Deafness is a common disabling disease and a major public health issue worldwide. According to the World Health Organization, there are 360 million deaf people in the world, including 32 million children. Approximately 1 in 1000 newborns suffer from severe to profound deafness at birth or during early childhood. At least 50% of hearing impairment is due to genetic factors. Mutations in various genes are responsible for hereditary deafness. Hereditary deafness is classified into syndromic deafness and nonsyndromic deafness. Nonsyndromic hearing loss (NSHL) is further categorized as autosomal recessive, autosomal dominant, X-linked or mitochondrial deafness.
Cochlea implantation (CI) has become a common therapy to restore hearing in patients with severe and extremely severe deafness. However, some patients have unsatisfactory results after CI. Postoperative effectiveness after CI involves not only the improvement of hearing ability, but also the rehabilitation of speech and language ability, and even the comprehensive response ability of the whole nervous system. In addition to the initial age of hearing loss, the amount of residual hearing, and the age at implantation, etiology of hearing loss is one of the most important factors affecting the postoperative rehabilitation of patients. Improvements in gene detection technology for deafness have shown that the effectiveness of CI is closely related to the factors that cause deafness. In recent decades, significant breakthroughs in molecular biology research have enabled an increasing number of deafness-causing genes to be discovered and tested. Different genes or mutations lead to different physiological changes or different loci of damage from the cochlea to the auditory nerve, which leads to different therapeutic effects after CI. The relationship between the effect of cochlear implant and gene mutation remains to be fully explored.
The articles used in this review were retrieved from PubMed via search terms. English language and full-text articles published between 2000 and June 2019 were included in this review. The literature search strategy was conducted as follows: First, the keyword deafness and gene mutation were searched for several common mutation genes. Next, the keywords cochlear implant, gene mutation and each gene combination were searched, and the articles related to the effect of cochlear implant after implantation were further screened out from the retrieved articles.
In addition, an electronic search has been completed in the PubMed for the development of cochlear implants. This included publications prior to March 2019, with the following search criteria: cochlear implant, hereditary deafness, deafness gene, pre-implantation genetic diagnosis.
Advances in the genetics of deafness
The causes of deafness are complex and include both genetic mutations and environmental factors, although more than 50% of deafness is related to genetic factors.  As the proportion of hearing impairments caused by infectious or iatrogenic factors diminishes and with continuous improvement in clinical diagnostic techniques, the importance of genetic factors in hearing impairment is increasing. In recent years, with the development and continuous improvement of gene diagnosis technology, research on deafness genes has made great progress, and more than 120 deafness genes have been identified. Hereditary deafness can be divided into syndromic hearing loss (SHL) and NSHL; in SHL, deafness is accompanied by involvement of one or more other organ systems, whereas in NSHL, the inner ear appears to be the only affected organ. To date, more than 120 genes for NSHL have been mapped in the human genome: 45 DFNA (autosomal dominant) loci, 73 DFNB (autosomal recessive) loci, and 5X-linked loci (http://hereditaryhearingloss.org/).
SHL The phenotype and genetic background of SHL is complex and diverse, and more than 400 deaf-related syndromes have been reported worldwide. SHL accounts for 20% to 30% of hereditary deafness.  In addition to hearing impairment, SHL patients usually have other clinical symptoms involving eye, kidney, skin, musculoskeletal, and nervous system abnormalities. A variety of SHL-related deafness genes have been identified. SHL is mainly divided into the following types: autosomal dominant inheritance, such as Crouzon syndrome; autosomal recessive inheritance, such as Jervell Lange-Nielsen syndrome or Pendred syndrome; X-linked comprehensive deafness, such as Alport syndrome; or mitochondrial syndrome hearing impairment, such as Kearn-Sayre syndrome. 
NSHL Aside from the hearing impairment, individuals with NSHL have no other clinical symptoms; this is the most common type of hereditary deafness. NSHL accounts for about 70% to 80% of hereditary deafness.  Most NSHL patients present with moderate or severe deafness at birth, and a few begin to show hearing loss at a certain time after birth NSHL can further be classified according to genetic patterns. In most cases of NSHL, the inheritance pattern is autosomal recessive (80%), although autosomal dominant (17%), X-linked (2–3%) and mitochondrial (>1%) inheritance also occur.  Each genetic pattern has its own pathological changes and clinical characteristics. At present, it is believed that hereditary nonsyndromic deafness involves single-gene inheritance. More than 120 single genes have been identified that cause deafness, many of which are involved in inner ear function, with mutations affecting the physiology and structure of the inner ear. The most commonly identified genes are GJB2, GJB6, SLC26A4, OTOF, MYO15A, MYO7A, POU3F4, TMC1, CDH23, and mitochondrial 12S rRNA.  We will discuss the function of some of these common deafness genes in detail below.
