DNA was extracted. A real-time qPCR using MGB probes (wild-type) in a single tube was used to detect the mtDNA C1494T mutation. The results were then compared to the DNA sequence of the PCR products., Results: A total of 13 of 3133 (0.4%) Chinese nonsyndromic hearing loss patients were C1494T-positive. The results of the TaqMan-MGB probe method were consistent with those of sequencing.

Abstract A 28-year-old woman with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE syndrome) undergoing evaluation for multichannel cochlear implantation is described. The case history, diagnosis of mitochondrial disease, and assessment of the benefits of cochlear implantation are documented. The hearing level with cochlear implant and speech recognition were improved significantly for this patient. MNGIE syndrome is a rare congenital disorder of mitochondrial DNA (mt-DNA). It is crucial for the otolaryngologist to have awareness of MNGIE syndrome and other mitochondrial encephalomyopathies when patients present with sensorineural hearing loss (SNHL). Cochlear implantation can be recommended to patients with MNGIE syndrome and satisfactory results can be achieved.

Aim: To analyze the mutations of AQP3 gene for the purpose of identifying the causative gene located in DFNA55 locus in a Chinese pedigree with autosomal dominant nonsyndromic deafness (DeaFNess Autosomal, DFNA)., Methods: There were 21 DNA sample in this pedigree, among whom 9 were patients and 12 had normal hearing. The coding sequences of AQP3 gene were amplified by polymerase chain reaction (PCR) with 5 pairs of primers, and PCR product s bidirectional sequencing were performed and analyzed with DNA Star Software., Results: Two point mutations were detected. The first mutant point was 390C>T/390C>T(F130F) nexon 4 all members in pedigree. The second mutant point was 394G>A/WT(D132N), which were found in 3 patients and 1 member with normal hearing., Conclusion: We found two point mutations that one caused no amino acid changed and the other caused D132N, but AQP3 gene isn't the responsible gene for this pedigree with auditory neuropathy.

Objective: To investigate whether GJB3 and GJB2 interaction to produce a deafness phenotype in a digenic mode of inheritance in Chinese deafness population., Methods: A series of 108 patients with severe or profound hearing loss carrying one heterozygous GJB2 pathogenic mutation were sequenced for GJB3 coding region, which compared with the data of control group., Results: Three GJB3 missense variants including V84I, A194T and N166S, and four GJB3 nonsense mutation were detected. N166S and A194T were considered as pathogenic which cause nonsyndromic autosomal recessive hearing loss and V84I was considered as polymorphisms in Chinese population. The two patients who carried N166S and A194T respectively in one allele also carried GJB2 235delC mutation in other allele, while the other patient who carried A194T in one allele also carried GJB2 299_300delAT mutation in other allele., Conclusions: GJB3 and GJB2 might interact to produce deafness in a digenic mode of inheritance, but the point need to be proved in further study.

Objective: To discuss how to determine the number of samples in epidemiological study about deafness genes and reveal the characteristics of GJB2, SLC26A4 and mitochondrial DNA A1555G mutations in deaf-mute patients in schools for deaf-mutes in Shandong Province., Methods: A total of 485 subjects were collected from the different schools for deaf-mutes in Shandong province. Amplified target fragments included GJB2 coding sequence, mtDNA12SrRNA and exon 8, 10, 17, 19 of SLC26A4 gene. The amplicons of mtDNA 12S rRNA were subjected to restriction enzyme Alw26I. The amplicons of patients whose enzyme reaction highly indicating A1555G mutation, amplicons of GJB2 and those exons PCR products of SLC26A4 were directly sequenced., Results: The study revealed that 36.29% patients had two mutated alleles (homozygote & compound heterozygote) of GJB2 (24.12%) and SLC26A4 (6.60%) and mtDNA12SrRNA A1555G (5.57%). The 235delC and IVS7-2A > G were still the mutational hot spot in GJB2 and SLC26A4 respectively., Conclusion: The method of determining the number of sample is very important in the epidemiological study. There were about 24 thousand deaf-mute patients who were caused by three sensitive deafness genes mutations in Shandong province. Screening the sensitive deafness genes in newborn is imminent.

