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Review

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review

by
Mirko Aldè
1,2,3,
Giovanna Cantarella
1,2,
Diego Zanetti
1,2,
Lorenzo Pignataro
1,2,
Ignazio La Mantia
4,
Luigi Maiolino
4,
Salvatore Ferlito
4,
Paola Di Mauro
4,
Salvatore Cocuzza
4,
Jérôme René Lechien
3,
Giannicola Iannella
3,
Francois Simon
3 and
Antonino Maniaci
3,4,*
1
Department of Clinical Sciences and Community Health, University of Milan, 20090 Milan, Italy
2
Department of Specialist Surgical Sciences, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20090 Milan, Italy
3
Otology Study Group of the Young-Otolaryngologists of the International Federations of Oto-Rhino-Laryngological Societies (YO-IFOS), 75000 Paris, France
4
Department of Medical, Surgical Sciences and Advanced Technologies G.F. Ingrassia, University of Catania, 95123 Catania, Italy
*
Author to whom correspondence should be addressed.
Biomedicines 2023, 11(6), 1616; https://doi.org/10.3390/biomedicines11061616
Submission received: 7 May 2023 / Revised: 26 May 2023 / Accepted: 29 May 2023 / Published: 1 June 2023
(This article belongs to the Special Issue Genetic Research on Hearing Loss 2.0)
Versions Notes

Abstract

:
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. However, in most cases, HL tends to be bilateral, post-lingual in onset (childhood to early adulthood), high-frequency (sloping audiometric configuration), progressive, and variable in severity (mild to profound degree). DFNA1 (DIAPH1 gene) and DFNA6/14/38 (WFS1 gene) are the most common forms of autosomal dominant non-syndromic HL affecting low frequencies, while DFNA16 (unknown gene) is characterized by fluctuating HL. A long audiological follow-up is of paramount importance to identify hearing threshold deteriorations early and ensure prompt treatment with hearing aids or cochlear implants.

1. Introduction

The World Health Organization (WHO) estimates that approximately 34 million children worldwide have disabling hearing loss (HL), defined as HL greater than 35 dB in the better ear [1]. HL can be present at birth (“congenital HL”) or appear sometime later in life (“acquired or delayed-onset HL”) [2]. The prevalence of congenital sensorineural HL ranges from 1 to 3 per 1000 live births in term healthy newborns to 3–6 per 100 in children admitted to neonatal intensive care units (NICU) [3]. Overall, the prevalence of HL increases over time, ranging from 2.8 per 1000 in school-age children to 3.5 per 1000 in adolescents [4]. Non-hereditary HL can be caused by prenatal, perinatal, or postnatal factors. Prenatal risk factors for HL include prenatal exposure to teratogens (e.g., valproic acid, ethanol, and thalidomide), congenital infections (e.g., cytomegalovirus [CMV], toxoplasmosis, rubella, syphilis, and Zika), and malformations (e.g., Michel aplasia, enlarged vestibular aqueduct, Mondini malformation) [4,5].
Particularly, congenital CMV infection is considered the leading nongenetic cause of sensorineural HL in the developed world [6]. The characteristics of HL due to congenital CMV infection are extremely variable concerning onset (at birth/late onset), side (unilateral/bilateral), degree (mild/moderate/severe/profound), audiometric configuration (rising/flat/sloping), and threshold changes over time (stable, fluctuating, sudden, progressive) [6]. There are also several perinatal risk factors for HL, such as prematurity, very low birth weight, hyperbilirubinemia, asphyxia, and hypoxic-ischemic encephalopathy [3,5]. Postnatal risk factors for HL include infections (e.g., bacterial meningitis, Herpes Simplex Virus, and Epstein–Barr virus), use of ototoxic drugs (e.g., aminoglycosides, vancomycin, and furosemide), head trauma, chemotherapy, and anemia [5,7,8]. However, approximately 50–60% of HL in children is due to genetic causes, and a genetic etiology should be considered for every patient with a hearing problem, even in the presence of other environmental risk factors [9]. Hereditary HL can be syndromic (if other signs and symptoms are present) or non-syndromic (in the absence of other clinical manifestations) [7,10]. More than 70% of genetic HL is non-syndromic, with great clinical and genetic heterogeneity (more than 120 genes have been identified to date) [9,11]. Non-syndromic HL generally follows simple Mendelian inheritance and is predominantly transmitted as an autosomal recessive trait (75–80%), although autosomal dominant (20%), X-linked (2–5%), and mitochondrial mutations (1%) can also cause HL [12]. Children born to consanguineous parents have a higher incidence of autosomal recessive disorders, including HL [13]. The loci in inherited non-syndromic HL are designed as “DFN” (standing for “DeaFNess”); the letters “A”, “B”, and “X” indicate that the inheritance patterns are autosomal dominant (DFNA), autosomal recessive (DFNB), and X-linked (DFNX), respectively [7,10]. A Y-linked inheritance pattern has also been described for HL [14]. The most effective strategy for the diagnosis of non-syndromic genetic HL is to perform a multi-step approach based on next-generation sequencing technologies and copy number variations assays and a thorough clinical evaluation, including physical examination and audiometric tests [15]. The aim of this narrative review is to provide a comprehensive and critical overview of autosomal dominant non-syndromic genetic HL. We screened titles, abstracts, and full texts from relevant literature to evaluate the content of the articles and extract valuable information.

2. Autosomal Dominant Non-Syndromic Hearing Loss (DFNA)

2.1. 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 [16]. Therefore, a heterozygous parent with autosomal dominant non-syndromic HL (DFNA) has a 50% chance of passing it on to their children [7,16]. 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 [16]. Males and females are equally likely to inherit the mutation [7,16]. Most patients diagnosed with autosomal dominant non-syndromic HL have a hearing-impaired parent [7]. 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 [7]. In particular, de novo mutations are possible causes of genetic HL and should be considered in all cases of sporadic HL [17]. 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 [11].
To date, more than 50 genes and 80 loci have been identified for autosomal dominant non-syndromic HL [11], and are summarized in Table 1.
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 [7].
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 [126]. 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 [126]. KCNQ4 (DFNA2A) and EYA4 (DFNA10) genes contribute 2.5% each, while the remaining genes are residually represented [126]. De novo mutations have been described in several genes, such as GJB2 (DFNA3A) [127,128], ACTG1 (DFNA20/26) [129,130], TECTA (DFNA8/12) [131], MYH14 (DFNA4A) [131], CEACAM16 (DFNA4B) [132], ATP2B2 (DFNA82) [118], and WFS1 (DFNA6/14/38) [133].