Correlations between gene mutations and effectiveness of cochlea implantation
Mutation in the GJB2 gene was first identified in 1997; the gene is located at the DFNB1 locus on chromosome 13 (13q12) and encodes Connexin26 (Cx26).  Mutation in GJB2 is the most common cause of congenital sensorineural deafness worldwide.  As complete DNA sequencing of the coding region of GJB2 has become routine, variability in the auditory phenotype has become increasingly evident. Several mutant alleles are particularly prevalent worldwide, such as 35delG, 235delC, 299delAT, V37I, and W24X. The most common mutation in the Asian or European population is 235delCor 35delG, respectively.  These mutations result in the truncating variants of Cx26 protein, which lose its function completely.  The degree of hearing loss with GJB2 mutations ranges from profound deafness at birth to mild, progressive hearing loss presenting in late childhood and is highly dependent on genotype. [4,10–12]
In the inner ear, Cx26 is widely distributed in the basal cells of stria vascularis, fibrocytes of spiral limbus and spiral ligament. [13,14] In cochlear epithelium, Cx26 immunostaining is observed among all types of supporting cells. [15,16] Cx26, together with the gap junction proteins of neighboring cells, constitutes a complete gap junction channel, which plays an important role in signal transduction and exchange of substances such as electrolytes, second messengers, and metabolites.
The mechanism of GJB2-related deafness was explored by different transgenic mouse models. The apoptosis of auditory hair cell was observed in the first Cx26 conditional knockout mouse models.  Moreover, the cell degeneration patterns of Cx26-null or Gjb2 mutation mouse models were studies by different groups, and hair cell loss was found in most of these models. [16,18–21] The function of outer hair cell's amplification detected by distortion product otoacoustic emission was also decreased in different transgenic mice lines. [22,23] However, the deformity of organ of Corti was observed prior to the death or dysfunction of auditory hair cell. [24,25] This deformity was described as the failure of the tunnel of Corti to open and the disappearance of Nuel space, which may be caused by developmental arrest of pillar and Deiter cells (two types of supporting cell).  Additionally, our study showed that null Cx26 in a few supporting cells affects the developmental status of pillar cells. The abnormal developmental status of pillar cells may be a potential cause of Gjb2-related hearing loss. In addition to above finding, ribbon synapses and afferent type I fibers was poorly developed in a Cx26-null mouse model.  However, the spiral ganglion neuron degeneration occurs later than above lesions. [18,20] These spiral ganglion neuron degeneration can be rescued by brain derived neurotrophic factor gene therapy or TrkB receptor agonist. [28,29] The oxidative damages was linked to the deafness and hair cell loss in a heterozygous Cx26-null models.  It was reported that the audiological phenotype of the GJB2 gene mutation was intrinsically related to the environmental factors.  In an animal study, reduced Cx26 in the mature cochlea increases susceptibility to noise-induced hearing loss in mice. 
In human beings, temporal bone pathology reveals that the outer hair cells and the peripheral vasculature of the cochlea are degenerated in individuals with the GJB2 mutation, but the spiral ganglion cells, which are the site of stimulation of the cochlear implant, are normal.  The number of spiral ganglions and the integrity of the auditory nerve and its posterior pathway are closely related to effectiveness after CI.  Therefore, we can assume that individuals with GJB2-associated deafness might have better results after CI than individuals whose deafness is associated with neural or central damage to the auditory system. However, the results of clinical studies are inconsistent. For example, Bauer et al  evaluated the speaking, reading, and cognitive scores of 22 patients with the GJB2 mutation and 33 patients without the GJB2 mutation. They concluded that the isolated insult to the cochlea created by GJB2 allele variants allows for preservation of central cognitive function; consequently, better reading performance is seen in children with GJB2-related sensorineural hearing loss. Janeschik et al  followed 163 patients with CI over the long term (average of 5.17 years) and they also found that patients with the GJB2 mutation had significantly better postoperative hearing recovery than patients of other types. Wu et al  reported that patients with GJB2 mutations showed better post-implant auditory performance and speech intelligibility than those without mutations only when implanted before age 3.5 years. However, other researchers have shown different results. After 1-year follow-up of 22 CI patients with the GJB2 gene mutation, Karamert et al  concluded that GJB2 gene mutations do not affect the outcome of CI. Cai et al  followed 120 CI patients in which 40 of them with GJB2 gene mutations and 80 patients without the mutations for 18 to 30 months. They used auditory threshold, category of auditory performance, Speech Intelligibility Rating, Mandarin Early Speech Perception Test, Meaningful Auditory Integration Scale, and other methods to evaluate the efficacy of CI after surgery. Their results showed that the postoperative auditory threshold of GJB2 gene mutations was better in patients with CI than in those of the control group, but no statistically significant differences between groups were found for the other tests.