Objective: To invesigate the molecular pathogenesis of deafness among the youth by means of genetic testing so as to provide pre-marriage genetic counseling and instruction for the deaf youth., Methods: 217 deaf young people, 126 males and 91 females, aged 18.9 (16 - 26), from Yunnan and Guizhou provinces, underwent history taking, auditory testing, and collection of peripheral blood samples. Genomic DNA and mitochondrial DNA were extracted to undergo sequence analysis of the entire gene GJB2, common point mutation of SLC26A4 gene, and mutation of mtDNA A1555G. Genetic prediction and marriage instruction were provided to each subject based on these results., Results: Twenty-three of the 117 persons (10.5%), 13 males and 10 females, were mtDNA A1555G mutation carriers and they were instructed that they, their maternal relatives, and the offspring of the female carriers, should they be born, should strictly avoid the administration of amino glycoside antibiotics. Twenty eight of the 115 persons (12.9%), were confirmed to carry homozygous or compound GJB2 mutations, 5 individuals (2.3%) carried heterozygous GJB2 mutation, 19 (8.8%) carried homozygous or compound SLC26A4 mutations, and one (0.5%) carried heterozygous SLC26A4 mutation. The suggestion for them was to avoid getting married with deaf partners caused by the same deaf gene or with individuals carrying mutations in the same deaf gene. Meanwhile, suggestions such as avoiding aggressive exercises and head injury were provided to the deaf young people with SLC26A4 mutations., Conclusion: Genetic testing can provide more accurate and useful genetic counseling and instruction to deaf young people for their partner selection and eugenics.

Objective: To investigate the Gap junction protein beta 2 (GJB2) gene mutation in cochlear implantation (CI) recipients and the treatment outcome of CI in the CI recipients with GJB2 gene mutation., Methods: Peripheral blood samples were collected from 253 CI recipients with autosomal recessive non-syndromic hearing impairment (NSHI), 174 males and 79 females, aged (8 +/- 9) (112 months-52.7 years), and 301 children with normal hearing level as controls. PCR was used to detect the GJB2 mutations. The auditory threshold with CI and speech recognition of the CI recipients with GJB2 mutation were compared with those of the CI recipients without GJB2 mutation (control group). Questionnaire survey, with meaningful auditory integration scale (MAIS), categories of auditory performance (CAP), and speech intelligibility rating (SIR), was used for young infants., Results: Sixty-seven of the 253 CI recipients (26.5%) were found to have GJB2 mutations. One novel mutation, GJB2 235delC/598G > A, was identified. The detection rates of GJB2 mutations in the CI recipients were significantly higher than those among the controls (all P < 0.05). The postoperative outcomes of CI in both the GJB2 gene mutation positive and negative groups were very good, however, without significant differences among these 2 groups (all P > 0.05)., Conclusion: GJB2 gene mutation is one of the major causes for CI recipients with autosomal recessive NSHI. The treatment outcomes of CI recipients with GJB2 gene mutations under 7 years old are satisfying.