2.2. MYO6 Gene

Mutations in the MYO6 gene can cause either autosomal dominant non-syndromic HL (DFNA22) or autosomal recessive non-syndromic HL (DFNB37) [11]. DFNA22 is caused by a heterozygous mutation in the myosin VI gene (MYO6) on chromosome 6q14 [11]. 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 [134]. Autosomal dominant HL associated with MYO6 mutations was reported in large Italian [135], Danish [136], Belgian [53,137], Dutch [138], German [139], and Austrian [140] families. However, several cases of DFNA22 were described in China [141,142,143], Japan [144,145], the Republic of Korea [146], and Brazil [147]. 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 [11,148]. Volk et al. suggested a favorable outcome of cochlear implantation in patients with DFNA22 [139].

2.3. TECTA Gene

Autosomal dominant non-syndromic sensorineural deafness 8/12 (DFNA8/12) is caused by heterozygous mutations in the TECTA gene on chromosome 11q23 [11]. Missense mutations of TECTA cause DFNA8/12, while nonsense mutations cause autosomal recessive non-syndromic HL (DFNB21) [11]. 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 [35]. HL associated with TECTA missense mutations was reported in families from different European countries, including Belgium [149,150], Austria [151,152], France [153], Sweden [154], Spain [155], and The Netherlands [156,157,158,159]. However, autosomal dominant non-syndromic HL caused by TECTA mutations was also reported in Japanese [160,161,162,163], Turkish [164], American [35,165], Korean [166,167], Brazilian [168], Chinese [141,169,170], Mongolian [171], and Algerian [172] 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 [11,35].

2.4. ACTG1 Gene

Autosomal dominant non-syndromic sensorineural deafness 20/26 (DFNA20/26) is caused by heterozygous mutations in the ACTG1 gene on chromosome 17q25 [11]. 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) [11,173]. 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 [173]. In Europe, DFNA20/26 was reported in Dutch [51,174,175], Norwegian [176], Spanish [177], and Italian [173] families. Mutations in the ACTG1 gene were also frequently described in American [50,178,179,180], Chinese [129,181,182,183,184], Korean [185,186,187], and Japanese [188,189,190] 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 [11].

2.5. 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 [11]. 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) [191]. 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) [11,191]. The WFS1 gene encodes “Wolframin”, a transmembrane protein located in the endoplasmic reticulum and ubiquitously expressed [191]. DFNA6/14/38 was largely described in the United States of America [192,193,194,195,196,197], Japan [198,199,200,201,202,203], and China [133,182,204,205,206,207,208,209,210]. In Europe, DFNA6/14/38 was reported in Dutch [191,211,212,213], Swiss [214], Danish [215], Hungarian [216], Finnish [217], and German [218] families. Other cases of DFNA6/14/38 were observed in Taiwan [219], the Republic of Korea [220,221], Iran [222], and India [223]. 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 [11]. 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 [191].

2.6. POU4F3 Gene

Autosomal dominant non-syndromic sensorineural deafness 15 (DFNA15) is caused by heterozygous mutations in the POU4F3 gene on chromosome 5q32 [11]. The POU4F3 gene encodes a transcription factor which plays a key role in the maintenance of inner ear hair cells [224]. DFNA15 was largely described in Israeli [44,225,226,227] and Chinese families [45,141,182,228,229,230,231,232]. In Europe, DFNA15 was widely reported in The Netherlands [233,234,235,236]. Other cases of DFNA15 were observed in the Republic of Korea [185,237,238], Brazil [239,240], Japan [188,241], and Taiwan [242]. HL is post-lingual (onset varies between the second and sixth decades of life), bilateral, and progressive [11]. It is characterized by high intrafamilial variability and tends to progress to the severe-to-profound range. Audiometric configuration can be sloping or flat [11]. HL may also be associated with vestibular dysfunctions, including areflexia [243].

2.7. KCNQ4 Gene

Autosomal dominant non-syndromic sensorineural deafness 2A (DFNA2A) is caused by a heterozygous mutation in the KCNQ4 gene on chromosome 1p34.2 [11].
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 [244]. Autosomal dominant HL due to KCNQ4 mutations was reported in Indonesian [245], American [246,247,248,249,250], Japanese [251,252,253,254], Taiwanese [255,256,257], Canadian [22], Brazilian [258], Pakistani [259], Iranian [260], Chinese [261,262,263,264], and Korean [265,266,267,268] families. In Europe, DFNA2A was observed in French [247,269], Dutch [247,252,270,271,272,273,274], Belgian [247,271], and Spanish [275] 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 [11]. Most patients had associated tinnitus but no vestibular symptoms except in a few cases [254].

2.8. EYA4 Gene

Autosomal dominant non-syndromic sensorineural deafness 10 (DFNA10) is caused by heterozygous mutations in the EYA4 gene on chromosome 6q23 [11]. 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 [276]. DFNA10 was observed in large American [277,278,279,280,281], Australian [38], Indian [223], Korean [282,283,284], Chinese [276,285,286,287,288,289,290], Brazilian [240], and Japanese [39,291] families. In Europe, HL due to mutations in the EYA4 gene were reported in Belgian [278,280,292,293], Norwegian [292], Hungarian [294], Swedish [295], Dutch [296], Italian [297], Slovakian [298], and Spanish [299] 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 [11]. The audiometric configuration of truncating variants tends to be flat, while that of non-truncating variants tends to be sloping [39]. DFNA10 patients are considered the least responsive to cochlear implantation [38].

2.9. 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 (Table 1). 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) (Table 1). 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 (Table 1). Interestingly, DFNA16 (unknown gene) is characterized by fluctuating HL that often benefits from treatment with oral steroids [46]. 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 (Table 1). 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) (Table 1).
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 [18,19]; conversely, DFNA6/14/38 is due to mutations in the WFS1 gene on chromosome 4p16 and does not progress to profound HL [33]. 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) (Table 1). 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) (Table 1).

2.10. 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 [7]. 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 [7]. 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 [139,300,301,302,303]. 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 [302].
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 [303].

2.11. 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 [12]. 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 [304]. 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 [305].
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 [306].
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 [307]. 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 [308].

3. Conclusions

Patients diagnosed with autosomal dominant non-syndromic HL typically have a parent affected by HL, although de novo mutations should be considered in the case of negative family history. Overall, autosomal dominant non-syndromic HL tends to be bilateral, post-lingual in onset, high-frequency, progressive, and variable in severity. However, congenital, low-frequency, and stable forms of HL are also possible. A long and accurate audiological follow-up is of paramount importance to early identify hearing threshold deterioration and ensure prompt treatment with hearing aids or cochlear implants according to the degree of HL.
Despite the importance of the major findings, the study has many limitations, including that it does not show the mutations described in each gene and whether there are “hot spots” mutations or domains in which these mutations are localized.