Theoretically, the effect of cochlear implant should be better in patients with GJB2 mutation. Several factors might explain these inconsistent conclusions.
(1) Length of follow-up—some evaluation indicators need time before they are meaningful; for example, postoperative speech rehabilitation takes much longer than hearing rehabilitation, and a short follow-up time may fail to reach nodes where some indicators are different. (2) Different evaluation indicators—some evaluation indicators increase significantly in the initial stage after CI. With extended postoperative rehabilitation time, the rehabilitation effect gradually stabilizes and evaluation indicators no longer changes, eliminating the statistical differences between groups. (3) Insufficient sample size. Therefore, in future studies, we need a more stringent research design and a multi-center study with a large sample size to obtain more rigorous scientific conclusions.
The SLC26A4 gene, located at 7q31, contains 21 exons and encodes the polytopic transmembrane protein pendrin, which is composed of 780 amino acid residues.  Mutations in SLC26A4 are closely related to large vestibular aqueduct syndrome, Pendred syndrome, and Mondini malformation; large vestibular aqueduct syndrome is one of the main causes of sensorineural deafness in China. It has been reported that IVS7-2A>G are common mutations of the SLC26A4 gene in Shanxi Province, China.  Enlarged vestibular aqueduct is the most commonly identified inner ear bony malformation and is associated with characteristic clinical findings including disequilibrium and fluctuating or progressive sensorineural hearing loss. 
Pendrinis an anion transporter transmembrane protein that can exchange a variety of anions across the plasma membrane, including HCO3−, Cl−, I−, and formate.  It is expressed in the endolymphatic sac or duct, in discrete areas adjacent to the maculae of the utricle and saccule, and in the spiral prominence of the scala media. This protein has been shown to be important for endolymphatic fluid resorption in the inner ear.  Mutations in SLC26A4 may lead to an imbalance of ion circulation in internal lymphatic fluid, resulting in deafness.
Patients with deafness due to SLC26A4 mutation have normal auditory nerve endings and a sufficient number of ganglion cells. Theoretically, patients with large vestibular aqueduct syndrome are candidates for CI. However, Yan et al  analyzed treatment outcomes in pediatric cochlear implant patients with mutations in GJB2 or SLC26A4 and found that the effectiveness of CI was worse in patients with SLC26A4 mutations than in patients with GJB2 mutations. There are two possible reasons for this: (1) the expression region of SLC26A4 gene is more extensive than that of GJB2, so the damage caused by its mutation is more extensive and direct; and (2) the sample size of the study was insufficient.
Mitochondrial 12S rRNA gene
In 1993, Prezant et al described the molecular pathological basis of nonsyndromic hearing impairment caused by aminoglycoside drugs as aA1555G point mutation in the mitochondrial (mt)DNA 12S rRNA gene. Since then, many studies have been carried out to identify other potential mitochondrial DNA pathogenic mutations associated with aminoglycoside ototoxicity. In China, deafness caused by aminoglycoside antibiotics is mainly due to mitochondrial mutation A1555G; the prevalence of the C1494T mutation is relatively low. 
The 12S rRNA Al555G mutation is located at the aminoacyl-transfer RNA acceptor site of the small ribosomal subunit, which is highly conserved from bacteria to mammals.  The mutation forms a region of DNA binding site that is very similar to the target of aminoglycoside drugs. Once exposed to aminoglycoside antibiotics, the antibiotic will bind tightly to the mutation region, affecting the synthesis of mitochondrial proteins in cells and possibly impairing the function of related cells, including hair cells.  This is referred to as “drug deafness.”
Mitochondria are the primary source of cellular adenosine triphosphate (ATP) and play a central role in a variety of cellular processes, including calcium signaling, generation of reactive oxygen species, and apoptosis.  The cochlea vascular striatum cell membrane contains a large number of highly active ATPases, which act as sodium pumps and obtain energy by decomposing ATP. Cochlear hair cells rely on this sodium pump to produce the appropriate cochlear potential.  Therefore, we can speculate that mitochondrial disorders may cause ion imbalance and cell damage, which may lead to hearing loss.
