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Aldè, M.; Cantarella, G.; Zanetti, D.; Pignataro, L.; La Mantia, I.; Maiolino, L.; Ferlito, S.; Di Mauro, P.; Cocuzza, S.; Lechien, J.R.; et al. Autosomal Dominant Non-Syndromic Hearing Loss. Encyclopedia. Available online: (accessed on 30 November 2023).
Aldè M, Cantarella G, Zanetti D, Pignataro L, La Mantia I, Maiolino L, et al. Autosomal Dominant Non-Syndromic Hearing Loss. Encyclopedia. Available at: Accessed November 30, 2023.
Aldè, Mirko, Giovanna Cantarella, Diego Zanetti, Lorenzo Pignataro, Ignazio La Mantia, Luigi Maiolino, Salvatore Ferlito, Paola Di Mauro, Salvatore Cocuzza, Jérôme René Lechien, et al. "Autosomal Dominant Non-Syndromic Hearing Loss" Encyclopedia, (accessed November 30, 2023).
Aldè, M., Cantarella, G., Zanetti, D., Pignataro, L., La Mantia, I., Maiolino, L., Ferlito, S., Di Mauro, P., Cocuzza, S., Lechien, J.R., Iannella, G., Simon, F., & Maniaci, A.(2023, June 26). Autosomal Dominant Non-Syndromic Hearing Loss. In Encyclopedia.
Aldè, Mirko, et al. "Autosomal Dominant Non-Syndromic Hearing Loss." Encyclopedia. Web. 26 June, 2023.
Autosomal Dominant Non-Syndromic Hearing Loss

Autosomal dominant non-syndromic hearing loss (HL) typically occurs when only one dominant allele within the disease gene is sufficient to express the phenotype. Therefore, most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent, although de novo mutations should be considered in all cases of negative family history. To date, more than 50 genes and 80 loci have been identified for autosomal dominant non-syndromic HL. DFNA22 (MYO6 gene), DFNA8/12 (TECTA gene), DFNA20/26 (ACTG1 gene), DFNA6/14/38 (WFS1 gene), DFNA15 (POU4F3 gene), DFNA2A (KCNQ4 gene), and DFNA10 (EYA4 gene) are some of the most common forms of autosomal dominant non-syndromic HL. The characteristics of autosomal dominant non-syndromic HL are heterogenous.

genetic hearing loss autosomal dominant inheritance non-syndromic hearing loss

1. Inheritance

Autosomal dominant inheritance occurs when only one dominant allele within the disease gene (located on one of the autosomal chromosomes) is sufficient to express the phenotype [1]. Therefore, a heterozygous parent with autosomal dominant non-syndromic HL (DFNA) has a 50% chance of passing it on to their children [1][2]. However, if one parent is homozygous, all offspring may inherit the disease. If both parents are heterozygous and affected by autosomal dominant non-syndromic HL, 75% of the offspring have the chance of inheriting the disease [1]. Males and females are equally likely to inherit the mutation [1][2]. Most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent [2]. However, although the family history is rarely negative, it may appear to be negative due to late-onset HL in a parent, reduced penetrance of the pathogenic variant in an asymptomatic parent, or a de novo variant [2]. In particular, de novo mutations are possible causes of genetic HL and should be considered in all cases of sporadic HL [3]. It is often difficult to distinguish between syndromic and non-syndromic HL, as symptoms can sometimes appear later. Furthermore, some genes (e.g., WFS1 and ACTG1) cause both syndromic and non-syndromic HL [4].
Unlike autosomal recessive non-syndromic HL (in which the majority of cases are caused by mutations in the GJB2 gene), autosomal dominant non-syndromic HL does not have a single identifiable gene responsible for the majority of cases worldwide [2].
In Europe, the most common forms of autosomal dominant non-syndromic HL are DFNA22 (MYO6 gene) and DFNA8/12 (TECTA gene), accounting for 21% and 18% of all cases, respectively [5]. Other frequent forms of autosomal dominant non-syndromic HL in Europe are DFNA20/26 (ACTG1 gene), DFNA6/14/38 (WFS1 gene), and DFNA15 (POU4F3 gene), accounting for 9%, 9%, and 6.5% of all cases, respectively [5]. KCNQ4 (DFNA2A) and EYA4 (DFNA10) genes contribute 2.5% each, while the remaining genes are residually represented [5]. De novo mutations have been described in several genes, such as GJB2 (DFNA3A) [6][7], ACTG1 (DFNA20/26) [8][9], TECTA (DFNA8/12) [10], MYH14 (DFNA4A) [10], CEACAM16 (DFNA4B) [11], ATP2B2 (DFNA82) [12], and WFS1 (DFNA6/14/38) [13].

2. MYO6 Gene

Mutations in the MYO6 gene can cause either autosomal dominant non-syndromic HL (DFNA22) or autosomal recessive non-syndromic HL (DFNB37) [4]. DFNA22 is caused by a heterozygous mutation in the myosin VI gene (MYO6) on chromosome 6q14 [4]. Myosin VI is an actin-based motor protein which plays a key role in the endocytic and exocytic membrane trafficking pathways. In the inner and outer hair cells of the organ of Corti, myosin VI serves as an anchor and maintains the structure of the stereocilia [14]. Autosomal dominant HL associated with MYO6 mutations was reported in large Italian [15], Danish [16], Belgian [17][18], Dutch [19], German [20], and Austrian [21] families. However, several cases of DFNA22 were described in China [22][23][24], Japan [25][26], the Republic of Korea [27], and Brazil [28]. HL is typically post-lingual (often occurs during childhood), is slowly progressive, ranges from a mild to profound degree, and may be associated with mild cardiac hypertrophy [4][29]. Volk et al. suggested a favorable outcome of cochlear implantation in patients with DFNA22 [20].

3. TECTA Gene

Autosomal dominant non-syndromic sensorineural deafness 8/12 (DFNA8/12) is caused by heterozygous mutations in the TECTA gene on chromosome 11q23 [4]. Missense mutations of TECTA cause DFNA8/12, while nonsense mutations cause autosomal recessive non-syndromic HL (DFNB21) [4]. The TECTA gene encodes alpha-tectorin, one of the major non-collagenous components of the tectorial membrane of the inner ear that bridges the stereocilia bundles of the sensory hair cells [30]. HL associated with TECTA missense mutations was reported in families from different European countries, including Belgium [31][32], Austria [33][34], France [35], Sweden [36], Spain [37], and The Netherlands [38][39][40][41]. However, autosomal dominant non-syndromic HL caused by TECTA mutations was also reported in Japanese [42][43][44][45], Turkish [46], American [30][47], Korean [48][49], Brazilian [50], Chinese [22][51][52], Mongolian [53], and Algerian [54] families. HL can be present before the child learns to speak (prelingual) or begin in childhood (first or second decade of life). The characteristics of HL depend on the domain in which the mutations occur: missense mutations in the zona pellucida domain lead to mid-frequency sensorineural HL (“U-shaped” or “cookie bite” audiometric configuration), while missense mutations in the zonadhesin region cause high-frequency sensorineural HL (“sloping” audiometric configuration). HL is progressive if cysteine residues are affected [4][30].

4. ACTG1 Gene

Autosomal dominant non-syndromic sensorineural deafness 20/26 (DFNA20/26) is caused by heterozygous mutations in the ACTG1 gene on chromosome 17q25 [4]. Mutations in the ACTG1 gene can be associated with autosomal dominant non-syndromic HL (DFNA20/26) and Baraitser–Winter syndrome (a rare condition characterized by ptosis, colobomata, neuronal migration disorder, distinct facial anomalies, and intellectual disability) [4][55]. The ACTG1 gene encodes gamma actin, which is a major actin protein in the cytoskeleton of auditory hair cells and is essential for the maintenance of stereocilia [55]. In Europe, DFNA20/26 was reported in Dutch [56][57][58], Norwegian [59], Spanish [60], and Italian [55] families. Mutations in the ACTG1 gene were also frequently described in American [61][62][63][64], Chinese [8][65][66][67][68], Korean [69][70][71], and Japanese [72][73][74] populations. HL is typically diagnosed in the first or second decade of life and affects high frequencies (“sloping” audiometric configuration). It is progressive and tends to become profound by the sixth decade of life [4].

5. WFS1 Gene

Autosomal dominant non-syndromic sensorineural deafness 6/14/38 (DFNA6/14/38) is caused by heterozygous mutations in the WFS1 gene on chromosome 4p16 [4]. The DFNA6, DFNA14, and DFNA38 loci were initially described separately but were later found to be associated with pathogenic variants in the same gene (WFS1) [75]. Mutations in the WSF1 gene can be responsible for both autosomal dominant non-syndromic HL (DFNA6/14/38) and Wolfram syndrome (an autosomal recessive disorder characterized by diabetes mellitus, diabetes insipidus, optic atrophy, and high-frequency sensorineural HL) [4][75]. The WFS1 gene encodes “Wolframin”, a transmembrane protein located in the endoplasmic reticulum and ubiquitously expressed [75]. DFNA6/14/38 was largely described in the United States of America [76][77][78][79][80][81], Japan [82][83][84][85][86][87], and China [13][66][88][89][90][91][92][93][94]. In Europe, DFNA6/14/38 was reported in Dutch [75][95][96][97], Swiss [98], Danish [99], Hungarian [100], Finnish [101], and German [102] families. Other cases of DFNA6/14/38 were observed in Taiwan [103], the Republic of Korea [104][105], Iran [106], and India [107]. HL is generally congenital, limited to low frequencies (2000 Hz and below), and slowly progressive (without reaching a severe-to-profound range). It may be associated with tinnitus, but speech perception is typically good [4]. Interestingly, although Wolframin is equally expressed in the basal and apical turns of the cochlea, HL involves the low frequencies in DFNA6/14/38 and the high frequencies in Wolfram syndrome [75].

6. POU4F3 Gene

Autosomal dominant non-syndromic sensorineural deafness 15 (DFNA15) is caused by heterozygous mutations in the POU4F3 gene on chromosome 5q32 [4]. The POU4F3 gene encodes a transcription factor which plays a key role in the maintenance of inner ear hair cells [108]. DFNA15 was largely described in Israeli [109][110][111][112] and Chinese families [22][66][113][114][115][116][117][118]. In Europe, DFNA15 was widely reported in The Netherlands [119][120][121][122]. Other cases of DFNA15 were observed in the Republic of Korea [69][123][124], Brazil [125][126], Japan [72][127], and Taiwan [128]. HL is post-lingual (onset varies between the second and sixth decades of life), bilateral, and progressive [4]. It is characterized by high intrafamilial variability and tends to progress to the severe-to-profound range. Audiometric configuration can be sloping or flat [4]. HL may also be associated with vestibular dysfunctions, including areflexia [129].