Author Contributions

Conceptualization, M.A. and A.M.; methodology, M.A. and A.M.; data curation, M.A.; writing—original draft preparation, M.A.; writing—review and editing, G.C., L.P. and A.M.; visualization, D.Z.; supervision, I.L.M., L.M., S.F., P.D.M., S.C., J.R.L., G.I. and F.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. World Health Organization (WHO). Deafness and Hearing Loss. 2023. Available online: https://www.who.int/news-room/fact-sheets/detail/deafness-and-hearing-loss (accessed on 25 March 2023).
  2. Centers for Disease Control and Prevention (CDC). Types of Hearing Loss. 2022. Available online: https://www.cdc.gov/ncbddd/hearingloss/types.html (accessed on 25 March 2023).
  3. Aldè, M.; Di Berardino, F.; Ambrosetti, U.; Barozzi, S.; Piatti, G.; Consonni, D.; Zanetti, D.; Pignataro, L.; Cantarella, G. Hearing outcomes in preterm infants with confirmed hearing loss. Int. J. Pediatr. Otorhinolaryngol. 2022, 161, 111262. [Google Scholar] [CrossRef] [PubMed]
  4. Korver, A.M.H.; Smith, R.J.H.; Van Camp, G.; Schleiss, M.R.; Bitner-Glindzicz, M.A.K.; Lustig, L.R.; Usami, S.-I.; Boudewyns, A.N. Congenital hearing loss. Nat. Rev. Dis. Primers. 2017, 3, 16094. [Google Scholar] [CrossRef]
  5. Joint Committee on Infant Hearing. Year 2019 position statement: Principles and Guidelines for Early Hearing Detection and Intervention Programs. J. Early Hear. Detect. Interv. 2019, 4, 1–44. [Google Scholar] [CrossRef]
  6. Aldè, M.; Caputo, E.; Di Berardino, F.; Ambrosetti, U.; Barozzi, S.; Piatti, G.; Zanetti, D.; Pignataro, L.; Cantarella, G. Hearing outcomes in children with congenital cytomegalovirus infection: From management controversies to lack of parents’ knowledge. Int. J. Pediatr. Otorhinolaryngol. 2023, 164, 111420. [Google Scholar] [CrossRef]
  7. 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: https://www.ncbi.nlm.nih.gov/books/NBK1434/ (accessed on 6 May 2023).
  8. Aldè, M.; Di Berardino, F.; Marchisio, P.; Cantarella, G.; Iacona, E.; Ambrosetti, U.; Zanetti, D. Sudden sensorineural hearing loss in children with dual positivity of serum anti-EBV IgM and anti-CMV IgM antibodies: A preliminary study. Minerva Pediatr. 2021. [Google Scholar] [CrossRef] [PubMed]
  9. Spedicati, B.; Santin, A.; Nardone, G.G.; Rubinato, E.; Lenarduzzi, S.; Graziano, C.; Garavelli, L.; Miccoli, S.; Bigoni, S.; Morgan, A.; et al. The Enigmatic Genetic Landscape of Hereditary Hearing Loss: A Multistep Diagnostic Strategy in the Italian Population. Biomedicines 2023, 11, 703. [Google Scholar] [CrossRef]
  10. Sheffield, A.M.; Smith, R.J.H. The Epidemiology of Deafness. Cold Spring Harb. Perspect. Med. 2018, 9, a033258. [Google Scholar] [CrossRef]
  11. Van Camp, G.; Smith, R.J.H. Hereditary Hearing Loss Homepage. Available online: https://hereditaryhearingloss.org (accessed on 25 March 2023).
  12. 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. [Google Scholar] [CrossRef]
  13. Almazroua, A.M.; Alsughayer, L.; Ababtain, R.; Al-Shawi, Y.; Hagr, A.A. The association between consanguineous marriage and offspring with congenital hearing loss. Ann. Saudi Med. 2020, 40, 456–461. [Google Scholar] [CrossRef]
  14. Wang, Q.; Xue, Y.; Zhang, Y.; Long, Q.; Yang, F.; Turner, D.J.; Fitzgerald, T.; Ng, B.L.; Zhao, Y.; Chen, Y.; et al. Genetic basis of Y-linked hearing impairment. Am. J. Hum. Genet. 2013, 92, 301–306. [Google Scholar] [CrossRef]
  15. Morgan, A.; Gasparini, P.; Girotto, G. Molecular testing for the study of non-syndromic hearing loss. Hear. Balance Commun. 2020, 18, 270–277. [Google Scholar] [CrossRef]
  16. Lewis, R.G.; Simpson, B. Genetics, Autosomal Dominant. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2022. Available online: https://www.ncbi.nlm.nih.gov/books/NBK557512/ (accessed on 6 May 2023).
  17. 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. [Google Scholar] [CrossRef]
  18. 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. [Google Scholar] [CrossRef] [PubMed]
  19. 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. [Google Scholar] [CrossRef] [PubMed]
  20. Wu, K.; Wang, H.; Guan, J.; Lan, L.; Zhao, C.; Zhang, M.; Wang, D.; Wang, Q. A novel variant in diaphanous homolog 1 (DIAPH1) as the cause of auditory neuropathy in a Chinese family. Int. J. Pediatr. Otorhinolaryngol. 2020, 133, 109947. [Google Scholar] [CrossRef]
  21. Nie, L. KCNQ4 mutations associated with nonsyndromic progressive sensorineural hearing loss. Curr. Opin. Otolaryngol. Head Neck Surg. 2008, 16, 441–444. [Google Scholar] [CrossRef]
  22. 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. [Google Scholar] [CrossRef]
  23. Xia, J.-H.; Liu, C.; Tang, B.-S.; Pan, Q.; Huang, L.; Dai, H.-P.; Zhang, B.-R.; Xie, W.; Hu, D.-X.; Zheng, D.; et al. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat. Genet. 1998, 20, 370–373, Correction in Nat. Genet. 1999, 21, 241. [Google Scholar] [CrossRef]