Recent animal studies have further elucidated the mechanism of hearing loss caused by the A1555G mutation in mitochondrial DNA in matrilineal deafness. Chen et al  simulated the pathological process of A1555G mutation in humans by constructing transgenic mice overexpressing mitochondrial 12S rRNA methyltransferase; they found increased E2F transcription factor 1 and apoptosis in the stria vascularis and spiral ganglion neurons of the inner ear and progressive E2F transcription factor 1-dependent hearing loss. This is similar to the progressive hearing loss in human patients with the A1555G mitochondrial DNA mutation. This study suggests that inhibition of methylation or apoptosis is a potential approach to treat mutagenic A1555G mitochondrial hearing impairment.
Studies have shown that the number of residual cochlear spiral ganglion cells in patients with aminoglycoside susceptibility to deafness is higher than that of patients with deafness from other causes,  and the effect of CI depends on the residual number of spiral ganglion cells and the integrity of the auditory nerve and its subsequent pathways. To date, a large number of clinical studies have confirmed that patients with aminoglycoside drug susceptibility to deafness caused by mutation of mitochondrial 12S rRNA gene have very good hearing and language communication ability after CI. 
The OTOF gene is located at 2p23.1 and contains 48 coding exons.  Mutations in OTOF are related to auditory neuropathy spectrum disorder, also called auditory neuropathy, which is a hearing impairment caused by the auditory synapse and inner hair cells or a defect in the function of the auditory nerve itself. [53,54] In 2008, Santarelli et al  proposed classifying the term “auditory neuropathy” into types by the site of the disorder. If the auditory neuropathy lesions were located at the level of the auditory nerve but the inner hair cells and synapses were normal, the disorder would be classified as “auditory nerve disorder.” Similarly, if the inner hair cell synapses were disordered but the auditory nerve was normal, the disorder would be classified as “auditory synaptic disorder.” In auditory synaptic disorder, otoacoustic emission can be elicited because the outer hair cells remain intact but the auditory brainstem response is abnormal or unelicited. Auditory neuropathy spectrum disorder may be caused by genetic factors (50%) or environmental factors (50%). If there is no obvious environmental factor, more than 56% of nonsyndromic auditory neuropathy spectrum disorder is caused by mutations in the OTOF gene. 
The OTOF gene encodes otoferlin, a protein that is only expressed in the inner hair cells. In the adult mouse cochlea, otoferlin is concentrated in the basolateral part of the inner hair cells, which is an important part of the presynaptic structure of the inner hair cells. The study also found that otoferlin, as a calcium ion sensor, triggers membrane fusion at the synaptic bands of the inner hair cells, thus playing an important role in the emulation process of the synaptic vesicles of the inner hair cells. [57,58] Mutations in OTOF can lead to abnormal expression of otoferlin; patients with OTOF mutations have lesions in the inner hair cells or the afferent synapses formed by the inner hair cells and the auditory nerve, whereas the acoustic nerve fibers are normal; therefore, this is classified as an auditory synaptic disorder. The effectiveness of CI in these patients should be better than in those patients where the lesion is located in the auditory nerve, which has been confirmed by clinical studies. 
Usher syndrome (USH) is the most common genetic cause for the dual impairment of deafness and blindness.  This autosomal recessive syndrome is characterized by sensorineural hearing impairment associated with retinitis pigmentosa. USH is found in 3% to 6% of children with congenital deafness, and it may account for as much as 50% of the deaf blind population. 
Three distinct forms of USH (USH1–3) have been characterized.  The severity and progression of the hearing impairment and the presence of vestibular dysfunction distinguish the three types. USH1 is the most severe, with profound congenital deafness, constant vestibular dysfunction, and a relatively severe form of retinitis pigmentosa associated with the onset of blindness in late childhood.  Children with USH2 present with moderate to severe sensorineural hearing loss and normal vestibular function. The visual impairment in USH2 begins in the second decade of life and some patients maintain useful vision into middle age. USH3 presents with progressive hearing loss and varying degrees of vestibular dysfunction.  Of all USH patients worldwide, it is estimated that 33% to 44% have USH1 and 56% to 67% have USH2, whereas only a minority of patients have USH3.  Since the first USH gene (MYO7A) was cloned in 1995, remarkable advances have been made in elucidating the genetic basis for this disorder; 11 distinct loci have been obtained and genes for 9 of them have been identified, including CDH23, PCDH15, and OSH1C.  Studies have shown that 75% of cases of USH1 are caused by mutations in the MYO7A gene.