7. KCNQ4 Gene

Autosomal dominant non-syndromic sensorineural deafness 2A (DFNA2A) is caused by a heterozygous mutation in the KCNQ4 gene on chromosome 1p34.2 [4].
The protein encoded by the KCNQ4 gene forms a potassium channel that plays a key role in the regulation of neuronal excitability, particularly in the sensory cells of the cochlea [130]. Autosomal dominant HL due to KCNQ4 mutations was reported in Indonesian [131], American [132][133][134][135][136], Japanese [137][138][139][140], Taiwanese [141][142][143], Canadian [144], Brazilian [145], Pakistani [146], Iranian [147], Chinese [148][149][150][151], and Korean [152][153][154][155] families. In Europe, DFNA2A was observed in French [133][156], Dutch [133][138][157][158][159][160][161], Belgian [133][158], and Spanish [162] families. HL is generally diagnosed between 5 and 15 years old and is initially limited to high frequencies, with later involvement of the middle and high frequencies. It tends to be severe by age 50 [4]. Most patients had associated tinnitus but no vestibular symptoms except in a few cases [140].

8. EYA4 Gene

Autosomal dominant non-syndromic sensorineural deafness 10 (DFNA10) is caused by heterozygous mutations in the EYA4 gene on chromosome 6q23 [4]. The EYA4 gene encodes a member of the eyes absent (EYA) family of proteins, which is a transcriptional activator required for proper eye development as well as for the maturation and maintenance of the organ of Corti. Mutations in EYA4 can also cause a syndromic variant characterized by HL and dilated cardiomyopathy [163]. DFNA10 was observed in large American [164][165][166][167][168], Australian [169], Indian [107], Korean [170][171][172], Chinese [163][173][174][175][176][177][178], Brazilian [126], and Japanese [179][180] families. In Europe, HL due to mutations in the EYA4 gene were reported in Belgian [165][167][181][182], Norwegian [181], Hungarian [183], Swedish [184], Dutch [185], Italian [186], Slovakian [187], and Spanish [188] families. HL is typically progressive and often involves all frequencies, although initially, it may be limited to middle frequencies. The onset of HL is highly variable [4]. The audiometric configuration of truncating variants tends to be flat, while that of non-truncating variants tends to be sloping [179]. DFNA10 patients are considered the least responsive to cochlear implantation [169].

9. Characteristics of Hearing Loss

The characteristics of autosomal dominant non-syndromic HL are heterogenous. Most autosomal dominant loci cause post-lingual HL, with onset ranging from childhood to late adulthood. However, HL tends to occur in childhood, adolescence, or early adulthood. Moreover, a non-negligible number of loci are associated with congenital HL, including DFNA3A (GJB2 gene), DFNA3B (GJB6 gene), DFNA6/14/38 (WFS1 gene), DFNA7 (LMX1A gene), DFNA8/12 (TECTA gene), DFNA13 (COL11A2 gene), DFNA19 (unknown gene), DFNA23 (SIX1 gene), DFNA24 (unknown gene), DFNA27 (REST gene), DFNA30 (unknown gene), DFNA37 (COL11A1 gene), DFNA40 (CRYM gene), DFNA59 (unknown gene), DFNA66 (CD164 gene), DFNA69 (KITLG gene), DFNA71 (DMXL2 gene), DFNA78 (SLC12A2 gene), DFNA80 (GREB1L gene), DFNA84 (ATP11A gene), DFNA87 (PI4KB gene), and DNA89 (ATOH1 gene). The degree of HL at onset ranges from mild to profound. Most cases of HL are progressive and worsen over the years, with the exceptions of DFNA8/12 (TECTA gene), DFNA13 (COL11A2 gene), DFNA19 (unknown gene), DFNA23 (SIX1 gene), DFNA24 (unknown gene), DFNA40 (CRYM gene), DFNA59 (unknown gene), DFNA66 (CD164 gene), DFNA69 (KITLG gene), DFNA76 (PLS1 gene), DFNA78 (SLC12A2 gene), and DFNA80 (GREB1L gene), which tend to be stable. Interestingly, DFNA16 (unknown gene) is characterized by fluctuating HL that often benefits from treatment with oral steroids [189]. Audiometric configuration is highly variable, although it often tends to be sloping, with the high frequencies more involved, especially at the onset of HL. A flat audiometric configuration is also frequent. However, some loci are associated with rising audiometric configuration, and HL is limited to the low frequencies: DFNA1 (DIAPH1 gene), DFNA6/14/38 (WFS1 gene), DFNA44 (CCDC50 gene), DFNA49 (unknown gene), DFNA54 (unknown gene), DFNA56 (TNC gene), DFNA57 (unknown gene), and sometimes DFNA11 (MYO7A gene), and DFNA69 (KITLG gene).
DFNA1 and DFNA6/14/38 are the most common forms of autosomal dominant non-syndromic HL affecting the low frequencies. DFNA1 is due to mutations in the DIAPH1 gene on chromosome 5q31 and causes progressive low-frequency HL, resulting in a profound degree by the fourth decade of life [190][191]; conversely, DFNA6/14/38 is due to mutations in the WFS1 gene on chromosome 4p16 and does not progress to profound HL [192]. The “U-shaped”, “saucer”, or “cookie bite” audiometric configuration indicates mid-range frequency HL and can be associated with some autosomal dominant loci, including DFNA8/12 (TECTA gene), DFNA13 (COL11A2 gene), DFNA31 (unknown gene), DFNA37 (COL11A1 gene), DFNA66 (CD164 gene), and DFNA72 (SLC44A4 gene). Although non-syndromic HL is typically not associated with other clinical manifestations, some autosomal dominant loci can cause other signs or symptoms than HL, such as thrombocytopenia (DFNA1), vertigo or vestibular dysfunction (DFNA7, DFNA9, DFNA11, DFNA15, DFNA16, DFNA36, DFNA54, DFNA69, DFNA78, and DFNA82), cochleosaccular dysplasia (DFNA17), hypertrophic cardiomyopathy (DFNA22), preauricular pits, hypodysplastic kidney, and vesicoureteral reflux (DFNA23), autoinflammatory disorders (DFNA34), dentinogenesis imperfecta (DFNA39), absent or malformed cochleae and eighth cranial nerves (DFNA80), and incomplete cochlea partition and enlarged vestibular aqueduct (DFNA87).

10. How Knowledge of Genetic Mutations May Influence Treatment

All children diagnosed with sensorineural HL should be screened early for genetic mutations to ensure timely appropriate treatments (e.g., hearing aid or cochlear implant), personalized rehabilitation programs (e.g., in the presence of additional symptoms), prognosis (e.g., stable, progressive, or fluctuant HL), and family planning [2]. The team evaluating and treating these children should consist of an otolaryngologist with expertise in the management of pediatric otologic disorders, an audiologist experienced in the assessment of childhood HL, a clinical geneticist, a speech-language pathologist specializing in working with children affected by HL, and a pediatrician [2]. For children with severe-to-profound HL, hearing aids may be insufficient for HL rehabilitation, and cochlear implantation should be considered.
Cochlear implantation has a high probability of being effective if the mutated lesion is located in the hair cells or afferent synapses between hair cells and the auditory nerve, such as in patients with pathogenic variants in GJB2, COCH, MYO7A, ACTG1, or MYO6 genes. Conversely, cochlear implants are generally less effective if genetic mutations affect auditory nerve function [20][193][194][195][196]. Moreover, genetic testing is useful not only for predicting performance after cochlear implantation but also for assessing residual hearing, estimating progression, and successful hearing preservation, leading to the most appropriate selection of candidates and electrodes [195].
As a matter of fact, better knowledge regarding genotype–phenotype correlation and cochlear implant outcome may provide effective auditory rehabilitation and would reduce unnecessary procedures, thereby limiting both surgical risks and healthcare costs [196].

11. Current Limitations and Future Trends

The genetics of non-syndromic HL are constantly evolving, and there are currently many limitations of knowledge in this field. The etiology of some patients with evident familial HL still remains unknown. Indeed, intra-familial variability in sensorineural HL is common not only from parent to child in dominant cases but also between siblings [197]. Many pathogenic variants affecting known deafness genes may go undetected using current diagnostic algorithms because they reside in non-coding (intronic and regulatory) sequences or unannotated exons [198]. Therefore, consideration should be given to implementing whole exome or whole genome sequencing with a virtual panel as the gold standard for genetic testing in HL instead of targeted gene sequencing panels [199].
Currently, many children with mild or progressive forms of HL remain undiagnosed during their critical period of speech development and neuroplasticity. Therefore, it appears to be a priority to develop a new cost-effective method of universal genetic screening that ensures early diagnosis of genetic HL in order to identify potential comorbid conditions and guide treatments [200].
In recent years, there have been major advances in the development of gene therapy vectors to treat sensorineural HL in animal models, representing a promising approach to prevent or slow down genetic HL. Interestingly, gene therapy is not limited to the addition of a healthy copy of the defective gene but may also involve gene silencing or editing through nucleic acid-based strategies, including antisense oligonucleotides, siRNA, microRNA, or nuclease-based gene editing [201]. However, many issues are still unresolved, such as the temporal window for therapeutic intervention, the need for viral vector optimization, the safety of surgery, and the type of immune response [202].