Objective: To investigate the prevalence of GJB2 mutations in Uigur and Han ethnic groups in Xinjiang Uigur Autonomous Region, China and to understand the mutation spectrum and frequency of the GJB2 gene in these 2 ethnic groups., Methods: Questionnaire survey was conducted among 61 Uigur deaf-mute students, 60 Han deaf-mute students, and 98 normal Uigurs and 301 normal Han people as controls. Peripheral blood samples were collected to undergo PCR and sequencing of GJB2 gene., Results: The GJB2 mutation rate of the Uigur deaf-mute students was 19.7%, not significantly different from that of the Han deaf-mute students (17.2%). GJB2 35delG was found only in the Uigur deaf-mutes with a carrier rate of 11.5%, whereas 235delC was identified in both Uigur and Han deaf-mutes. The allelic frequency of 35delG mutation in the Uigur and Han deaf-mutes and the Uigur controls were 7.4% (9/122), 0 (0/128), and 0 (0/196) respectively. The allelic frequencies of the GJB2 235delC mutations in the Uigur and Han deaf-mute students were 5.7% and 9.8%, and the allelic frequencies of 299 - 300delAT were 0.8% and 5.5%. V27I and E114G were the most frequent types of polymorphism., Conclusion: There is a rather high mutation rate of GJB2 gene in Xinjiang. The carrier frequency of 35delG of the Uigurs is significantly higher than that of the Han population. 235delC is common in both Uigur and Han people.

Objective: To investigate the prevalence of the mitochondrial DNA (mtDNA) A1555G mutation in nonsyndromic hearing impairment (NSHI) patients from Gansu province., Methods: Subjects included 802 students selected from five Deaf-Mute Schools in Gansu. DNA was extracted from peripheral blood of all patients. The mitochondrial DNA target fragments were amplified by polymerase chain reaction (PCR). The Mutations were detected by AIw26I digestion and sequence analysis., Results: The homoplasmic A1555G mutation was found in 67 individuals from 802 patients (8.4%). Fifteen of these 67 patients had family histories., Conclusions: The mtDNA A1555G mutation had a higher incidence in Gansu population with nonsyndromic hearing impairment than other studies. The data not only gaven more evidences that the prevalence of mtDNA A1555G mutation in china was higher than that in Europe and America, but also gaven valuable information for gene diagnosis, genetic counseling and would improve the safety of aminoglycoside antibiotic therapy.

Objective: To provide prenatal diagnosis for deaf families, which the first child was confirmed to be hereditary deafness caused by gap junction beta-2 (GJB2) or SLC26A4 (PDS) mutation, to avoid another deaf birth in these families., Methods: Eight deaf families joined in this study. Each family had one child with severe to profound hearing loss while parents had normal hearing except a deaf father from family 8; mothers had been pregnant for 6-28 weeks. Genetic testing of GJB2, SLC26A4 and mitochondrial DNA (mtDNA) A1555G mutation were firstly performed in probands and their parents whose DNA was extracted from peripheral blood, and then prenatal testing was carried out in the fetus whose DNA was extracted from different fetus materials depending on the time of gestation., Results: The probands from family 1-4 were found to carry homozygous or compound GJB2 mutations while their parents carried corresponding heterozygous GJB2 mutations. The probands from family 5-8 and the deaf father from family 8 were found to carry compound SLC26A4 mutations while their parents and the mother from family 8 carried a single SLC26A4 mutation. Prenatal testing showed that the fetuses from family 1, 5, 8 only carried the paternal mutation and the fetuses from family 2, 3, 6 didn't carry any GJB2 or SLC26A4 mutations. The new born babies from these six families all had normal hearing revealed by new born hearing screening. However, the fetuses from family 4,7 carried the same mutations with probands in each family. The parents from family 4, 7 decide to terminate pregnancy., Conclusion: Prenatal diagnosis assisted by genetic testing can provide efficient information about hearing condition of their offsprings.