MYO7A (USH1B) encodes myosin 7A, an unconventional myosin that is mainly expressed in inner ear and outer hair cells and is crucial for adhesion between static cilia. Yan et al  concluded that USH proteins mainly colocalize in the stereocilia and at the synaptic regions of hair cells of the inner ear; therefore, degeneration of cochlea hair cells is the basis of USH hearing loss. The main lesion site of USH1 patients is the stereocilia of hair cells, whereas the cells of spiral ganglion and the auditory nerve and its subsequent pathways are normal. In theory, the effect of CI on USH1 patients is better compared with patients without MYO7A gene mutation. Clinical studies have shown that age is the most important factor for the post-CI effect in USH patients, and early CI can achieve satisfactory auditory and speech effects. [64,65]
The PJVK gene, also known as DFNB59, was first discovered and named by Delmaghani et al  in 2006. It is another pathogenic gene related to nonsyndromic recessive hereditary auditory neuropathy spectrum disorder, similar to OTOF. The DFNB59 gene is located on chromosome 2 in region q31.1 to q31.3, and it encodes pejvakin, which is expressed in hair cells, spiral ganglion neurons, and brainstem auditory nuclei in mammals. [66,67] By means of polyclonal antibody immunofluorescence staining, Delmaghani et al  found that pejvakin was only expressed in the neuron cell body, not in the fiber bundle in the afferent neural pathway.
Based on the clinical audiology characteristics of patients with PJVK mutations, it was determined that the lesion site was mainly in the auditory conduction pathway, affecting the conduction of action potential and intracellular substance exchange; the function of inner hair cells was not affected. Because the lesion site is often not located in hair cells or synapses, CI in these patients is less effective, as confirmed by clinical studies. 
To date, there has been a lack of effective drug treatment and other therapeutic interventions for sensorineural deafness. CI is the only effective treatment for severe and extremely severe deafness, and it will play an increasingly important role in the treatment of human hearing loss.
The peripheral auditory sensory system involves serial integration of (1) the sensory portion—the organ of Corti and supporting cells, which enable mechano transduction of sound into an ionic gradient; (2) the synapse between hair cells and the spiral ganglion afferent neuron, which converts the ionic gradient to a neural action potential; and (3) the bipolar spiral ganglion neurons, which transmit the neural signal to the central auditory system. In the context of how a CI functions, there are only 2 partitions—the sensory partition, which includes the organ of Corti and the synapse and is therefore bypassed by the CI, and the neural partition. 
A cochlear implant is made up of an inner ear implant and an external sound processor. The sound processor converts the external sound information received by the microphone into digital signals, which are sent to the implant through coils. The implant converts the digital signals into electrical signals, and the electrical stimulation sent by the electrodes stimulates the auditory nerve located in the inner ear (spiral ganglion cells), constructing the auditory pathway.
Therefore, CI will be effective if the mutated lesion is located in the hair cells or the afferent synapses formed between the hair cells and auditory nerve (ie, the sensory partition) and the auditory nerve and its subsequent pathways are normal, such as in patients with mutations in the GJB2, SLC26A4, MYO7A, OTOF, and mitochondrial 12S rRNA genes, as noted above; CI is generally less effective if genetic mutations affect the function of the auditory nerve.
Improving outcomes associated with hereditary deafness
At present, hereditary hearing impairment caused by gene mutations accounts for more than half the cases of congenital deafness, and different types of gene mutations lead to differences in inner ear lesions, directly affecting the effectiveness of CI.  Most patients with hereditary deafness have achieved high efficacy in hearing and speech following CI, but not all patients achieve the same good outcomes. Reasons for the differences need to be analyzed in detail, and the performance of cochlear implants should be further improved to adapt to the needs of patients with different forms of genetic deafness. CI has many limitations. Although it can solve the hearing impairment caused by genetic factors, many patients and their families have difficulty in managing the high cost and sometimes poor efficacy after CI. Other effective methods to treat sensorineural deafness are needed, such as hair cell regeneration and deafness gene therapy.
Preventive strategies of hereditary deafness
Active prevention is an effective way to solve hereditary deafness. At present, genetic testing for deafness is available clinically and provides new options for the prevention of deafness. In addition to genetic counseling and medical guidance, thousands of families in the past 10 years have undergone traditional invasive prenatal diagnostic procedures to determine whether their fetus carries genes for deafness. We are eager to develop an effective and convenient pre-implantation genetic diagnosis procedure that more families will benefit.