  1. Lewis, R.G.; Simpson, B. Genetics, Autosomal Dominant. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. Available online: (accessed on 6 May 2023).
  2. Shearer, A.E.; Hildebrand, M.S.; Schaefer, A.M.; Smith, R.J.H. Hereditary Hearing Loss and Deafness Overview. In GeneReviews®; Adam, M.P., Mirzaa, G.M., Pagon, R.A., Eds.; University of Washington: Seattle, WA, USA, 2017. Available online: (accessed on 6 May 2023).
  3. Klimara, M.J.; Nishimura, C.; Wang, D.; Kolbe, D.L.; Schaefer, A.M.; Walls, W.D.; Frees, K.L.; Smith, R.J.; Azaiez, H. De novo variants are a common cause of genetic hearing loss. Genet. Med. 2022, 24, 2555–2567.
  4. Van Camp, G.; Smith, R.J.H. Hereditary Hearing Loss Homepage. Available online: (accessed on 25 March 2023).
  5. del Castillo, I.; Morín, M.; Domínguez-Ruiz, M.; Moreno-Pelayo, M.A. Genetic etiology of non-syndromic hearing loss in Europe. Hum. Genet. 2022, 141, 683–696.
  6. Janecke, A.R.; Nekahm, D.; Löffler, J.; Hirst-Stadlmann, A.; Müller, T.; Utermann, G. De novo mutation of the connexin 26 gene associated with dominant non-syndromic sensorineural hearing loss. Hum. Genet. 2001, 108, 269–270.
  7. Onsori, H.; Rahmati, M.; Fazli, D. A Novel De Novo Dominant Mutation in GJB2 Gene Associated with a Sporadic Case of Nonsyndromic Sensorineural Hearing Loss. Iran. J. Public Health 2014, 43, 1710–1713.
  8. Wang, H.; Guan, J.; Lan, L.; Yu, L.; Xie, L.; Liu, X.; Yang, J.; Zhao, C.; Wang, D.; Wang, Q. A novel de novo mutation of ACTG1 in two sporadic non-syndromic hearing loss cases. Sci. China Life Sci. 2018, 61, 729–732.
  9. Morgan, A.; Lenarduzzi, S.; Cappellani, S.; Pecile, V.; Morgutti, M.; Orzan, E.; Ghiselli, S.; Ambrosetti, U.; Brumat, M.; Gajendrarao, P.; et al. Genomic Studies in a Large Cohort of Hearing Impaired Italian Patients Revealed Several New Alleles, a Rare Case of Uniparental Disomy (UPD) and the Importance to Search for Copy Number Variations. Front. Genet. 2018, 9, 681.
  10. Kim, N.K.; Kim, A.R.; Park, K.T.; Kim, S.Y.; Kim, M.Y.; Nam, J.-Y.; Woo, S.J.; Oh, S.-H.; Park, W.-Y.; Choi, B.Y. Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population. Genet. Med. 2015, 17, 901–911, Correction in Genet. Med. 2015, 17, 839.
  11. Hofrichter, M.A.; Nanda, I.; Gräf, J.; Schröder, J.; Shehata-Dieler, W.; Vona, B.; Haaf, T. A Novel de novo Mutation in CEACAM16 Associated with Postlingual Hearing Impairment. Mol. Syndr. 2015, 6, 156–163.
  12. Smits, J.J.; DOOFNL Consortium; Oostrik, J.; Beynon, A.J.; Kant, S.G.; Gans, P.A.M.D.K.; Rotteveel, L.J.C.; Wassink-Ruiter, J.S.K.; Free, R.H.; Maas, S.M.; et al. De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment. Hum. Genet. 2018, 138, 61–72.
  13. Guan, J.; Wang, H.; Lan, L.; Wu, Y.; Chen, G.; Zhao, C.; Wang, D.; Wang, Q. Recurrent de novo WFS1 pathogenic variants in Chinese sporadic patients with nonsyndromic sensorineural hearing loss. Mol. Genet. Genom. Med. 2020, 8, e1367.
  14. Hertzano, R.; Shalit, E.; Rzadzinska, A.K.; Dror, A.A.; Song, L.; Ron, U.; Tan, J.T.; Shitrit, A.S.; Fuchs, H.; Hasson, T.; et al. A Myo6 Mutation Destroys Coordination between the Myosin Heads, Revealing New Functions of Myosin VI in the Stereocilia of Mammalian Inner Ear Hair Cells. PLoS Genet. 2008, 4, e1000207.
  15. Melchionda, S.; Ahituv, N.; Bisceglia, L.; Sobe, T.; Glaser, F.; Rabionet, R.; Arbones, M.; Notarangelo, A.; Di Iorio, E.; Carella, M.; et al. MYO6, the Human Homologue of the Gene Responsible for Deafness in Snell’s Waltzer Mice, Is Mutated in Autosomal Dominant Nonsyndromic Hearing Loss. Am. J. Hum. Genet. 2001, 69, 635–640.
  16. Sanggaard, K.M.; Kjaer, K.W.; Eiberg, H.; Nürnberg, G.; Nürnberg, P.; Hoffman, K.; Jensen, H.; Sørum, C.; Rendtorff, N.D.; Tranebjaerg, L. A novel nonsense mutation in MYO6 is associated with progressive nonsyndromic hearing loss in a Danish DFNA22 family. Am. J. Med. Genet. Part A 2008, 146A, 1017–1025.
  17. Topsakal, V.; Hilgert, N.; van Dinther, J.; Tranebjærg, L.; Rendtorff, N.D.; Zarowski, A.; Offeciers, E.; Van Camp, G.; van de Heyning, P. Genotype-phenotype correlation for DFNA22: Characterization of non-syndromic, autosomal dominant, progressive sensorineural hearing loss due to MYO6 mutations. Audiol. Neurotol. 2010, 15, 211–220.
  18. Hilgert, N.; Topsakal, V.; Van Dinther, J.; Offeciers, E.; Van de Heyning, P.; Van Camp, G. A splice-site mutation and overexpression of MYO6 cause a similar phenotype in two families with autosomal dominant hearing loss. Eur. J. Hum. Genet. 2008, 16, 593–602.
  19. Oonk, A.; Leijendeckers, J.; Lammers, E.; Weegerink, N.; Oostrik, J.; Beynon, A.; Huygen, P.; Kunst, H.; Kremer, H.; Snik, A.; et al. Progressive hereditary hearing impairment caused by a MYO6 mutation resembles presbyacusis. Hear. Res. 2013, 299, 88–98.
  20. Volk, A.E.; Lang-Roth, R.; Yigit, G.; Borck, G.; Nuernberg, G.; Rosenkranz, S.; Nuernberg, P.; Kubisch, C.; Beutner, D. A Novel MYO6 Splice Site Mutation Causes Autosomal Dominant Sensorineural Hearing Loss Type DFNA22 with a Favourable Outcome after Cochlear Implantation. Audiol. Neurotol. 2013, 18, 192–199.
  21. Frohne, A.; Koenighofer, M.; Liu, D.T.; Laccone, F.; Neesen, J.; Gstoettner, W.; Schoefer, C.; Lucas, T.; Frei, K.; Parzefall, T. High Prevalence of MYO6 Variants in an Austrian Patient Cohort with Autosomal Dominant Hereditary Hearing Loss. Otol. Neurotol. 2021, 42, e648–e657.
  22. Yang, T.; Wei, X.; Chai, Y.; Li, L.; Wu, H. Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. Orphanet J. Rare Dis. 2013, 8, 85.
  23. Cheng, J.; Zhou, X.; Lu, Y.; Han, B.; Zhu, Y.; Liu, L.; Choy, K.-W.; Han, D.; Sham, P.C.; Zhang, M.Q.; et al. Exome Sequencing Identifies a Novel Frameshift Mutation of MYO6 as the Cause of Autosomal Dominant Nonsyndromic Hearing Loss in a Chinese Family. Ann. Hum. Genet. 2014, 78, 410–423.
  24. Tian, T.; Lu, Y.; Yao, J.; Cao, X.; Wei, Q.; Li, Q. Identification of a novel MYO6 mutation associated with autosomal dominant non-syndromic hearing loss in a Chinese family by whole-exome sequencing. Genes Genet. Syst. 2018, 93, 171–179.
  25. Miyagawa, M.; Nishio, S.-Y.; Kumakawa, K.; Usami, S.-I. Massively Parallel DNA Sequencing Successfully Identified Seven Families with Deafness-Associated MYO6 Mutations: The mutational spectrum and clinical characteristics. Ann. Otol. Rhinol. Laryngol. 2015, 124, 148S–157S.
  26. Oka, S.-I.; Day, T.F.; Nishio, S.-Y.; Moteki, H.; Miyagawa, M.; Morita, S.; Izumi, S.; Ikezono, T.; Abe, S.; Nakayama, J.; et al. Clinical Characteristics and In Vitro Analysis of MYO6 Variants Causing Late-onset Progressive Hearing Loss. Genes 2020, 11, 273.
  27. Kim, B.J.; Han, J.H.; Park, H.-R.; Kim, M.Y.; Kim, A.R.; Oh, S.-H.; Park, W.-Y.; Oh, D.Y.; Lee, S.; Choi, B.Y. A clinical guidance to DFNA22 drawn from a Korean cohort study with an autosomal dominant deaf population: A retrospective cohort study. J. Gene Med. 2018, 20, e3019.
  28. Sampaio-Silva, J.; Batissoco, A.C.; Jesus-Santos, R.; Abath-Neto, O.; Scarpelli, L.C.; Nishimura, P.Y.; Galindo, L.T.; Bento, R.F.; Oiticica, J.; Lezirovitz, K. Exome Sequencing Identifies a Novel Nonsense Mutation of MYO6 as the Cause of Deafness in a Brazilian Family. Ann. Hum. Genet. 2017, 82, 23–34.
  29. A Mohiddin, S.; Ahmed, Z.M.; Griffith, A.J.; Tripodi, D.; Friedman, T.B.; Fananapazir, L.; Morell, R.J. Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin VI (MYO6). J. Med. Genet. 2004, 41, 309–314.
  30. Hildebrand, M.S.; Morín, M.; Meyer, N.C.; Mayo, F.; Modamio-Hoybjor, S.; Mencía, A.; Olavarrieta, L.; Morales-Angulo, C.; Nishimura, C.J.; Workman, H.; et al. DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss. Hum. Mutat. 2011, 32, 825–834.
  31. Verhoeven, K.; Van Laer, L.; Kirschhofer, K.; Legan, P.K.; Hughes, D.; Schatteman, I.; Verstreken, M.; Van Hauwe, P.; Coucke, P.; Chen, A.; et al. Mutations in the human α-tectorin gene cause autosomal dominant non-syndromic hearing impairment. Nat. Genet. 1998, 19, 60–62, Correction in Nat. Genet. 1999, 21, 449.
  32. Govaerts, P.J.; De Ceulaer, G.; Daemers, K.; Verhoeven, K.; Van Camp, G.; Schatteman, I.; Verstreken, M.; Willems, P.J.; Somers, T.; Offeciers, F.E. Clinical presentation of DFNA8-DFNA12. Adv. Otorhinolaryngol. 2002, 61, 60–65.