Objective: To analyze the clinical features of audiological and vestibular function in a Chinese family with late onset autosomal dominant nonsyndromic sensorineural hearing loss., Methods: Comprehensive audiological and vestibular evaluation including pure tone audiometry, auditory brainstem response (ABR), electrocochleogram (EcochG), oculomotor testing, caloric tests, rotational testing, computerized dynamic posturography and vestibular evoked myogenic potentials (VEMP) were conducted to identify the hearing and vestibular impairment., Results: All affected family members shared sensorineural hearing loss with full penetrance starting between the second and fifth decade of life as a high frequency loss which progresses to a severe to profound loss at the sixth to seventh decade. The extensive vestibular evaluation indicated that all affected members performed normally in computerized dynamic posturography and caloric testing. Impairment of the saccular otolith in all of six affected members was suggested by results of the VEMP test. The velocity step test generated abnormal time constants and sinusoidal oscillation test generated abnormal gains and phase in affected members indicated that horizontal canal vestibular hyporeflexia in history. All affected subjects examined in this family showed completely normal ocular motor responses in oculomotor testing, including smooth pursuit, optokinetic nystagmus, gaze and saccade., Conclusions: The predominant feature of the Chinese DFNA9 family was that all the affected subjects harboring COCH mutation in the vWFA2 domain didn't suffer the vestibular symptoms during their life time and comprehensive vestibular assessment revealed only subtle vestibular hypofunction in affected members of this family. There is a genotype-phenotype correlation in DFNA9.

Objective: To analyze the molecular pathogenesis of deaf couples by means of genetic testing. To provide accurate genetic counseling and instruction for deaf couples with different etiology based upon results of genetic testing., Methods: Four deaf families from July 2005 to May 2006. Each subject was with moderate to profound hearing loss. Genomic and mitochondrial DNA (mtDNA) of each subject were extracted from whole blood. Genetic testing of GJB2, SLC26A4 (PDS) and mtDNA A1555G mutation were offered to each individuals., Results: The husband from family 1 didn't carry GJB2, SLC26A4 and mtDNA A1555G mutation while his wife was confirmed to carry compound SLC26A4 mutations. The possibility of their offspring's to be SLC26A4 single mutation carrier was 100%. The couple from family 2 both didn't carry GJB2, SLC26A4 and mtDNA A1555G mutation. The possibility of their offspring's having hereditary deafness caused by GJB2, SLC26A4 and mtDNA A1555G mutation was excluded. The husband from family 3 was confirmed to carry homozygous GJB2 mutations and a single SLC26A4 mutation while his wife who was diagnosed with enlarged vestibular aqueduct syndrome (EVAS) by CT scan was proven to carry a single SLC26A4 mutation. The risk of their offspring's suffering EVAS was 50%. The husband from family 4 was mtDNA A1555G positive while his wife who was diagnosed with cochlear malformation by CT scan didn't carry GJB2, SLC26A4 and mtDNA A1555G mutation. The risk of their offspring's having hereditary deafness caused by GJB2, SLC26A4 and mtDNA A1555G mutation was excluded., Conclusions: Genetic testing could be applied to offer the more accurate genetic counseling and instruction to deaf couples.

Objective: To map the gene locus in a Chinese pedigree with autosomal dominant nonsyndromic hearing loss., Methods: A genome wide screening was performed with 394 microsatellite markers distributed with an average spacing of 10 cM (ABI Prism Linkage Mapping Set 2, Applied Biosystems, Foster City, CA, U.S.A.)., Results: Affected family members showed a bilateral, symmetrical, progressive neurosensory deafness. Significant linkage was found to marker D1 S937 (maximum two point LOD score of 5. 71 at theta = 0.05) on chromosome 11q. The position of the novel deafness locus, DFNA11, was delimited by analysis of the recombinant haplotypes (D11S165-D11S1874). This analysis placed DFNA11 between the proximal marker D11S1314 and the distal marker D11S898, which define a critical interval of 25.34 cM., Conclusions: Mapping of the DFNA11 locus further confirms the great genetic heterogeneity underlying the autosomal dominant forms of hereditary deafness. Reports of more families with hearing impairment linked to this locus should contribute to the identification of the responsible gene, providing insights into the auditory function and the molecular pathophysiology of age related hearing loss.