Pre-implantation genetic diagnosis refers to the process of biopsy and genetic analysis of blastocysts or embryos in the process of artificial assisted reproduction (eg, in vitro fertilization), from which embryos with normal genetics are selected for implantation to obtain a healthy next generation.
Pre-implantation genetic diagnosis technology for hereditary deafness can combine the most advanced single-cell whole-genome amplification technology (multiple displacement amplification) with next-generation sequencing technology, which improves the sensitivity and accuracy of single-gene deafness detection and improves the survival rate of embryo implantation.
In addition, gene therapy, the precise medical treatment of sensorineural deafness, is a hot topic of research. Although it is currently only in the stage of animal experiments,  it is believed that future breakthroughs will make gene therapy for human deafness possible.
In conclusion, most patients with hereditary deafness (severe/very severe sensorineural deafness) have achieved good therapeutic effects after receiving CI and auditory and speech rehabilitation; the effectiveness of rehabilitation is related to the specific genes that caused the deafness. In addition to CI for hereditary deafness, precise medical treatments and prevention strategies for hereditary deafness should be explored.
This work was supported by grants from The National Nature Science Foundation of China (No. 81771003, 81470696, 81570923, and 81500793).
Conception and design of the work: XX and YS. Acquisition, analysis, interpretation of data and manuscript writing: XX and KX. Manuscript revision: SC and LX. Project administration: YS and WK. All authors read and approved the final manuscript.
Conflicts of interest
The authors declare that they have no conflict of interest.
. Adadey SM, Awandare G, Amedofu GK, et al Public health burden of hearing impairment and the promise of genomics and environmental research: a case study in Ghana, Africa. OMICS 2017;21:638–646.
. Markova TG, Bliznetz EA, Polyakov AV, et al Twenty years of clinical studies of GJB2-linked hearing loss in Russia. Vestn Otorinolaringol 2018;83:31–36.
. Burke WF, Lenarz T, Maier H. Hereditary hearing loss: Part 2: Syndromic forms of hearing loss. HNO 2014;62:759–769. quiz 770.
. Vona B, Nanda I, Hofrichter MA, et al Non-syndromic hearing loss gene identification: a brief history and glimpse into the future. Mol Cell Probes 2015;29:260–270.
. Ouyang XM, Yan D, Yuan HJ, et al The genetic bases for non-syndromic hearing loss among Chinese. J Hum Genet 2009;54:131–140.
. Kelsell DP, Dunlop J, Stevens HP, et al Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 1997;387:80–83.
. Nonose RW, Lezirovitz K, de Mello Auricchio MTB, et al Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects. BMC Med Genet 2018;19:73.
. Chan DK, Chang KW. GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope 2014;124:E34–E53.
. Azaiez H, Chamberlin GP, Fischer SM, et al GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat 2004;24:305–311.
. Zheng J, Ying Z, Cai Z, et al GJB2 mutation spectrum and genotype-phenotype correlation in 1067 Han Chinese subjects with non-syndromic hearing loss. PLoS One 2015;10:e0128691.
. Martines F, Salvago P, Bartolotta C, et al A genotype-phenotype correlation in Sicilian patients with GJB2 biallelic mutations. Eur Arch Otorhinolaryngol 2015;272:1857–1865.
. Dai ZY, Sun BC, Huang SS, et al Correlation analysis of phenotype and genotype of GJB2 in patients with non-syndromic hearing loss in China. Gene 2015;570:272–276.
. Jun AI, McGuirt WT, Hinojosa R, et al Temporal bone histopathology in connexin 26-related hearing loss. Laryngoscope 2000;110:269–275.
. Liu W, Edin F, Blom H, et al Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man. Cell Tissue Res 2016;365:13–27.
. Kikuchi T, Kimura RS, Paul DL, et al Gap junction systems in the mammalian cochlea. Brain Res Brain Res Rev 2000;32:163–166.
. Chen S, Xu K, Xie L, et al The spatial distribution pattern of Connexin26 expression in supporting cells and its role in outer hair cell survival. Cell Death Dis 2018;9:1180.
. Cohen-Salmon M, Ott T, Michel V, et al Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Curr Biol 2002;12:1106–1111.
. Sun Y, Tang W, Chang Q, et al Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea. J Comp Neurol 2009;516:569–579.
. Crispino G, Di Pasquale G, Scimemi P, et al BAAV mediated GJB2 gene
transfer restores gap junction coupling in cochlear organotypic cultures from deaf Cx26Sox10Cre mice. PLoS One 2011;6:e23279.