  33. Kirschhofer, K.; Kenyon, J.; Hoover, D.; Franz, P.; Weipoltshammer, K.; Wachtler, F.; Kimberling, W. Autosomal-dominant, prelingual, nonprogressive sensorineural hearing loss: Localization of the gene (DFNA8) to chromosome 11q by linkage in an Austrian family. Cytogenet. Genome Res. 1998, 82, 126–130.
  34. Ramsebner, R.; Koenighofer, M.; Parzefall, T.; Lucas, T.; Schoefer, C.; Frei, K. Despite a lack of otoacoustic emission, word recognition is not seriously influenced in a TECTA DFNA8/12 family. Int. J. Pediatr. Otorhinolaryngol. 2014, 78, 837–842.
  35. Alloisio, N.; Morlé, L.; Bozon, M.; Godet, J.; Verhoeven, K.; Van Camp, G.; Plauchu, H.; Muller, P.; Collet, L.; Lina-Granade, G. Mutation in the zonadhesin-like domain of α-tectorin associated with autosomal dominant non-syndromic hearing loss. Eur. J. Hum. Genet. 1999, 7, 255–258.
  36. Balciuniene, J.; Dahl, N.; Jalonen, P.; Verhoeven, K.; Van Camp, G.; Borg, E.; Pettersson, U.; Jazin, E. Alpha-tectorin involvement in hearing disabilities: One gene—Two phenotypes. Hum. Genet. 1999, 105, 211–216.
  37. Moreno-Pelayo, M.A.; del Castillo, I.; Villamar, M.; Romero, L.; Hernández-Calvín, F.J.; Herraiz, C.; Barberá, R.; Navas, C.; Moreno, F. A cysteine substitution in the zona pellucida domain of alpha-tectorin results in autosomal dominant, postlingual, progressive, mid frequency hearing loss in a Spanish family. J. Med. Genet. 2001, 38, e13.
  38. Plantinga, R.F.; de Brouwer, A.P.M.; Huygen, P.L.M.; Kunst, H.P.M.; Kremer, H.; Cremers, C.W.R.J. A Novel TECTA Mutation in a Dutch DFNA8/12 Family Confirms Genotype–Phenotype Correlation. J. Assoc. Res. Otolaryngol. 2006, 7, 173–181.
  39. Plantinga, R.F.; Cremers, C.W.R.J.; Huygen, P.L.M.; Kunst, H.P.M.; Bosman, A.J. Audiological Evaluation of Affected Members from a Dutch DFNA8/12 (TECTA) Family. J. Assoc. Res. Otolaryngol. 2006, 8, 1–7.
  40. Collin, R.W.J.; De Heer, A.-M.R.; Oostrik, J.; Pauw, R.-J.; Plantinga, R.F.; Huygen, P.L.; Admiraal, R.; De Brouwer, A.P.M.; Strom, T.M.; Cremers, C.W.R.J.; et al. Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer. Eur. J. Hum. Genet. 2008, 16, 1430–1436.
  41. de Heer, A.; Pauw, R.; Huygen, P.; Collin, R.; Kremer, H.; Cremers, C. Flat Threshold and Mid-Frequency Hearing Impairment in a Dutch DFNA8/12 Family with a Novel Mutation in TECTA: Some evidence for protection of the inner ear. Audiol. Neurotol. 2008, 14, 153–162.
  42. Iwasaki, S.; Harada, D.; Usami, S.-I.; Nagura, M.; Takeshita, T.; Hoshino, T. Association of Clinical Features with Mutation of TECTA in a Family with Autosomal Dominant Hearing Loss. Arch. Otolaryngol. Neck Surg. 2002, 128, 913–917.
  43. Moteki, H.; Nishio, S.-Y.; Hashimoto, S.; Takumi, Y.; Iwasaki, S.; Takeichi, N.; Fukuda, S.; Usami, S.-I. TECTA mutations in Japanese with mid-frequency hearing loss affected by zona pellucida domain protein secretion. J. Hum. Genet. 2012, 57, 587–592.
  44. Yamamoto, N.; Mutai, H.; Namba, K.; Morita, N.; Masuda, S.; Nishi, Y.; Nakano, A.; Masuda, S.; Fujioka, M.; Kaga, K.; et al. Prevalence of TECTA mutation in patients with mid-frequency sensorineural hearing loss. Orphanet J. Rare Dis. 2017, 12, 157.
  45. Yasukawa, R.; Moteki, H.; Nishio, S.-Y.; Ishikawa, K.; Abe, S.; Honkura, Y.; Hyogo, M.; Mihashi, R.; Ikezono, T.; Shintani, T.; et al. The Prevalence and Clinical Characteristics of TECTA-Associated Autosomal Dominant Hearing Loss. Genes 2019, 10, 744.
  46. Pfister, M.; Thiele, H.; van Camp, G.; Fransen, E.; Apaydin, F.; Aydin, Ö.; Leistenschneider, P.; Devoto, M.; Zenner, H.-P.; Blin, N.; et al. A Genotype-Phenotype Correlation with Gender-Effect for Hearing Impairment Caused by TECTA Mutations. Cell. Physiol. Biochem. 2004, 14, 369–376.
  47. Meyer, N.; Nishimura, C.; McMordie, S.; Smith, R. Audioprofiling identifies TECTA and GJB2-related deafness segregating in a single extended pedigree. Clin. Genet. 2007, 72, 130–137.
  48. Sagong, B.; Park, R.; Kim, Y.-H.; Lee, K.-Y.; Baek, J.-I.; Cho, H.-J.; Cho, I.-J.; Kim, U.-K.; Lee, S.-H. Two novel missense mutations in the TECTA gene in Korean families with autosomal dominant nonsyndromic hearing loss. Ann. Clin. Lab. Sci. 2010, 40, 380–385.
  49. Kim, A.R.; Chang, M.Y.; Koo, J.-W.; Oh, S.H.; Choi, B.Y. Novel TECTA Mutations Identified in Stable Sensorineural Hearing Loss and Their Clinical Implications. Audiol. Neurotol. 2014, 20, 17–25.
  50. Lezirovitz, K.; Batissoco, A.C.; Lima, F.T.; Auricchio, M.T.; Nonose, R.W.; dos Santos, S.R.; Guilherme, L.; Oiticica, J.; Mingroni-Netto, R.C. Aberrant transcript produced by a splice donor site deletion in the TECTA gene is associated with autosomal dominant deafness in a Brazilian family. Gene 2012, 511, 280–284.
  51. Li, Z.; Guo, Y.; Lu, Y.; Li, J.; Jin, Z.; Li, H.; Lu, Y.; Dai, P.; Han, N.; Cheng, J.; et al. Identification of a Novel TECTA Mutation in a Chinese DFNA8/12 Family with Prelingual Progressive Sensorineural Hearing Impairment. PLoS ONE 2013, 8, e70134.
  52. Su, Y.; Tang, W.-X.; Gao, X.; Yu, F.; Dai, Z.-Y.; Zhao, J.-D.; Lu, Y.; Ji, F.; Huang, S.-S.; Yuan, Y.-Y.; et al. A Novel Mutation in the TECTA Gene in a Chinese Family with Autosomal Dominant Nonsyndromic Hearing Loss. PLoS ONE 2014, 9, e89240.
  53. Bai, H.; Yang, X.; Narisu, N.; Wu, H.; Chen, Y.; Liu, Y.; Wu, Q. A rare novel mutation in TECTA causes autosomal dominant nonsyndromic hearing loss in a Mongolian family. BMC Med. Genet. 2014, 15, 34.
  54. Talbi, S.; Bonnet, C.; Riahi, Z.; Boudjenah, F.; Dahmani, M.; Hardelin, J.-P.; Tai, F.W.J.; Louha, M.; Ammar-Khodja, F.; Petit, C. Genetic heterogeneity of congenital hearing impairment in Algerians from the Ghardaïa province. Int. J. Pediatr. Otorhinolaryngol. 2018, 112, 1–5.
  55. Sorrentino, U.; Piccolo, C.; Rigon, C.; Brasson, V.; Trevisson, E.; Boaretto, F.; Martini, A.; Cassina, M. DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature. Audiol. Res. 2021, 11, 582–593.
  56. van Wijk, E.; Krieger, E.; Kemperman, M.H.; De Leenheer, E.M.R.; Huygen, P.L.M.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, H. A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26). J. Med. Genet. 2003, 40, 879–884.
  57. Kemperman, M.H.; De Leenheer, E.M.R.; Huygen, P.L.M.; van Wijk, E.; van Duijnhoven, G.; Cremers, F.P.M.; Kremer, H.; Cremers, C.W.R.J. A Dutch Family with Hearing Loss Linked to the DFNA20/26 Locus: Longitudinal analysis of hearing impairment. Arch. Otolaryngol. Neck Surg. 2004, 130, 281–288.
  58. de Heer, A.-M.R.; Huygen, P.L.M.; Collin, R.W.J.; Oostrik, J.; Kremer, H.; Cremers, C.W.R.J. Audiometric and Vestibular Features in a Second Dutch DFNA20/26 Family with a Novel Mutation in ACTG1. Ann. Otol. Rhinol. Laryngol. 2009, 118, 382–390.
  59. Rendtorff, N.D.; Zhu, M.; Fagerheim, T.; Antal, T.L.; Jones, M.; Teslovich, T.M.; Gillanders, E.M.; Barmada, M.M.; Teig, E.; Trent, J.M.; et al. A novel missense mutation in ACTG1 causes dominant deafness in a Norwegian DFNA20/26 family, but ACTG1 mutations are not frequent among families with hereditary hearing impairment. Eur. J. Hum. Genet. 2006, 14, 1097–1105.
  60. Morín, M.; Bryan, K.E.; Mayo-Merino, F.; Goodyear, R.; Mencía, A.; Modamio-Høybjør, S.; del Castillo, I.; Cabalka, J.M.; Richardson, G.; Moreno, F.; et al. In vivo and in vitro effects of two novel gamma-actin (ACTG1) mutations that cause DFNA20/26 hearing impairment. Hum. Mol. Genet. 2009, 18, 3075–3089.
  61. Morell, R.J.; Friderici, K.H.; Wei, S.; Elfenbein, J.L.; Friedman, T.B.; Fisher, R.A. A new locus for late-onset, progressive, hereditary hearing loss DFNA20 maps to 17q25. Genomics 2000, 63, 1–6.
  62. Elfenbein, J.L.; Fisher, R.A.; Wei, S.; Morell, R.; Stewart, C.; Friedman, T.B.; Friderici, K. Audiologic Aspects of the Search for DFNA20: A Gene Causing Late-Onset, Progressive, Sensorineural Hearing Loss. Ear Hear. 2001, 22, 279–288.
  63. Zhu, M.; Yang, T.; Wei, S.; DeWan, A.; Morell, R.; Elfenbein, J.; Fisher, R.; Leal, S.; Smith, R.J.; Friderici, K. Mutations in the γ-Actin Gene (ACTG1) Are Associated with Dominant Progressive Deafness (DFNA20/26). Am. J. Hum. Genet. 2003, 73, 1082–1091.
  64. DeWan, A.; Parrado, A.; Leal, S. A second kindred linked to DFNA20 (17q25.3) reduces the genetic interval. Clin. Genet. 2002, 63, 39–45.