Objective: To establish the method of clinic genetic testing for common deaf genes such as mtDNA nt1555, GJB2 gene and SLC26A4 (Pendrin's syndrome gene, PDS) gene., Methods: Three hundred and sixty seven sporadic patients with hearing loss from out-patient department of General Hospital of Chinese People's Liberation Army, 60 patients with history of maternal inherited hearing loss from 27 family, 20 congenital deaf patients from special educational school for deaf and dumb, 3 deaf patients with enlarged vestibular aqueduct (EVA) confirmed by CT scan, 50 control individuals with normal bone conductive hearing were analyzed. The genetic testing kit for mtDNA A1555G mutation was used to detect mtDNA A1555G mutation. The whole gene sequencing were accomplished in 20 congenital deaf patients. In 3 patients with EVA, fragments covering all exons of PDS gene were analyzed by denatured high productive liquid chromatogram and special exons were sequenced when DHPLC showed abnormal wave patterns of amplicons covering these exons., Results: Fifty nine patients from 26 family and 5 sporadic patients were found to carry mtDNA A1555G mutation. Among 20 congenital deaf patients, 2 cases were found to have homozygous GJB2 235 del C mutation, 1 case had compound 235del C and 299-300 del AT mutation. Other 2 cases carried heterozygous 109 A-G mutation. Among 3 patients with EVA, 1 case was found to have heterozygous PDS G316X mutation and other 2 cases had homozygous 919-2 A-G mutation. CONCLUSIONS Genetic testing for deafness is feasible procedure with remarkable clinic significance.

Objective: To analyze the mutations of candidate POU3F4 gene in the Chinese pedigree with Y linked hereditary hearing impairment., Methods: Polymerase chain reaction (PCR) reactions were performed with five pairs of primer in the coding sequence of POU3F4 gene. PCR-single-strand conformation polymorphism (PCR-SSCP) was subsequently applied in the 43 individuals of DFNY1 family for screening the gene mutations., Results: The PCR amplification fragments showed well quality in the five pairs of primer and further analysis with PCR-SSCP showed no any polymorphism and mutations in the members., Conclusions: The possibility of the deafness gene POU3F4, which locates on the translocation region on X and Y chromosome, contributed to the Y linked family deafness was successfully ruled out. It may imply that the causal gene of the DFNY1 family locate on the Y chromosome.

Objective: To evaluate the effect of cochlear implanted's aural/oral rehabilitation using rating evaluation method by questionnaires, to analyze the relationship between rehabilitation effect and its possible influence factors including type of implant, age at surgery, pathology, etc, and to explore the rating questionnaire method for cochlear implanted's aural/oral rehabilitation effect evaluation., Methods: Ninety-seven pre-lingual cochlear implanted's were involved in this investigation, all of which were severe or profound deafness before implantation. Interviewed the implanted's parents or teachers, asking them to rate the implanted's aural ability objectively from 1 to 8 according to Categories of Auditory Performance (CAP) and speech producing ability from 1 to 5 according to Speech Intelligibility Rating (SIR), then analyzed the relationship between effect of aural/oral rehabilitation represented by CAP/SIR rating results and its possible 9 influence factors including type of implant, age at surgery, pathology, duration of hearing loss, hearing aid wearing, inserting length of electrodes, implanted period, rehabilitation mode and financial conditions. Univariate test and multivariate stepwise logistic regression model were used for the analysis., Results: In a univariate analysis, it was confirmed that 4 factors i.e. type of implant (P = 0.0439), implanted period (P = 0.0001), rehabilitation mode (P = 0.0460) and financial conditions (0.0140) were correlated to CAP; 2 factors i.e. implanted period (P = 0.0001), rehabilitation mode (P = 0.0271) were correlated to SIR. In a multivariate analysis using stepwise logistic regression model, the more significant influence factor for CAP was implanted period and financial conditions, and for SIR was implanted period., Conclusions: Cochlear implants will be more effective for aural/oral rehabilitation of implanted's with longer implanted period. Rehabilitation mode and method contribute to the effect of rehabilitation.