. Chen S, Sun Y, Lin X, et al Down regulated connexin26 at different postnatal stage displayed different types of cellular degeneration and formation of organ of Corti. Biochem Biophys Res Commun 2014;445:71–77.
. Inoshita A, Karasawa K, Funakubo M, et al Dominant negative connexin26 mutation R75W causing severe hearing loss influences normal programmed cell death in postnatal organ of Corti. BMC Genet 2014;15:1.
. Lukashkina VA, Yamashita T, Zuo J, et al Amplification mode differs along the length of the mouse cochlea as revealed by connexin 26 deletion from specific gap junctions. Sci Rep 2017;7:5185.
. Minekawa A, Abe T, Inoshita A, et al Cochlear outer hair cells in a dominant-negative connexin26 mutant mouse preserve non-linear capacitance in spite of impaired distortion product otoacoustic emission. Neuroscience 2009;164:1312–1319.
. Wang Y, Chang Q, Tang W, et al Targeted connexin26 ablation arrests postnatal development of the organ of Corti. Biochem Biophys Res Commun 2009;385:33–37.
. Inoshita A, Iizuka T, Okamura HO, et al Postnatal development of the organ of Corti in dominant-negative Gjb2 transgenic mice. Neuroscience 2008;156:1039–1047.
. Chen S, Xie L, Xu K, et al Developmental abnormalities in supporting cell phalangeal processes and cytoskeleton in the Gjb2 knockdown mouse model. Dis Model Mech 2018;11:dmm033019.
. Chang Q, Tang W, Kim Y, et al Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing. Neurobiol Dis 2015;73:418–427.
. Yu Q, Chang Q, Liu X, et al Protection of spiral ganglion neurons from degeneration using small-molecule TrkB receptor agonists. J Neurosci 2013;33:13042–13052.
. Takada Y, Beyer LA, Swiderski DL, et al Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy. Hear Res 2014;309:124–135.
. Fetoni AR, Zorzi V, Paciello F, et al Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway. Redox Biol 2018;19:301–317.
. Wang SL, Yu LG, Liu RP, et al Gene-gene interaction of GJB2, SOD2, and CAT on occupational noise-induced hearing loss in Chinese Han population. Biomed Environ Sci 2014;27:965–968.
. Zhou XX, Chen S, Xie L, et al Reduced Connexin26 in the mature cochlea increases susceptibility to noise-induced hearing lossin mice. Int J Mol Sci 2016;17:301.
. Tong MC, Leung EK, Au A, et al Age and outcome of cochlear implantation for patients with bilateral congenital deafness in a Cantonese-speaking population. Ear Hear 2007;28:56S–58S.
. Bauer PW, Geers AE, Brenner C, et al The effect of GJB2 allele variants on performance after cochlear implantation. Laryngoscope 2003;113:2135–2140.
. Janeschik S, Teschendorf M, Bagus H, et al Influence of etiologic factors on speech perception of cochlear-implanted children. Cochlear Implants Int 2013;14:190–199.
. Wu CM, Ko HC, Tsou YT, et al Long-term cochlear implant
outcomes in children with GJB2 and SLC26A4 mutations. PLoS One 2015;10:e0138575.
. Karamert R, Bayazit YA, Altinyay S, et al Association of GJB2 gene
mutation with cochlear implant
performance in genetic non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol 2011;75:1572–1575.
. Cai C, Huang S, Gao X, et al Assessment of the curative effective of cochlear implantation in childer with GJB2-associated NSSNHL. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2014;28:972–974.
. Everett LA, Glaser B, Beck JC, et al Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997;17:411–422.
. Zhou Y, Li C, Li M, et al Mutation analysis of common deafness genes among 1201 patients with non-syndromic hearing loss in Shanxi Province. Mol Genet Genomic Med 2019;7:e537.
. Zalewski CK, Chien WW, King KA, et al Vestibular dysfunction in patients with enlarged vestibular aqueduct. Otolaryngol Head Neck Surg 2015;153:257–262.
. Scott DA, Wang R, Kreman TM, et al Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4). Hum Mol Genet 2000;9:1709–1715.
. Honda K, Kim SH, Kelly MC, et al Molecular architecture underlying fluid absorption by the developing inner ear. Elife 2017;6:e26851.
. Yan YJ, Li Y, Yang T, et al The effect of GJB2 and SLC26A4 gene
mutations on rehabilitative outcomes in pediatric cochlear implant
patients. Eur Arch Otorhinolaryngol 2013;270:2865–2870.