  65. Liu, P.; Li, H.; Ren, X.; Mao, H.; Zhu, Q.; Zhu, Z.; Yang, R.; Yuan, W.; Liu, J.; Wang, Q.; et al. Novel ACTG1 mutation causing autosomal dominant non-syndromic hearing impairment in a Chinese family. J. Genet. Genom. 2008, 35, 553–558.
  66. Wei, Q.; Zhu, H.; Qian, X.; Chen, Z.; Yao, J.; Lu, Y.; Cao, X.; Xing, G. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. J. Transl. Med. 2014, 12, 311.
  67. Yuan, Y.; Gao, X.; Huang, B.; Lu, J.; Wang, G.; Lin, X.; Qu, Y.; Dai, P. Phenotypic Heterogeneity in a DFNA20/26 family segregating a novel ACTG1 mutation. BMC Genet. 2016, 17, 33.
  68. Wang, L.; Yan, D.; Qin, L.; Li, T.; Liu, H.; Li, W.; Mittal, R.; Yong, F.; Chapagain, P.; Liao, S.; et al. Amino acid 118 in the deafness causing (DFNA20/26) ACTG1 gene is a mutational hot spot. Gene Rep. 2018, 11, 264–269.
  69. Baek, J.-I.; Oh, S.-K.; Kim, D.-B.; Choi, S.-Y.; Kim, U.-K.; Lee, K.-Y.; Lee, S.-H. Targeted massive parallel sequencing: The effective detection of novel causative mutations associated with hearing loss in small families. Orphanet J. Rare Dis. 2012, 7, 60.
  70. Park, G.; Gim, J.; Kim, A.R.; Han, K.-H.; Kim, H.-S.; Oh, S.-H.; Park, T.; Park, W.-Y.; Choi, B.Y. Multiphasic analysis of whole exome sequencing data identifies a novel mutation of ACTG1 in a nonsyndromic hearing loss family. BMC Genom. 2013, 14, 191.
  71. Lee, C.G.; Jang, J.; Jin, H. A novel missense mutation in the ACTG1 gene in a family with congenital autosomal dominant deafness: A case report. Mol. Med. Rep. 2018, 17, 7611–7617.
  72. Mutai, H.; Suzuki, N.; Shimizu, A.; Torii, C.; Namba, K.; Morimoto, N.; Kudoh, J.; Kaga, K.; Kosaki, K.; Matsunaga, T. Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: A cross-sectional, multi-center next-generation sequencing study. Orphanet J. Rare Dis. 2013, 8, 172.
  73. Miyagawa, M.; Nishio, S.-Y.; Ichinose, A.; Iwasaki, S.; Murata, T.; Kitajiri, S.-I.; Usami, S.-I. Mutational Spectrum and Clinical Features of Patients with ACTG1 Mutations Identified by Massively Parallel DNA Sequencing. Ann. Otol. Rhinol. Laryngol. 2015, 124 (Suppl. S1), 84S–93S.
  74. Miyajima, H.; Moteki, H.; Day, T.; Nishio, S.-Y.; Murata, T.; Ikezono, T.; Takeda, H.; Abe, S.; Iwasaki, S.; Takahashi, M.; et al. Novel ACTG1 mutations in patients identified by massively parallel DNA sequencing cause progressive hearing loss. Sci. Rep. 2020, 10, 7056.
  75. Velde, H.M.; Huizenga, X.J.J.; Yntema, H.G.; Haer-Wigman, L.; Beynon, A.J.; Oostrik, J.; Pegge, S.A.H.; Kremer, H.; Lanting, C.P.; Pennings, R.J.E. Genotype and Phenotype Analyses of a Novel WFS1 Variant (c.2512C>T p.(Pro838Ser)) Associated with DFNA6/14/38. Genes 2023, 14, 457.
  76. Vanderbilt Hereditary Deafness Study Group. Dominantly inherited low-frequency hearing loss. Arch. Otolaryngol. 1968, 88, 242–250.
  77. Konigsmark, B.W.; Mengel, M.; Berlin, C.I. Familial Low Frequency Hearing Loss. Laryngoscope 1971, 81, 759–771.
  78. Lesperance, M.M.; Hall, J.W.; Bess, F.H.; Fukushima, K.; Jain, P.K.; Ploplis, B.; Agustin, T.B.; Skarka, H.; Smith, R.J.; Wills, M.; et al. A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. Hum. Mol. Genet. 1995, 4, 1967–1972.
  79. Lesperance, M.M.; Hall, J.W.; Agustin, T.B.S.; Leal, S.M. Mutations in the Wolfram Syndrome Type 1 Gene (WFS1) Define a Clinical Entity of Dominant Low-Frequency Sensorineural Hearing Loss. Arch. Otolaryngol. Neck Surg. 2003, 129, 411–420.
  80. Bespalova, I.N.; Van Camp, G.; Bom, S.J.H.; Brown, D.J.; Cryns, K.; DeWan, A.T.; Erson, A.E.; Flothmann, K.; Kunst, H.P.; Kurnool, P.; et al. Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum. Mol. Genet. 2001, 10, 2501–2508.
  81. Bramhall, N.F.; Kallman, J.C.; Verrall, A.M.; A Street, V. A novel WFS1 mutation in a family with dominant low frequency sensorineural hearing loss with normal VEMP and EcochG findings. BMC Med. Genet. 2008, 9, 48.
  82. Komatsu, K.; Nakamura, N.; Ghadami, M.; Matsumoto, N.; Kishino, T.; Ohta, T.; Niikawa, N.; Yoshiura, K.-I. Confirmation of genetic homogeneity of nonsyndromic low-frequency sensorineural hearing loss by linkage analysis and a DFNA6/14 mutation in a Japanese family. J. Hum. Genet. 2002, 47, 395–399.
  83. Noguchi, Y.; Yashima, T.; Hatanaka, A.; Uzawa, M.; Yasunami, M.; Kimura, A.; Kitamura, K. A mutation in Wolfram syndrome type 1 gene in a Japanese family with autosomal dominant low-frequency sensorineural hearing loss. Acta Oto-Laryngologica 2005, 125, 1189–1194.
  84. Fukuoka, H.; Kanda, Y.; Ohta, S.; Usami, S.-I. Mutations in the WFS1 gene are a frequent cause of autosomal dominant nonsyndromic low-frequency hearing loss in Japanese. J. Hum. Genet. 2007, 52, 510–515.
  85. Fujikawa, T.; Noguchi, Y.; Ito, T.; Takahashi, M.; Kitamura, K. Additional heterozygous 2507A>C mutation of WFS1 in progressive hearing loss at lower frequencies. Laryngoscope 2009, 120, 166–171.
  86. Kasakura-Kimura, N.; Masuda, M.; Mutai, H.; Masuda, S.; Morimoto, N.; Ogahara, N.; Misawa, H.; Sakamoto, H.; Saito, K.; Matsunaga, T. WFS1 and GJB2 mutations in patients with bilateral low-frequency sensorineural hearing loss. Laryngoscope 2017, 127, E324–E329.
  87. Kobayashi, M.; Miyagawa, M.; Nishio, S.-Y.; Moteki, H.; Fujikawa, T.; Ohyama, K.; Sakaguchi, H.; Miyanohara, I.; Sugaya, A.; Naito, Y.; et al. WFS1 mutation screening in a large series of Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis. PLoS ONE 2018, 13, e0193359.
  88. Sun, Y.; Cheng, J.; Lu, Y.; Li, J.; Lu, Y.; Jin, Z.; Dai, P.; Wang, R.; Yuan, H. Identification of two novel missense WFS1 mutations, H696Y and R703H, in patients with non-syndromic low-frequency sensorineural hearing loss. J. Genet. Genom. 2011, 38, 71–76.
  89. Bai, X.; Lv, H.; Zhang, F.; Liu, J.; Fan, Z.; Xu, L.; Han, Y.; Chai, R.; Li, J.; Wang, H. Identification of a novel missense mutation in the WFS1 gene as a cause of autosomal dominant nonsyndromic sensorineural hearing loss in all-frequencies. Am. J. Med. Genet. Part A 2014, 164, 3052–3060.
  90. Niu, Z.; Feng, Y.; Hu, Z.; Li, J.; Sun, J.; Chen, H.; He, C.; Wang, X.; Jiang, L.; Liu, Y.; et al. Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non-syndromic low-frequency hearing loss in a Chinese family. Int. J. Pediatr. Otorhinolaryngol. 2017, 100, 1–7.
  91. Cheng, H.; Zhang, Q.; Wang, W.; Meng, Q.; Wang, F.; Liu, M.; Mao, J.; Shi, Y.; Wang, W.; Li, H. Whole exome sequencing identifies a pathogenic mutation in WFS1 in two large Chinese families with autosomal dominant all-frequency hearing loss and prenatal counseling. Int. J. Pediatr. Otorhinolaryngol. 2018, 106, 113–119.
  92. Li, J.; Xu, H.; Sun, J.; Tian, Y.; Liu, D.; Qin, Y.; Liu, H.; Li, R.; Neng, L.; Deng, X.; et al. Missense Variant of Endoplasmic Reticulum Region of WFS1 Gene Causes Autosomal Dominant Hearing Loss without Syndromic Phenotype. BioMed Res. Int. 2021, 2021, 6624744.
  93. Ma, J.; Wang, R.; Zhang, L.; Wang, S.; Tong, S.; Bai, X.; Lu, Z. A Novel Missense WFS1 Variant: Expanding the Mutational Spectrum Associated with Nonsyndromic Low-Frequency Sensorineural Hearing Loss. BioMed Res. Int. 2022, 2022, 5068869.
  94. Zhao, J.; Zhang, S.; Jiang, Y.; Liu, Y.; Wang, J.; Zhu, Q. Mutation analysis of the WFS1 gene in a Chinese family with autosomal-dominant non-syndrome deafness. Sci. Rep. 2022, 12, 22180.
  95. Van Camp, G.; Kunst, H.; Flothmann, K.; McGuirt, W.; Wauters, J.; Marres, H.; Verstreken, M.; Bespalova, I.N.; Burmeister, M.; Van de Heyning, P.H.; et al. A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus. J. Med Genet. 1999, 36, 532–536.
  96. Kunst, H.; Marres, H.; Huygen, P.; van Camp, G.; Joosten, F.; Cremers, C. Autosomal Dominant Non-syndromal Low-frequency Sensorineural Hearing Impairment Linked to Chromosome 4p16 (DFNA14): Statistical Analysis of Hearing Threshold in Relation to Age and Evaluation of Vestibulo-ocular Functions. Int. J. Audiol. 1999, 38, 165–173.
  97. Pennings, R.J.E.; Bom, S.J.H.; Cryns, K.; Flothmann, K.; Huygen, P.L.M.; Kremer, H.; Van Camp, G.; Cremers, C.W.R.J. Progression of Low-Frequency Sensorineural Hearing Loss (DFNA6/14-WFS1). Arch. Otolaryngol. Head Neck Surg. 2003, 129, 421–426.
  98. Gürtler, N.; Kim, Y.; Mhatre, A.; Schlegel, C.; Mathis, A.; Daniels, R.; Shelton, C.; Lalwani, A.K. Two families with nonsyndromic low-frequency hearing loss harbor novel mutations in Wolfram syndrome gene 1. J. Mol. Med. 2005, 83, 553–560.