  24. Mhatre, A.N.; Weld, E.; Lalwani, A.K. Mutation analysis of Connexin 31 (GJB3) in sporadic non-syndromic hearing impairment. Clin. Genet. 2003, 63, 154–159. [Google Scholar] [CrossRef]
  25. Gao, X.; Yuan, Y.Y.; Lin, Q.F.; Xu, J.-C.; Wang, W.-Q.; Qiao, Y.-H.; Kang, D.-Y.; Bai, D.; Xin, F.; Huang, S.-S.; et al. Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss. J. Med. Genet. 2018, 55, 298–306. [Google Scholar] [CrossRef]
  26. Denoyelle, F.; Lina-Granade, G.; Plauchu, H.; Bruzzone, R.; Chaïb, H.; Lévi-Acobas, F.; Weil, D.; Petit, C. Connexin 26 gene linked to a dominant deafness. Nature 1998, 393, 319–320. [Google Scholar] [CrossRef] [PubMed]
  27. Grifa, A.; Wagner, C.A.; D’Ambrosio, L.; Melchionda, S.; Bernardi, F.; Lopez-Bigas, N.; Rabionet, R.; Arbones, M.; Della Monica, M.; Estivill, X.; et al. Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat. Genet. 1999, 23, 16–18. [Google Scholar] [CrossRef] [PubMed]
  28. Kim, B.J.; Kim, A.R.; Han, J.H.; Lee, C.; Oh, D.Y.; Choi, B.Y. Discovery of MYH14 as an important and unique deafness gene causing prelingually severe autosomal dominant nonsyndromic hearing loss. J. Gene Med. 2017, 19, e2950. [Google Scholar] [CrossRef] [PubMed]
  29. Hiramatsu, K.; Nishio, S.-y.; Kitajiri, S.-i.; Kitano, T.; Moteki, H.; Usami, S.-i.; on behalf of the Deafness Gene Study Consortium. Prevalence and Clinical Characteristics of Hearing Loss Caused by MYH14 Variants. Genes 2021, 12, 1623. [Google Scholar] [CrossRef]
  30. Wang, H.; Wang, X.; He, C.; Li, H.; Qing, J.; Grati, M.; Hu, Z.; Li, J.; Hu, Y.; Xia, K.; et al. Exome sequencing identifies a novel CEACAM16 mutation associated with autosomal dominant nonsyndromic hearing loss DFNA4B in a Chinese family. J. Hum. Genet. 2015, 60, 119–126. [Google Scholar] [CrossRef]
  31. Van Laer, L.; Huizing, E.H.; Verstreken, M.; van Zuijlen, D.; Wauters, J.G.; Bossuyt, P.J.; Van de Heyning, P.; McGuirt, W.T.; Smith, R.J.; Willems, P.J.; et al. Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat. Genet. 1998, 20, 194–197. [Google Scholar] [CrossRef]
  32. Zhang, Z.; Zhang, Y.; Xia, S.; Kong, Q.; Li, S.; Liu, X.; Junqueira, C.; Meza-Sosa, K.F.; Mok, T.M.Y.; Ansara, J.; et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 2020, 579, 415–420. [Google Scholar] [CrossRef]
  33. 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. [Google Scholar] [CrossRef]
  34. Wesdorp, M.; Gans, P.A.M.D.K.; Schraders, M.; Oostrik, J.; Huynen, M.A.; Venselaar, H.; Beynon, A.J.; van Gaalen, J.; Piai, V.; Voermans, N.; et al. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction. Hum. Genet. 2018, 137, 389–400. [Google Scholar] [CrossRef]
  35. 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. [Google Scholar] [CrossRef]
  36. Robertson, N.G.; Lu, L.; Heller, S.; Merchant, S.N.; Eavey, R.D.; McKenna, M.; Nadol, J.B.; Miyamoto, R.T.; Linthicum, F.H.; Neto, J.F.L.; et al. Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nat. Genet. 1998, 20, 299–303. [Google Scholar] [CrossRef]
  37. Verdoodt, D.; Van Camp, G.; Ponsaerts, P.; Van Rompaey, V. On the pathophysiology of DFNA9: Effect of pathogenic variants in the COCH gene on inner ear functioning in human and transgenic mice. Hear. Res. 2021, 401, 108162. [Google Scholar] [CrossRef]
  38. 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. [Google Scholar] [CrossRef]
  39. 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. [Google Scholar] [CrossRef]
  40. Tamagawa, Y.; Ishikawa, K.; Ishikawa, K.; Ishida, T.; Kitamura, K.; Makino, S.; Tsuru, T.; Ichimura, K. Phenotype of DFNA11: A nonsyndromic hearing loss caused by a myosin VIIA mutation. Laryngoscope 2002, 112, 292–297. [Google Scholar] [CrossRef] [PubMed]
  41. Sun, Y.; Chen, J.; Sun, H.; Cheng, J.; Li, J.; Lu, Y.; Lu, Y.; Jin, Z.; Zhu, Y.; Ouyang, X.; et al. Novel missense mutations in MYO7A underlying postlingual high- or low-frequency non-syndromic hearing impairment in two large families from China. J. Hum. Genet. 2011, 56, 64–70. [Google Scholar] [CrossRef] [PubMed]
  42. McGuirt, W.T.; Prasad, S.D.; Griffith, A.J.; Kunst, H.P.; Green, G.E.; Shpargel, K.; Runge, C.; Huybrechts, C.; Mueller, R.F.; Lynch, E.; et al. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat. Genet. 1999, 23, 413–419. [Google Scholar] [CrossRef]
  43. De Leenheer, E.M.R.; Kunst, H.P.M.; McGuirt, W.T.; Prasad, S.D.; Brown, M.R.; Huygen, P.L.M.; Smith, R.J.H.; Cremers, C.W.R.J. Autosomal dominant inherited hearing impairment caused by a missense mutation in COL11A2 (DFNA13). Arch. Otolaryngol. Head Neck Surg. 2001, 127, 13–17. [Google Scholar] [CrossRef] [PubMed]
  44. 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. [Google Scholar] [CrossRef]
  45. 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. [Google Scholar] [CrossRef]
  46. 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. [Google Scholar] [CrossRef]