. Prezant TR, Agapian JV, Bohlman MC, et al Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 1993;4:289–294.
. Wang L, Wang X, Cai X, et al Study of mitochondrial DNA A1555G and C1494T mutations in a large cohort of women individuals. Mitochondrial DNA A DNA Mapp Seq Anal 2019;30:222–225.
. Ding Y, Leng J, Fan F, et al The role of mitochondrial DNA mutations in hearing loss. Biochem Genet 2013;51:588–602.
. Yamasoba T, Someya S, Yamada C, et al Role of mitochondrial dysfunction and mitochondrial DNA mutations in age-related hearing loss. Hear Res 2007;226:185–193.
. Chen H, Tang J. The role of mitochondria in age-related hearing loss. Biogerontology 2014;15:13–19.
. Nadol JB Jr, Young YS, Glynn RJ. Survival of spiral ganglion cells in profound sensorineural hearing loss: implications for cochlear implantation. Ann Otol Rhinol Laryngol 1989;98:411–416.
. Ulubil SA, Furze AD, Angeli SI. Cochlear implantation in a patient with profound hearing loss with the A1555G mitochondrial DNA mutation and no history of aminoglycoside exposure. J Laryngol Otol 2006;120:230–232.
. Yasunaga S, Grati M, Cohen-Salmon M, et al A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet 1999;21:363–369.
. Berlin CI, Hood LJ, Morlet T, et al Multi-site diagnosis and management of 260 patients with auditory neuropathy/dys-synchrony (auditory neuropathy spectrum disorder). Int J Audiol 2010;49:30–43.
. Norrix LW, Velenovsky DS. Auditory neuropathy spectrum disorder: a review. J Speech Lang Hear Res 2014;57:1564–1576.
. Santarelli R, Starr A, Michalewski HJ, et al Neural and receptor cochlear potentials obtained by transtympanic electrocochleography in auditory neuropathy. Clin Neurophysiol 2008;119:1028–1041.
. Kim BJ, Jang JH, Han JH, et al Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics. J Transl Med 2018;16:330.
. Roux I, Safieddine S, Nouvian R, et al Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell 2006;127:277–289.
. Rouillon I, Marcolla A, Roux I, et al Results of cochlear implantation in two children with mutations in the OTOF gene
. Int J Pediatr Otorhinolaryngol 2006;70:689–696.
. Pater JA, Green J, O’Rielly DD, et al Novel Usher syndrome
pathogenic variants identified in cases with hearing and vision loss. BMC Med Genet 2019;20:68.
. Qu C, Liang F, Long Q, et al Genetic screening revealed usher syndrome
in a paediatric Chinese patient. Hearing Balance Commun 2017;15:98–106.
. Kumar A, Fishman G, Torok N. Vestibular and auditory function in Usher's syndrome. Ann Otol Rhinol Laryngol 1984;93:600–608.
. Kochhar A, Hildebrand MS, Smith RJ. Clinical aspects of hereditary hearing loss. Genet Med 2007;9:393–408.
. Yan D, Liu XZ. Genetics and pathological mechanisms of Usher syndrome
. J Hum Genet 2010;55:327–335.
. Hartel BP, van Nierop JWI, Huinck WJ, et al Cochlear Implantation in patients with usher syndrome
type IIa increases performance and quality of life. Otol Neurotol 2017;38:e120–e127.
. Pennings RJ, Damen GW, Snik AF, et al Audiologic performance and benefit of cochlear implantation in Usher syndrome
type I. Laryngoscope 2006;116:717–722.
. Delmaghani S, del Castillo FJ, Michel V, et al Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet 2006;38:770–778.
. Kazmierczak M, Kazmierczak P, Peng AW, et al Pejvakin, a candidate stereociliary rootlet protein, regulates hair cell function in a cell-autonomous manner. J Neurosci 2017;37:3447–3464.
. Wu CC, Lin YH, Liu TC, et al Identifying children with poor cochlear implantation outcomes using massively parallel sequencing. Medicine (Baltimore) 2015;94:e1073.
. Shearer AE, Eppsteiner RW, Frees K, et al Genetic variants in the peripheral auditory system significantly affect adult cochlear implant
performance. Hear Res 2017;348:138–142.
. Broomfield SJ, Bruce IA, Henderson L, et al Cochlear implantation in children with syndromic deafness. Int J Pediatr Otorhinolaryngol 2013;77:1312–1316.
. Lentz JJ, Jodelka FM, Hinrich AJ, et al Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat Med 2013;19:345–350.