  99. Bille, M.; Munk-Nielsen, L.; Tranebjaerg, L.; Fagerheim, T.; Parving, A. Two families with phenotypically different hereditary low frequency hearing impairment: Longitudinal data and linkage analysis. Scand. Audiol. 2001, 30, 246–254.
  100. Tóth, T.; Pfister, M.; Zenner, H.-P.; Sziklai, I. Phenotypic characterization of a DFNA6 family showing progressive low-frequency sensorineural hearing impairment. Int. J. Pediatr. Otorhinolaryngol. 2005, 70, 201–206.
  101. Häkli, S.; Kytövuori, L.; Luotonen, M.; Sorri, M.; Majamaa, K. WFS1 mutations in hearing-impaired children. Int. J. Audiol. 2014, 53, 446–451.
  102. Tropitzsch, A.; Schade-Mann, T.; Gamerdinger, P.; Dofek, S.; Schulte, B.; Schulze, M.; Battke, F.; Fehr, S.; Biskup, S.; Heyd, A.; et al. Diagnostic Yield of Targeted Hearing Loss Gene Panel Sequencing in a Large German Cohort with a Balanced Age Distribution from a Single Diagnostic Center: An Eight-year Study. Ear Hear. 2021, 43, 1049–1066.
  103. Tsai, H.-T.; Wang, Y.-P.; Chung, S.-F.; Lin, H.-C.; Ho, G.-M.; Shu, M.-T. A novel mutation in the WFS1 gene identified in a Taiwanese family with low-frequency hearing impairment. BMC Med. Genet. 2007, 8, 26.
  104. Choi, B.Y.; Park, G.; Gim, J.; Kim, A.R.; Kim, B.-J.; Kim, H.-S.; Park, J.H.; Park, T.; Oh, S.-H.; Han, K.-H.; et al. Diagnostic Application of Targeted Resequencing for Familial Nonsyndromic Hearing Loss. PLoS ONE 2013, 8, e68692.
  105. Choi, H.J.; Lee, J.S.; Yu, S.; Cha, D.H.; Gee, H.Y.; Choi, J.Y.; Lee, J.D.; Jung, J. Whole-exome sequencing identified a missense mutation in WFS1 causing low-frequency hearing loss: A case report. BMC Med. Genet. 2017, 18, 151.
  106. Asl, J.M.; Saki, N.; Dehdashtiyan, M.; Neissi, M.; Mardasi, F.G. Identification of a Novel WFS1 Mutation Using the Whole Exome Sequencing in an Iranian Pedigree with Autosomal Dominant Hearing Loss. Iran. J. Otorhinolaryngol. 2021, 33, 173–176.
  107. Panigrahi, I.; Kumari, D.; Kumar, B.N.A. Single gene variants causing deafness in Asian Indians. J. Genet. 2021, 100, 35.
  108. Weiss, S.; Gottfried, I.; Mayrose, I.; Khare, S.L.; Xiang, M.; Dawson, S.J.; Avraham, K.B. The DFNA15 Deafness Mutation Affects POU4F3 Protein Stability, Localization, and Transcriptional Activity. Mol. Cell. Biol. 2003, 23, 7957–7964.
  109. Vahava, O.; Morell, R.; Lynch, E.D.; Weiss, S.; Kagan, M.E.; Ahituv, N.; Morrow, J.E.; Lee, M.K.; Skvorak, A.B.; Morton, C.C.; et al. Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science 1998, 279, 1950–1954.
  110. Frydman, M.; Vreugde, S.; Nageris, B.I.; Weiss, S.; Vahava, O.; Avraham, K.B. Clinical Characterization of Genetic Hearing Loss Caused by a Mutation in the POU4F3 Transcription Factor. Arch. Otolaryngol. Neck Surg. 2000, 126, 633–637.
  111. Avraham, K. DFNA15. Adv Otorhinolaryngol. 2000, 56, 107–115.
  112. Gottfried, I.; Huygen, P.L.M.; Avraham, K.B. The Clinical Presentation of DFNA15/POU4F3. Adv. Otorhinolaryngol. 2002, 61, 92–97.
  113. Zhang, C.; Wang, M.; Xiao, Y.; Zhang, F.; Zhou, Y.; Li, J.; Zheng, Q.; Bai, X.; Wang, H. A Novel Nonsense Mutation of POU4F3 Gene Causes Autosomal Dominant Hearing Loss. Neural. Plast. 2016, 2016, 1512831, Correction in Neural. Plast. 2017, 2017, 9202847.
  114. He, L.; Pang, X.; Chen, P.; Wu, H.; Yang, T. Mutation in the Hair Cell Specific Gene POU4F3 Is a Common Cause for Autosomal Dominant Nonsyndromic Hearing Loss in Chinese Hans. Neural Plast. 2016, 2016, 9890827.
  115. Cai, X.Z.; Li, Y.; Xia, L.; Peng, Y.; He, C.F.; Jiang, L.; Feng, Y.; Xia, K.; Liu, X.Z.; Mei, L.Y.; et al. Exome sequencing identifies POU4F3 as the causative gene for a large Chinese family with non-syndromic hearing loss. J. Hum. Genet. 2016, 62, 317–320.
  116. Gao, X.; Xu, J.-C.; Wang, W.-Q.; Yuan, Y.-Y.; Bai, D.; Huang, S.-S.; Wang, G.-J.; Su, Y.; Li, J.; Kang, D.-Y.; et al. A Missense Mutation in POU4F3 Causes Midfrequency Hearing Loss in a Chinese ADNSHL Family. BioMed Res. Int. 2018, 2018, 5370802.
  117. Bai, X.; Zhang, F.; Xiao, Y.; Jin, Y.; Zheng, Q.; Wang, H.; Xu, L. Identification of two novel mutations in POU4F3 gene associated with autosomal dominant hearing loss in Chinese families. J. Cell. Mol. Med. 2020, 24, 6978–6987.
  118. Cui, T.-Y.; Gao, X.; Huang, S.-S.; Sun, Y.-Y.; Zhang, S.-Q.; Jiang, X.-X.; Yang, Y.-Z.; Kang, D.-Y.; Zhu, Q.-W.; Yuan, Y.-Y. Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss. Neural Plast. 2020, 2020, 6137083.
  119. Collin, R.W.; Chellappa, R.; Pauw, R.-J.; Vriend, G.; Oostrik, J.; van Drunen, W.; Huygen, P.L.; Admiraal, R.; Hoefsloot, L.H.; Cremers, F.P.; et al. Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding. Hum. Mutat. 2008, 29, 545–554.
  120. Pauw, R.J.; van Drunen, F.J.W.; Collin, R.W.J.; Huygen, P.L.M.; Kremer, H.; Cremers, C.W.R.J. Audiometric Characteristics of a Dutch Family Linked to DFNA15 with a Novel Mutation (p.L289F) in POU4F3. Arch. Otolaryngol. Head Neck Surg. 2008, 134, 294–300.
  121. van Drunen, F.W.; Pauw, R.J.; Collin, R.W.; Kremer, H.; Huygen, P.L.; Cremers, C.W. Vestibular Impairment in a Dutch DFNA15 Family with an L289F Mutation in POU4F3. Audiol. Neurotol. 2009, 14, 303–307.
  122. de Heer, A.-M.R.; Huygen, P.L.M.; Collin, R.W.J.; Kremer, H.; Cremers, C.W.R.J. Mild and Variable Audiometric and Vestibular Features in a Third DFNA15 Family with a Novel Mutation in POU4F3. Ann. Otol. Rhinol. Laryngol. 2009, 118, 313–320.
  123. Lee, H.K.; Park, H.-J.; Lee, K.-Y.; Park, R.; Kim, U.-K. A novel frameshift mutation of POU4F3 gene associated with autosomal dominant non-syndromic hearing loss. Biochem. Biophys. Res. Commun. 2010, 396, 626–630, Correction in Biochem. Biophys. Res. Commun. 2010, 398, 790.
  124. Kim, H.-J.; Won, H.-H.; Park, K.-J.; Hong, S.H.; Ki, C.-S.; Cho, S.S.; Venselaar, H.; Vriend, G.; Kim, J.-W. SNP Linkage Analysis and Whole Exome Sequencing Identify a Novel POU4F3 Mutation in Autosomal Dominant Late-Onset Nonsyndromic Hearing Loss (DFNA15). PLoS ONE 2013, 8, e79063.
  125. Freitas, É.L.; Oiticica, J.; Silva, A.G.; Bittar, R.S.; Rosenberg, C.; Mingroni-Netto, R.C. Deletion of the entire POU4F3 gene in a familial case of autosomal dominant non-syndromic hearing loss. Eur. J. Med. Genet. 2014, 57, 125–128.
  126. Rosenberg, C.; Freitas, É.L.; Uehara, D.T.; Auricchio, M.T.B.M.; Costa, S.S.; Oiticica, J.; Silva, A.G.; Krepischi, A.C.; Mingroni-Netto, R.C. Genomic copy number alterations in non-syndromic hearing loss. Clin. Genet. 2015, 89, 473–477.
  127. Kitano, T.; Miyagawa, M.; Nishio, S.-Y.; Moteki, H.; Oda, K.; Ohyama, K.; Miyazaki, H.; Hidaka, H.; Nakamura, K.-I.; Murata, T.; et al. POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss. PLoS ONE 2017, 12, e0177636.
  128. Lin, Y.-H.; Lin, Y.-H.; Lu, Y.-C.; Liu, T.-C.; Chen, C.-Y.; Hsu, C.-J.; Chen, P.-L.; Wu, C.-C. A novel missense variant in the nuclear localization signal of POU4F3 causes autosomal dominant non-syndromic hearing loss. Sci. Rep. 2017, 7, 7551.
  129. Frejo, L.; Giegling, I.; Teggi, R.; Lopez-Escamez, J.A.; Rujescu, D. Genetics of vestibular disorders: Pathophysiological insights. J. Neurol. 2016, 263 (Suppl. S1), 45–53.
  130. Kharkovets, T.; Hardelin, J.-P.; Safieddine, S.; Schweizer, M.; El-Amraoui, A.; Petit, C.; Jentsch, T.J. KCNQ4, a K + channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc. Natl. Acad. Sci. USA 2000, 97, 4333–4338.
  131. Coucke, P.; Van Camp, G.; Djoyodiharjo, B.; Smith, S.D.; Frants, R.R.; Padberg, G.W.; Darby, J.K.; Huizing, E.H.; Cremers, C.; Kimberling, W.J.; et al. Linkage of Autosomal Dominant Hearing Loss to the Short Arm of Chromosome 1 in Two Families. N. Engl. J. Med. 1994, 331, 425–431.
  132. Talebizadeh, Z.; Kelley, P.M.; Askew, J.W.; Beisel, K.W.; Smith, S.D. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum. Mutat. 1999, 14, 493–501.
  133. Coucke, P.; Van Hauwe, P.; Kelley, P.M.; Kunst, H.; Schatteman, I.; Van Velzen, D.; Meyers, J.; Ensink, R.J.; Verstreken, M.; Declau, F.; et al. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum. Mol. Genet. 1999, 8, 1321–1328.
  134. Goldstein, J.A.; Lalwani, A.K. Further evidence for a third deafness gene within the DFNA2 locus. Am. J. Med. Genet. 2002, 108, 304–309.