  47. Lalwani, A.K.; Goldstein, J.A.; Kelley, M.J.; Luxford, W.; Castelein, C.M.; Mhatre, A.N. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am. J. Hum. Genet. 2000, 67, 1121–1128. [Google Scholar] [CrossRef]
  48. Bönsch, D.; Scheer, P.; Neumann, C.; Lang-Roth, R.; Seifert, E.; Storch, P.; Weiller, C.; Lamprecht-Dinnesen, A.; Deufel, T. A novel locus for autosomal dominant, non-syndromic hearing impairment (DFNA18) maps to chromosome 3q22 immediately adjacent to the DM2 locus. Eur. J. Hum. Genet. 2001, 9, 165–170. [Google Scholar] [CrossRef] [PubMed]
  49. Green, G.E.; Whitehead, S.; Van Camp, G.; Smith, R.J. Identification of a new locus-DFNA19-for dominant hearing impairment. In Proceedings of the Molecular Biology of Hearing and Deafness Meeting, Bathesda, MD, USA, 8 October 1998. [Google Scholar]
  50. 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. [Google Scholar] [CrossRef] [PubMed]
  51. 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. [Google Scholar] [CrossRef] [PubMed]
  52. Kunst, H.; Marres, H.; Huygen, P.; Van Duijnhoven, G.; Krebsova, A.; Van Der Velde, S.; Reis, A.; Cremers, F. Non-syndromic autosomal dominant progressive non-specific mid-frequency sensorineural hearing impairment with childhood to late adolescence onset (DFNA21). Clin. Otolaryngol. Allied Sci. 2000, 25, 45–54. [Google Scholar] [CrossRef]
  53. 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. [Google Scholar] [CrossRef]
  54. Salam, A.A.; Häfner, F.M.; Linder, T.E.; Spillmann, T.; Schinzel, A.A.; Leal, S.M. A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred. Am. J. Hum. Genet. 2000, 66, 1984–1988. [Google Scholar] [CrossRef]
  55. Häfner, F.M.; Salam, A.A.; Linder, T.E.; Balmer, D.; Baumer, A.; Schinzel, A.A.; Spillmann, T.; Leal, S.M. A novel locus (DFNA24) for prelingual nonprogressive autosomal dominant nonsyndromic hearing loss maps to 4q35-qter in a large Swiss German kindred. Am. J. Hum. Genet. 2000, 66, 1437–1442. [Google Scholar] [CrossRef]
  56. Greene, C.C.; McMillan, P.M.; Barker, S.E.; Kurnool, P.; Lomax, M.I.; Burmeister, M.; Lesperance, M.M. DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24. Am. J. Hum. Genet. 2001, 68, 254–260. [Google Scholar] [CrossRef]
  57. Peters, L.; Fridell, R.; Boger, E.; Agustin, T.S.; Madeo, A.; Griffith, A.; Friedman, T.; Morell, R.; Morell, R. A locus for autosomal dominant progressive non-syndromic hearing loss, DFNA27, is on chromosome 4q12-13. Clin. Genet. 2008, 73, 367–372. [Google Scholar] [CrossRef] [PubMed]
  58. Nakano, Y.; Kelly, M.C.; Rehman, A.U.; Boger, E.T.; Morell, R.J.; Kelley, M.W.; Friedman, T.B.; Bánfi, B. Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness. Cell 2018, 174, 536–548.e21. [Google Scholar] [CrossRef] [PubMed]
  59. Vona, B.; Nanda, I.; Neuner, C.; Müller, T.; Haaf, T. Confirmation of GRHL2 as the gene for the DFNA28 locus. Am. J. Med. Genet. A 2013, 161 Pt A, 2060–2065. [Google Scholar] [CrossRef] [PubMed]
  60. Mangino, M.; Flex, E.; Capon, F.; Sangiuolo, F.; Carraro, E.; Gualandi, F.; Mazzoli, M.; Martini, A.; Novelli, G.; Dallapiccola, B. Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26. Eur. J. Hum. Genet. 2001, 9, 667–671. [Google Scholar] [CrossRef]
  61. Snoeckx, R.L.; Kremer, H.; Ensink, R.J.H.; Flothmann, K.; De Brouwer, A.; Smith, R.; Cremers, C.W.R.J.; Van Camp, G. A novel locus for autosomal dominant non-syndromic hearing loss, DFNA31, maps to chromosome 6p21.3. J. Med. Genet. 2004, 41, 11–13. [Google Scholar] [CrossRef]
  62. Li, X.C.; Saal, H.M.; Friedman, T.B.; Friedman, R.A. A gene for autosomal dominant nonsyndromic sensorineural hearing loss (DFNA32) maps to 11p. Am. J. Hum. Genet. 2000, 67 (Suppl. S2), 314. [Google Scholar]
  63. Bönsch, D.; Schmidt, C.M.; Scheer, P.; Bohlender, J.E.; Neumann, C.; Zehnhoff-Dinnesen, A.A.; Deufel, T. Ein neuer Genort für eine autosomal-dominante, nichtsyndromale Schwerhörigkeit (DFNA33) liegt auf Chromosom 13q34-qter [A new gene locus for an autosomal-dominant non-syndromic hearing impairment (DFNA 33) is situated on chromosome 13q34-qter]. HNO 2009, 57, 371–376. [Google Scholar] [CrossRef]
  64. Nakanishi, H.; Kawashima, Y.; Kurima, K.; Muskett, J.A.; Kim, H.J.; Brewer, C.C.; Griffith, A.J. Gradual Symmetric Progression of DFNA34 Hearing Loss Caused by an NLRP3 Mutation and Cochlear Autoinflammation. Otol. Neurotol. 2018, 39, e181–e185. [Google Scholar] [CrossRef]
  65. Makishima, T.; Kurima, K.; Brewer, C.C.; Griffith, A.J. Early onset and rapid progression of dominant nonsyndromic DFNA36 hearing loss. Otol. Neurotol. 2004, 25, 714–719. [Google Scholar] [CrossRef]
  66. Nishio, S.Y.; Usami, S.I. Prevalence and clinical features of autosomal dominant and recessive TMC1-associated hearing loss. Hum. Genet. 2022, 141, 929–937. [Google Scholar] [CrossRef]
  67. Booth, K.T.; Askew, J.W.; Talebizadeh, Z.; Huygen, P.L.M.; Eudy, J.; Kenyon, J.; Hoover, D.; Hildebrand, M.S.; Smith, K.R.; Bahlo, M.; et al. Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37. Genet. Med. 2019, 21, 948–954. [Google Scholar] [CrossRef] [PubMed]
  68. Xiao, S.; Yu, C.; Chou, X.; Yuan, W.; Wang, Y.; Bu, L.; Fu, G.; Qian, M.; Yang, J.; Shi, Y.; et al. Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP. Nat. Genet. 2001, 27, 201–204, Correction in Nat. Genet. 2001, 27, 345. [Google Scholar] [CrossRef] [PubMed]
  69. Abe, S.; Katagiri, T.; Saito-Hisaminato, A.; Usami, S.-I.; Inoue, Y.; Tsunoda, T.; Nakamura, Y. Identification of CRYM as a candidate responsible for nonsyndromic deafness, through cDNA microarray analysis of human cochlear and vestibular tissues. Am. J. Hum. Genet. 2003, 72, 73–82. [Google Scholar] [CrossRef]
  70. Yan, D.; Zhu, Y.; Walsh, T.; Xie, D.; Yuan, H.; Sirmaci, A.; Fujikawa, T.; Wong, A.C.Y.; Loh, T.L.; Du, L.; et al. Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proc. Natl. Acad. Sci. USA 2013, 110, 2228–2233. [Google Scholar] [CrossRef] [PubMed]
  71. Liu, X.Z.; Yan, D.; Mittal, R.; Ballard, M.E.; Feng, Y. Progressive Dominant Hearing Loss (Autosomal Dominant Deafness-41) and P2RX2 Gene Mutations: A Phenotype-Genotype Study. Laryngoscope 2020, 130, 1657–1663. [Google Scholar] [CrossRef]
  72. Xia, J.; Deng, H.; Feng, Y.; Zhang, H.; Pan, Q.; Dai, H.; Long, Z.; Tang, B.; Chen, Y.; Zhang, R.; et al. A novel locus for autosomal dominant nonsyndromic hearing loss identified at 5q31.1-32 in a Chinese pedigree. J. Hum. Genet. 2002, 47, 635–640. [Google Scholar] [CrossRef]
  73. Qiong, P.; Hu, Z.; Feng, Y.; Pan, Q.; Xia, J.; Xia, K. Bioinformatics analysis of candidate genes and mutations in a congenital sensorineural hearing loss pedigree: Detection of 52 genes for the DFNA52 locus. J. Laryngol. Otol. 2008, 122, 1029–1036. [Google Scholar] [CrossRef]
  74. Flex, E.; Mangino, M.; Mazzoli, M.; Martini, A.; Migliosi, V.; Colosimo, A.; Mingarelli, R.; Pizzuti, A.; Dallapiccola, B. Mapping of a new autosomal dominant non-syndromic hearing loss locus (DFNA43) to chromosome 2p12. J. Med. Genet. 2003, 40, 278–281. [Google Scholar] [CrossRef]
  75. Modamio-Høybjør, S.; Moreno-Pelayo, M.; Mencía, A.; del Castillo, I.; Chardenoux, S.; Armenta, D.; Lathrop, M.; Petit, C.; Moreno, F. A novel locus for autosomal dominant nonsyndromic hearing loss (DFNA44) maps to chromosome 3q28-29. Hum. Genet. 2003, 112, 24–28. [Google Scholar] [CrossRef]
  76. D’Adamo, P.; Donaudy, F.; D’Eustacchio, A.; Di Iorio, E.; Melchionda, S.; Gasparini, P. A new locus (DFNA47) for autosomal dominant non-syndromic inherited hearing loss maps to 9p21-22 in a large Italian family. Eur. J. Hum. Genet. 2003, 11, 121–124. [Google Scholar] [CrossRef]
  77. Donaudy, F.; Ferrara, A.; Esposito, L.; Hertzano, R.; Ben-David, O.; Bell, R.E.; Melchionda, S.; Zelante, L.; Avraham, K.B.; Gasparini, P. Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. Am. J. Hum. Genet. 2003, 72, 1571–1577. [Google Scholar] [CrossRef] [PubMed]
  78. D’Adamo, P.; Pinna, M.; Capobianco, S.; Cesarani, A.; D’Eustacchio, A.; Fogu, P.; Carella, M.; Seri, M.; Gasparini, P. A novel autosomal dominant non-syndromic deafness locus (DFNA48) maps to 12q13-q14 in a large Italian family. Hum. Genet. 2003, 112, 319–320. [Google Scholar] [CrossRef] [PubMed]
  79. Moreno-Pelayo, M.A.; Modamio-Høybjør, S.; Mencía, A.; del Castillo, I.; Chardenoux, S.; Fernandez-Burriel, M.; Lathrop, M.; Petit, C.; Moreno, F. DFNA49, a novel locus for autosomal dominant non-syndromic hearing loss, maps proximal to DFNA7/DFNM1 region on chromosome 1q21-q23. J. Med. Genet. 2003, 40, 832–836, Correction in J. Med. Genet. 2004, 41, 98. [Google Scholar] [CrossRef] [PubMed]
  80. Modamio-Hoybjor, S.; Moreno-Pelayo, M.A.; Mencía, A.; del Castillo, I.; Chardenoux, S.; Morais, D.; Lathrop, M.; Petit, C.; Moreno, F. A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA50, maps to chromosome 7q32 between the DFNB17 and DFNB13 deafness loci. J. Med. Genet. 2004, 41, e14. [Google Scholar] [CrossRef] [PubMed]
  81. Mencía, Á.; Modamio-Høybjør, S.; Redshaw, N.; Morín, M.; Mayo-Merino, F.; Olavarrieta, L.; Aguirre, L.A.; del Castillo, I.; Steel, K.P.; Dalmay, T.; et al. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat. Genet. 2009, 41, 609–613. [Google Scholar] [CrossRef]
  82. Walsh, T.; Pierce, S.B.; Lenz, D.R.; Brownstein, Z.; Dagan-Rosenfeld, O.; Shahin, H.; Roeb, W.; McCarthy, S.; Nord, A.; Gordon, C.R.; et al. Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51. Am. J. Hum. Genet. 2010, 87, 101–109. [Google Scholar] [CrossRef]
  83. Yan, D.; Ke, X.; Blanton, S.H.; Ouyang, X.M.; Pandya, A.; Du, L.L.; Nance, W.E.; Liu, X.Z. A novel locus for autosomal dominant non-syndromic deafness, DFNA53, maps to chromosome 14q11.2-q12. J. Med. Genet. 2006, 43, 170–174. [Google Scholar] [CrossRef]
  84. Gürtler, N.; Kim, Y.; Mhatre, A.; Schlegel, C.; Mathis, A.; Lalwani, A.K. DFNA54, a third locus for low-frequency hearing loss. J. Mol. Med. 2004, 82, 775–780. [Google Scholar] [CrossRef]