  135. Hildebrand, M.S.; Tack, D.; McMordie, S.J.; Deluca, A.; Hur, I.A.; Nishimura, C.; Huygen, P.; Casavant, T.L.; Smith, R.J. Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus. Anesthesia Analg. 2008, 10, 797–804.
  136. Arnett, J.; Emery, S.B.; Kim, T.B.; Boerst, A.K.; Lee, K.; Leal, S.M.; Lesperance, M.M. Autosomal Dominant Progressive Sensorineural Hearing Loss Due to a Novel Mutation in the KCNQ4 Gene. Arch. Otolaryngol. Neck Surg. 2011, 137, 54–59, Correction in Arch. Otolaryngol. Head Neck Surg. 2011, 137, 711.
  137. Akita, J.; Abe, S.; Shinkawa, H.; Kimberling, W.J.; Usami, S.-I. Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese. J. Hum. Genet. 2001, 46, 355–361.
  138. Van Camp, G.; Coucke, P.J.; Akita, J.; Fransen, E.; Abe, S.; De Leenheer, E.M.; Huygen, P.L.; Cremers, C.W.; Usami, S.-I. A mutational hot spot in theKCNQ4 gene responsible for autosomal dominant hearing impairment. Hum. Mutat. 2002, 20, 15–19.
  139. Kamada, F.; Kure, S.; Kudo, T.; Suzuki, Y.; Oshima, T.; Ichinohe, A.; Kojima, K.; Niihori, T.; Kanno, J.; Narumi, Y.; et al. A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: Implication for the genotype–phenotype correlation. J. Hum. Genet. 2006, 51, 455–460.
  140. Naito, T.; Nishio, S.-Y.; Iwasa, Y.-I.; Yano, T.; Kumakawa, K.; Abe, S.; Ishikawa, K.; Kojima, H.; Namba, A.; Oshikawa, C.; et al. Comprehensive Genetic Screening of KCNQ4 in a Large Autosomal Dominant Nonsyndromic Hearing Loss Cohort: Genotype-Phenotype Correlations and a Founder Mutation. PLoS ONE 2013, 8, e63231.
  141. Su, C.-C.; Yang, J.-J.; Shieh, J.-C.; Su, M.-C.; Li, S.-Y. Identification of Novel Mutations in the KCNQ4 Gene of Patients with Nonsyndromic Deafness from Taiwan. Audiol. Neurotol. 2006, 12, 20–26.
  142. Wu, C.-C.; Lin, Y.-H.; Lu, Y.-C.; Chen, P.-J.; Yang, W.-S.; Hsu, C.-J.; Chen, P.-L. Application of Massively Parallel Sequencing to Genetic Diagnosis in Multiplex Families with Idiopathic Sensorineural Hearing Impairment. PLoS ONE 2013, 8, e57369.
  143. Yen, T.-T.; Chen, I.-C.; Hua, M.-W.; Wei, C.-Y.; Shih, K.-H.; Li, J.-L.; Lin, C.-H.; Hsiao, T.-H.; Chen, Y.-M.; Jiang, R.-S. A KCNQ4 c.546C>G Genetic Variant Associated with Late Onset Non-Syndromic Hearing Loss in a Taiwanese Population. Genes 2021, 12, 1711.
  144. Abdelfatah, N.; McComiskey, D.A.; Doucette, L.; Griffin, A.; Moore, S.J.; Negrijn, C.; Hodgkinson, K.A.; King, J.J.; Larijani, M.; Houston, J.; et al. Identification of a novel in-frame deletion in KCNQ4 (DFNA2A) and evidence of multiple phenocopies of unknown origin in a family with ADSNHL. Eur. J. Hum. Genet. 2013, 21, 1112–1119.
  145. Uehara, D.T.; Freitas, É.L.; Alves, L.U.; Mazzeu, J.F.; Auricchio, M.T.; Tabith, A., Jr.; Monteiro, M.L.; Rosenberg, C.; Mingroni-Netto, R.C. A novel KCNQ4 mutation and a private IMMP2L-DOCK4 duplication segregating with nonsyndromic hearing loss in a Brazilian family. Hum. Genome Var. 2015, 2, 15038.
  146. Ramzan, M.; Idrees, H.; Mujtaba, G.; Sobreira, N.; Witmer, P.D.; Naz, S. Bi-allelic Pro291Leu variant in KCNQ4 leads to early onset non-syndromic hearing loss. Gene 2019, 705, 109–112.
  147. Mehregan, H.; Mohseni, M.; Akbari, M.; Jalalvand, K.; Arzhangi, S.; Nikzat, N.; Kahrizi, K.; Najmabadi, H. Novel Mutations in KCNQ4, LHFPL5 and COCH Genes in Iranian Families with Hearing Impairment. Arch. Iran. Med. 2019, 22, 189–197.
  148. Jiang, L.; Liu, Y.; Feng, Y.; Hu, Z.; Mei, L.; Long, L.; Chen, H.; Xue, J.; Xia, K.; He, C. Gene localization in a Chinese family with autosomal dominant non-syndromic deafness. Acta Oto-Laryngologica 2011, 131, 1061–1068.
  149. Wang, H.; Zhao, Y.; Yi, Y.; Gao, Y.; Liu, Q.; Wang, D.; Li, Q.; Lan, L.; Li, N.; Guan, J.; et al. Targeted High-Throughput Sequencing Identifies Pathogenic Mutations in KCNQ4 in Two Large Chinese Families with Autosomal Dominant Hearing Loss. PLoS ONE 2014, 9, e103133.
  150. Huang, B.; Liu, Y.; Gao, X.; Xu, J.; Dai, P.; Zhu, Q.; Yuan, Y. A novel pore-region mutation, c.887G > A (p.G296D) in KCNQ4, causing hearing loss in a Chinese family with autosomal dominant non-syndromic deafness 2. BMC Med. Genet. 2017, 18, 36.
  151. Li, Q.; Liang, P.; Wang, S.; Li, W.; Wang, J.; Yang, Y.; An, X.; Chen, J.; Zha, D. A novel KCNQ4 gene variant (c.857A>G; p.Tyr286Cys) in an extended family with non-syndromic deafness 2A. Mol. Med. Rep. 2021, 23, 12059.
  152. Baek, J.-I.; Park, H.-J.; Park, K.; Choi, S.-J.; Lee, K.-Y.; Yi, J.H.; Friedman, T.B.; Drayna, D.; Shin, K.S.; Kim, U.-K. Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology. Biochim. Biophys. Acta Mol. Basis Dis. 2011, 1812, 536–543.
  153. Jung, J.; Choi, H.B.; Koh, Y.I.; Rim, J.H.; Choi, H.J.; Kim, S.H.; Lee, J.H.; An, J.; Kim, A.; Lee, J.S.; et al. Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss. Sci. Rep. 2018, 8, 16659.
  154. Shin, D.H.; Jung, J.; Koh, Y.I.; Rim, J.H.; Lee, J.S.; Choi, H.J.; Joo, S.Y.; Yu, S.; Cha, D.H.; Lee, S.Y.; et al. A recurrent mutation in KCNQ4 in Korean families with nonsyndromic hearing loss and rescue of the channel activity by KCNQ activators. Hum. Mutat. 2019, 40, 335–346.
  155. Lee, S.-Y.; Choi, H.B.; Park, M.; Choi, I.S.; An, J.; Kim, A.; Kim, E.; Kim, N.; Han, J.H.; Kim, M.Y.; et al. Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss. Exp. Mol. Med. 2021, 53, 1192–1204.
  156. Kubisch, C.; Schroeder, B.C.; Friedrich, T.; Lütjohann, B.; El-Amraoui, A.; Marlin, S.; Petit, C.; Jentsch, T.J. KCNQ4, a Novel Potassium Channel Expressed in Sensory Outer Hair Cells, Is Mutated in Dominant Deafness. Cell 1999, 96, 437–446.
  157. Marres, H.; van Ewijk, M.; Huygen, P.; Kunst, H.; van Camp, G.; Coucke, P.; Willems, P.; Cremers, C. Inherited Nonsyndromic Hearing Loss: An Audiovestibular Study in a Large Family with Autosomal Dominant Progressive Hearing Loss Related to DFNA2. Arch. Otolaryngol. Head Neck Surg. 1997, 123, 573–577.
  158. Van Camp, G.; Coucke, P.J.; Kunstb, H.; Schattemana, I.; Van Velzen, D.; Marresb, H.; van Ewijk, M.; Declauc, F.; Van Hauwe, P.; Meyersa, J.; et al. Linkage Analysis of Progressive Hearing Loss in Five Extended Families Maps the DFNA2 Gene to a 1.25-Mb Region on Chromosome 1p. Genomics 1997, 41, 70–74.
  159. Van Hauwe, P.; Coucke, P.; Ensink, R.J.; Huygen, P.; Cremers, C.W.; Van Camp, G. Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am. J. Med. Genet. 2000, 93, 184–187.
  160. Topsakal, V.; Pennings, R.J.E.; Brinke, H.T.; Hamel, B.; Huygen, P.L.M.; Kremer, H.; Cremers, C.W.R.J. Phenotype Determination Guides Swift Genotyping of a DFNA2/KCNQ4 Family with a Hot Spot Mutation (W276S). Otol. Neurotol. 2005, 26, 52–58.
  161. de Heer, A.-M.R.; Schraders, M.; Jaap, O.; Hoefsloot, L.; Huygen, P.L.M.; Cremers, C.W.R.J. Audioprofile-Directed Successful Mutation Analysis in a DFNA2/KCNQ4 (p.Leu274His) Family. Ann. Otol. Rhinol. Laryngol. 2011, 120, 243–248.
  162. Mencía, A.; Nieto, D.G.; Modamio-Høybjør, S.; Etxeberría, A.; Aránguez, G.; Salvador, N.; del Castillo, I.; Villarroel, A.; Moreno, F.; Barrio, L.; et al. A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Hum. Genet. 2007, 123, 41–53.
  163. Liu, F.; Hu, J.; Xia, W.; Hao, L.; Ma, J.; Ma, D.; Ma, Z. Exome Sequencing Identifies a Mutation in EYA4 as a Novel Cause of Autosomal Dominant Non-Syndromic Hearing Loss. PLoS ONE 2015, 10, e0126602.
  164. O’Neill, M.E.; Marietta, J.; Nishimura, D.; Wayne, S.; Van Camp, G.; Van Laer, L.; Negrini, C.; Wilcox, E.R.; Chen, A.; Fukushima, K.; et al. A gene for autosomal dominant late-onset progressive non-syndromic hearing loss, DFNA10, maps to chromosome. Hum. Mol. Genet. 1996, 5, 853–856.
  165. Wayne, S.; Robertson, N.G.; Declau, F.; Chen, N.; Verhoeven, K.; Prasad, S.; Tranebjärg, L.; Morton, C.C.; Ryan, A.F.; Van Camp, G.; et al. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum. Mol. Genet. 2001, 10, 195–200.
  166. De Leenheer, E.M.R.; Huygen, P.L.M.; Smith, R.; Wayne, S.; Cremers, C.W.R.J. The DFNA10 Phenotype. Ann. Otol. Rhinol. Laryngol. 2001, 110, 861–866.
  167. De Leenheer, E.; Huygen, P.; Wayne, S.; Verstreken, M.; Declau, F.; Van Camp, G.; Van de Heyning, P.; Smith, R.; Cremers, C. DFNA10/EYA4—The Clinical Picture. Adv. Oto-Rhino-Laryngology 2002, 61, 73–78.
  168. Makishima, T.; Madeo, A.C.; Brewer, C.C.; Zalewski, C.K.; Butman, J.A.; Sachdev, V.; Arai, A.E.; Holbrook, B.M.; Rosing, D.R.; Griffith, A.J. Nonsyndromic hearing loss DFNA10 and a novel mutation of EYA4: Evidence for correlation of normal cardiac phenotype with truncating mutations of the Eya domain. Am. J. Med Genet. Part A 2007, 143A, 1592–1598.
  169. Hildebrand, M.S.; Coman, D.; Yang, T.; Gardner, R.M.; Rose, E.; Smith, R.J.; Bahlo, M.; Dahl, H.-H.M. A novel splice site mutation in EYA4 causes DFNA10 hearing loss. Am. J. Med. Genet. A 2007, 143 Pt A, 1599–1604, Correction in Am. J. Med. Genet. A 2008, 146 Pt A, 1099.
  170. Jo, H.D.; Han, J.H.; Lee, S.M.; Choi, D.H.; Lee, S.-Y.; Choi, B.Y. Genetic Load of Alternations of Transcription Factor Genes in Non-Syndromic Deafness and the Associated Clinical Phenotypes: Experience from Two Tertiary Referral Centers. Biomedicines 2022, 10, 2125.
  171. Kim, Y.-R.; Kim, M.-A.; Sagong, B.; Bae, S.-H.; Lee, H.-J.; Kim, H.-J.; Choi, J.Y.; Lee, K.-Y.; Kim, U.-K. Evaluation of the Contribution of the EYA4 and GRHL2 Genes in Korean Patients with Autosomal Dominant Non-Syndromic Hearing Loss. PLoS ONE 2015, 10, e0119443.
  172. Choi, H.S.; Kim, A.R.; Kim, S.H.; Choi, B.Y. Identification of a novel truncation mutation of EYA4 in moderate degree hearing loss by targeted exome sequencing. Eur. Arch. Otorhinolaryngol. 2015, 273, 1123–1129.
  173. Tan, M.; Shen, X.; Yao, J.; Wei, Q.; Lu, Y.; Cao, X.; Xing, G. Identification of I411K, a novel missense EYA4 mutation causing autosomal dominant non-syndromic hearing loss. Int. J. Mol. Med. 2014, 34, 1467–1472.
  174. Huang, A.; Yuan, Y.; Liu, Y.; Zhu, Q.; Dai, P. A novel EYA4 mutation causing hearing loss in a Chinese DFNA family and genotype-phenotype review of EYA4 in deafness. J. Transl. Med. 2015, 13, 154.
  175. Sun, Y.; Zhang, Z.; Cheng, J.; Lu, Y.; Yang, C.-L.; Luo, Y.-Y.; Yang, G.; Yang, H.; Zhu, L.; Zhou, J.; et al. A novel mutation of EYA4 in a large Chinese family with autosomal dominant middle-frequency sensorineural hearing loss by targeted exome sequencing. J. Hum. Genet. 2015, 60, 299–304.
  176. Xiao, S.-Y.; Qu, J.; Zhang, Q.; Ao, T.; Zhang, J.; Zhang, R.-H. Identification of a novel missense eya4 mutation causing autosomal dominant non"‘syndromic hearing loss in a chinese family. Cell. Mol. Biol. 2019, 65, 84–88.
  177. Mi, Y.; Liu, D.; Zeng, B.; Tian, Y.; Zhang, H.; Chen, B.; Zhang, J.; Xue, H.; Tang, W.; Zhao, Y.; et al. Early truncation of the N-terminal variable region of EYA4 gene causes dominant hearing loss without cardiac phenotype. Mol. Genet. Genom. Med. 2020, 9, e1569.
  178. Zhang, W.; Song, J.; Tong, B.; Ma, M.; Guo, L.; Yuan, Y.; Yang, J. Identification of a novel CNV at the EYA4 gene in a Chinese family with autosomal dominant nonsyndromic hearing loss. BMC Med. Genom. 2022, 15, 1.
  179. Shinagawa, J.; Moteki, H.; Nishio, S.-Y.; Ohyama, K.; Otsuki, K.; Iwasaki, S.; Masuda, S.; Oshikawa, C.; Ohta, Y.; Arai, Y.; et al. Prevalence and clinical features of hearing loss caused by EYA4 variants. Sci. Rep. 2020, 10, 3662.
  180. Ishino, T.; Ogawa, Y.; Sonoyama, T.; Taruya, T.; Kono, T.; Hamamoto, T.; Ueda, T.; Takeno, S.; Moteki, H.; Nishio, S.-Y.; et al. Identification of a Novel Copy Number Variation of EYA4 Causing Autosomal Dominant Non-Syndromic Hearing Loss. Otol. Neurotol. 2021, 42, e866–e874.
  181. Verhoeven, K.; Fagerheim, T.; Prasad, S.; Wayne, S.; De Clau, F.; Balemans, W.; Verstreken, M.; Schatteman, I.; Solem, B.; Van de Heyning, P.; et al. Refined localization and two additional linked families for the DFNA10 locus for nonsyndromic hearing impairment. Hum. Genet. 2000, 107, 7–11.
  182. Verstreken, M.; Declau, F.; Schatteman, I.; Van Velzen, D.; Verhoeven, K.; Van Camp, G.; Willems, P.J.; Kuhweide, E.W.; Verhaert, E.; D’Haese, P.; et al. Audiometric analysis of a Belgian family linked to the DFNA10 locus. Am. J. Otol. 2000, 21, 675–681.
  183. Pfister, M.; Tóth, T.; Thiele, H.; Haack, B.; Blin, N.; Zenner, H.-P.; Sziklai, I.; Nürnberg, P.; Kupka, S. A 4bp-Insertion in the eya-Homologous Region (eyaHR) of EYA4 Causes Hearing Impairment in a Hungarian Family Linked to DFNA10. Mol. Med. 2002, 8, 607–611.
  184. Frykholm, C.; Klar, J.; Arnesson, H.; Rehnman, A.-C.; Lodahl, M.; Wedén, U.; Dahl, N.; Tranebjærg, L.; Rendtorff, N.D. Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation. Gene 2015, 563, 10–16.
  185. van Beelen, E.; Oonk, A.M.M.; Leijendeckers, J.M.; Hoefsloot, E.H.; Pennings, R.J.E.; Feenstra, I.; Dieker, H.-J.; Huygen, P.L.M.; Snik, A.F.M.; Kremer, H.; et al. Audiometric Characteristics of a Dutch DFNA10 Family with Mid-Frequency Hearing Impairment. Ear Hear. 2016, 37, 103–111.
  186. Cesca, F.; Bettella, E.; Polli, R.; Cama, E.; Scimemi, P.; Santarelli, R.; Murgia, A. A novel mutation of the EYA4 gene associated with post-lingual hearing loss in a proband is co-segregating with a novel PAX3 mutation in two congenitally deaf family members. Int. J. Pediatr. Otorhinolaryngol. 2018, 104, 88–93.
  187. Varga, L.; Danis, D.; Skopkova, M.; Masindova, I.; Slobodova, Z.; Demesova, L.; Profant, M.; Gasperikova, D. Novel EYA4 variant in Slovak family with late onset autosomal dominant hearing loss: A case report. BMC Med. Genet. 2019, 20, 84.
  188. Morín, M.; Borreguero, L.; Booth, K.T.; Lachgar, M.; Huygen, P.; Villamar, M.; Mayo, F.; Barrio, L.C.; de Castro, L.S.S.; Morales, C.; et al. Insights into the pathophysiology of DFNA10 hearing loss associated with novel EYA4 variants. Sci. Rep. 2020, 10, 6213.
  189. Fukushima, K.; Kasai, N.; Ueki, Y.; Nishizaki, K.; Sugata, K.; Hirakawa, S.; Masuda, A.; Gunduz, M.; Ninomiya, Y.; Masuda, Y.; et al. A gene for fluctuating, progressive autosomal dominant nonsyndromic hearing loss, DFNA16, maps to chromosome 2q23-24.3. Am. J. Hum. Genet. 1999, 65, 141–150.
  190. Lynch, E.D.; Lee, M.K.; Morrow, J.E.; Welcsh, P.L.; León, P.E.; King, M.C. Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science 1997, 278, 1315–1318.
  191. Ueyama, T.; Ninoyu, Y.; Nishio, S.; Miyoshi, T.; Torii, H.; Nishimura, K.; Sugahara, K.; Sakata, H.; Thumkeo, D.; Sakaguchi, H.; et al. Constitutive activation of DIA1 (DIAPH1) via C-terminal truncation causes human sensorineural hearing loss. EMBO Mol. Med. 2016, 8, 1310.
  192. Hildebrand, M.S.; Sorensen, J.L.; Jensen, M.; Kimberling, W.J.; Smith, R.J. Autoimmune disease in a DFNA6/14/38 family carrying a novel missense mutation in WFS. Am. J. Med. Genet. A 2008, 146 Pt A, 2258–2265.
  193. Xiong, X.; Xu, K.; Chen, S.; Xie, L.; Sun, Y.; Kong, W. Advances in cochlear implantation for hereditary deafness caused by common mutations in deafness genes. J. Bio-X Res. 2019, 2, 74–80.
  194. Sharma, N.; Kumari, D.; Panigrahi, I.; Khetarpal, P. A systematic review of the monogenic causes of Non-Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options. Clin. Genet. 2022, 103, 16–34.
  195. Usami, S.; Nishio, S.; Moteki, H.; Miyagawa, M.; Yoshimura, H. Cochlear Implantation from the Perspective of Genetic Background. Anat. Rec. 2019, 303, 563–593.
  196. Eshraghi, A.A.; Polineni, S.P.; Davies, C.; Shahal, D.; Mittal, J.; Al-Zaghal, Z.; Sinha, R.; Jindal, U.; Mittal, R. Genotype-Phenotype Correlation for Predicting Cochlear Implant Outcome: Current Challenges and Opportunities. Front. Genet. 2020, 11, 678.
  197. Vona, B.; Nanda, I.; Hofrichter, M.A.; Shehata-Dieler, W.; Haaf, T. Non-syndromic hearing loss gene identification: A brief history and glimpse into the future. Mol. Cell. Probes 2015, 29, 260–270.
  198. Vona, B.; Doll, J.; Hofrichter, M.A.H.; Haaf, T. Non-syndromic hearing loss: Clinical and diagnostic challenges. Med. Genet. 2020, 32, 117–129.
  199. Clabout, T.; Maes, L.; Acke, F.; Wuyts, W.; Van Schil, K.; Coucke, P.; Janssens, S.; De Leenheer, E. Negative Molecular Diagnostics in Non-Syndromic Hearing Loss: What Next? Genes 2022, 14, 105.
  200. Thorpe, R.K.; Smith, R.J.H. Future directions for screening and treatment in congenital hearing loss. Precis. Clin. Med. 2020, 3, 175–186.
  201. Delmaghani, S.; El-Amraoui, A. Inner Ear Gene Therapies Take off: Current Promises and Future Challenges. J. Clin. Med. 2020, 9, 2309.
  202. Lahlou, G.; Calvet, C.; Giorgi, M.; Lecomte, M.-J.; Safieddine, S. Towards the Clinical Application of Gene Therapy for Genetic Inner Ear Diseases. J. Clin. Med. 2023, 12, 1046.
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