  85. Liu, Q.; Han, D.Y.; Ji, Y.B.; Li, J.Q.; Lan, L.; Zhao, C.; Wang, Q.J. Analyzing GRIA3 gene mutations located in AUNX1 locus in a Chinese pedigree with auditory neuropathy. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2010, 26, 376–378. [Google Scholar]
  86. Zhao, Y.; Zhao, F.; Zong, L.; Zhang, P.; Guan, L.; Zhang, J.; Wang, D.; Wang, J.; Chai, W.; Lan, L.; et al. Exome sequencing and linkage analysis identified tenascin-C (TNC) as a novel causative gene in nonsyndromic hearing loss. PLoS ONE 2013, 8, e69549. [Google Scholar] [CrossRef]
  87. Bönsch, D.; Schmidt, C.; Scheer, P.; Bohlender, J.E.; Neumann, C.; Zehnhoff-Dinnesen, A.A.; Deufel, T. Ein neuer Genort für eine autosomal dominante, nichtsyndromale Hörstörung (DFNA57) kartiert auf Chromosom 19p13.2 und überlappt mit DFNB15 [A new locus for an autosomal dominant, non-syndromic hearing impairment (DFNA57) located on chromosome 19p13.2 and overlapping with DFNB15]. HNO 2008, 56, 177–182. [Google Scholar] [CrossRef] [PubMed]
  88. Lezirovitz, K.; Vieira-Silva, G.A.; Batissoco, A.C.; Levy, D.; Kitajima, J.P.; Trouillet, A.; Ouyang, E.; Zebarjadi, N.; Sampaio-Silva, J.; Pedroso-Campos, V.; et al. A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58. Hum. Mol. Genet. 2020, 29, 1520–1536. [Google Scholar] [CrossRef] [PubMed]
  89. Chatterjee, A.; Jalvi, R.; Pandey, N.; Rangasayee, R.; Anand, A. A novel locus DFNA59 for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14.2-q12.3. Hum. Genet. 2009, 124, 669–675. [Google Scholar] [CrossRef]
  90. Ouyang, X.M.; Yan, D.; Du, L.L.; Chen, Z.Y.; Liu, X.Z. A Novel Locus for Autosomal Dominant Non-Syndromic Hearing Loss, Maps to Chromosome 2q21.3-q24. In Proceedings of the Midwinter Meeting for the Association for Research in Otolaryngology, Denver, CO, USA, 10–15 February 2007; Volume 30, p. 68. [Google Scholar]
  91. HGNC. CNR2. Available online: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:2160 (accessed on 15 July 2020).
  92. Cheng, J.; Zhu, Y.; He, S.; Lu, Y.; Chen, J.; Han, B.; Petrillo, M.; Wrzeszczynski, K.O.; Yang, S.; Dai, P.; et al. Functional Mutation of SMAC/DIABLO, Encoding a Mitochondrial Proapoptotic Protein, Causes Human Progressive Hearing Loss DFNA64. Am. J. Hum. Genet. 2011, 89, 56–66. [Google Scholar] [CrossRef]
  93. Azaiez, H.; Booth, K.T.; Bu, F.; Huygen, P.; Shibata, S.B.; Shearer, A.E.; Kolbe, D.; Meyer, N.; Black-Ziegelbein, E.A.; Smith, R.J.H. TBC1D24Mutation Causes Autosomal-Dominant Nonsyndromic Hearing Loss. Hum. Mutat. 2014, 35, 819–823. [Google Scholar] [CrossRef]
  94. Oziębło, D.; Leja, M.L.; Lazniewski, M.; Sarosiak, A.; Tacikowska, G.; Kochanek, K.; Plewczynski, D.; Skarżyński, H.; Ołdak, M. TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss. Sci. Rep. 2021, 11, 10300. [Google Scholar] [CrossRef] [PubMed]
  95. Nyegaard, M.; Rendtorff, N.D.; Nielsen, M.S.; Corydon, T.J.; Demontis, D.; Starnawska, A.; Hedemand, A.; Buniello, A.; Niola, F.; Overgaard, M.T.; et al. A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment. PLOS Genet. 2015, 11, e1005386. [Google Scholar] [CrossRef] [PubMed]
  96. Thoenes, M.; Zimmermann, U.; Ebermann, I.; Ptok, M.; A Lewis, M.; Thiele, H.; Morlot, S.; Hess, M.M.; Gal, A.; Eisenberger, T.; et al. OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67). Orphanet J. Rare Dis. 2015, 10, 15. [Google Scholar] [CrossRef] [PubMed]
  97. Lu, X.; Wang, Q.; Gu, H.; Zhang, X.; Qi, Y.; Liu, Y. Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness. Clin. Genet. 2018, 94, 419–428. [Google Scholar] [CrossRef]
  98. Lachgar, M.; Morín, M.; Villamar, M.; del Castillo, I.; Moreno-Pelayo, M. A Novel Truncating Mutation in HOMER2 Causes Nonsyndromic Progressive DFNA68 Hearing Loss in a Spanish Family. Genes 2021, 12, 411. [Google Scholar] [CrossRef]
  99. Seco, C.Z.; de Castro, L.S.; van Nierop, J.W.; Morín, M.; Jhangiani, S.; Verver, E.J.; Schraders, M.; Maiwald, N.; Wesdorp, M.; Venselaar, H.; et al. Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2. Am. J. Hum. Genet. 2015, 97, 647–660. [Google Scholar] [CrossRef]
  100. Gao, J.; Wang, Q.; Dong, C.; Chen, S.; Qi, Y.; Liu, Y. Whole Exome Sequencing Identified MCM2 as a Novel Causative Gene for Autosomal Dominant Nonsyndromic Deafness in a Chinese Family. PLoS ONE 2015, 10, e0133522. [Google Scholar] [CrossRef] [PubMed]
  101. Zeraatpisheh, Z.; Sichani, A.S.; Kamal, N.; Khamirani, H.J.; Zoghi, S.; Ehsani, E.; Mohammadi, S.; Tabei, S.S.; Dastgheib, S.A.; Dianatpour, M. MCM2 mutation causes autosomal dominant nonsyndromic hearing loss (DFNA70): Novel variant in the second family. J. Genet. 2022, 101, 24. [Google Scholar] [CrossRef]
  102. Chen, D.-Y.; Liu, X.-F.; Lin, X.-J.; Zhang, D.; Chai, Y.-C.; Yu, D.-H.; Sun, C.-L.; Wang, X.-L.; Zhu, W.-D.; Chen, Y.; et al. A dominant variant in DMXL2 is linked to nonsyndromic hearing loss. Anesthesia Analg. 2017, 19, 553–558. [Google Scholar] [CrossRef]
  103. Wonkam-Tingang, E.; Schrauwen, I.; Esoh, K.K.; Bharadwaj, T.; Nouel-Saied, L.M.; Acharya, A.; Nasir, A.; Leal, S.M.; Wonkam, A. A novel variant in DMXL2 gene is associated with autosomal dominant non-syndromic hearing impairment (DFNA71) in a Cameroonian family. Exp. Biol. Med. 2021, 246, 1524–1532, Correction in Exp. Biol. Med. 2021, 246, NP5. [Google Scholar] [CrossRef] [PubMed]
  104. Ma, Z.; Xia, W.; Liu, F.; Ma, J.; Sun, S.; Zhang, J.; Jiang, N.; Wang, X.; Hu, J.; Ma, D. SLC44A4mutation causes autosomal dominant hereditary postlingual non-syndromic mid-frequency hearing loss. Hum. Mol. Genet. 2016, 26, 383–394, Correction in Hum. Mol. Genet. 2017, 26, 3234. [Google Scholar] [CrossRef] [PubMed]
  105. Eisenberger, T.; Di Donato, N.; Decker, C.; Vedove, A.D.; Neuhaus, C.; Nürnberg, G.; Toliat, M.; Nürnberg, P.; Mürbe, D.; Bolz, H.J. A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73. Anesthesia Analg. 2017, 20, 614–621. [Google Scholar] [CrossRef]
  106. Oziębło, D.; Sarosiak, A.; Leja, M.L.; Budde, B.S.; Tacikowska, G.; Di Donato, N.; Bolz, H.J.; Nürnberg, P.; Skarżyński, H.; Ołdak, M. First confirmatory study on PTPRQ as an autosomal dominant non-syndromic hearing loss gene. J. Transl. Med. 2019, 17, 351–357. [Google Scholar] [CrossRef]
  107. Wang, L.; Feng, Y.; Yan, D.; Qin, L.; Grati, M.; Mittal, R.; Li, T.; Sundhari, A.K.; Liu, Y.; Chapagain, P.; et al. A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss. Hum. Genet. 2018, 137, 437–446. [Google Scholar] [CrossRef]
  108. Xia, W.; Hu, J.; Ma, J.; Huang, J.; Wang, X.; Jiang, N.; Zhang, J.; Ma, Z.; Ma, D. Novel TRRAP mutation causes autosomal dominant non-syndromic hearing loss. Clin. Genet. 2019, 96, 300–308. [Google Scholar] [CrossRef]
  109. Morgan, A.; Koboldt, D.C.; Barrie, E.S.; Crist, E.R.; García, G.G.; Mezzavilla, M.; Faletra, F.; Mosher, T.M.; Wilson, R.K.; Blanchet, C.; et al. Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss. Hum. Mutat. 2019, 40, 2286–2295. [Google Scholar] [CrossRef] [PubMed]
  110. Xu, L.; Wang, X.; Li, J.; Chen, L.; Wang, H.; Xu, S.; Zhang, Y.; Li, W.; Yao, P.; Tan, M.; et al. A novel PLS1 c.981+ 1G >A variant causes autosomal-dominant hereditary hearing loss in a family. Clin. Genet. 2023, 103, 413–423. [Google Scholar] [CrossRef] [PubMed]
  111. Li, M.; Mei, L.; He, C.; Chen, H.; Cai, X.; Liu, Y.; Tian, R.; Tian, Q.; Song, J.; Jiang, L.; et al. Extrusion pump ABCC1 was first linked with nonsyndromic hearing loss in humans by stepwise genetic analysis. Anesthesia Analg. 2019, 21, 2744–2754. [Google Scholar] [CrossRef] [PubMed]
  112. Mutai, H.; Wasano, K.; Momozawa, Y.; Kamatani, Y.; Miya, F.; Masuda, S.; Morimoto, N.; Nara, K.; Takahashi, S.; Tsunoda, T.; et al. Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans. PLOS Genet. 2020, 16, e1008643. [Google Scholar] [CrossRef] [PubMed]
  113. Adadey, S.M.; Schrauwen, I.; Aboagye, E.T.; Bharadwaj, T.; Esoh, K.K.; Basit, S.; Acharya, A.; Nouel-Saied, L.M.; Liaqat, K.; Wonkam-Tingang, E.; et al. Further confirmation of the association of SLC12A2 with non-syndromic autosomal-dominant hearing impairment. J. Hum. Genet. 2021, 66, 1169–1175. [Google Scholar] [CrossRef]
  114. Lu, X.; Zhang, Y.; Chen, L.; Wang, Q.; Zeng, Z.; Dong, C.; Qi, Y.; Liu, Y. Whole exome sequencing identifies SCD5 as a novel causative gene for autosomal dominant nonsyndromic deafness. Eur. J. Med. Genet. 2020, 63, 103855. [Google Scholar] [CrossRef]
  115. Schrauwen, I.; Liaqat, K.; Schatteman, I.; Bharadwaj, T.; Nasir, A.; Acharya, A.; Ahmad, W.; Van Camp, G.; Leal, S.M. Autosomal Dominantly Inherited GREB1L Variants in Individuals with Profound Sensorineural Hearing Impairment. Genes 2020, 11, 687. [Google Scholar] [CrossRef]
  116. Adadey, S.M.; Aboagye, E.T.; Esoh, K.; Acharya, A.; Bharadwaj, T.; Lin, N.S.; Amenga-Etego, L.; Awandare, G.A.; Schrauwen, I.; Leal, S.M.; et al. A novel autosomal dominant GREB1L variant associated with non-syndromic hearing impairment in Ghana. BMC Med. Genom. 2022, 15, 237. [Google Scholar] [CrossRef]
  117. Li, W.; Sun, J.; Ling, J.; Li, J.; He, C.; Liu, Y.; Chen, H.; Men, M.; Niu, Z.; Deng, Y.; et al. ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss. Hum. Genet. 2018, 137, 329–342. [Google Scholar] [CrossRef]
  118. 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. [Google Scholar] [CrossRef]
  119. Cui, L.; Zheng, J.; Zhao, Q.; Chen, J.-R.; Liu, H.; Peng, G.; Wu, Y.; Chen, C.; He, Q.; Shi, H.; et al. Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss. J. Clin. Investig. 2020, 5, 136046. [Google Scholar] [CrossRef] [PubMed]
  120. Pater, J.A.; Penney, C.; O’rielly, D.D.; Griffin, A.; Kamal, L.; Brownstein, Z.; Vona, B.; Vinkler, C.; Shohat, M.; Barel, O.; et al. Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene. Hum. Genet. 2022, 141, 431–444. [Google Scholar] [CrossRef] [PubMed]
  121. Bassani, S.; van Beelen, E.; Rossel, M.; Voisin, N.; Morgan, A.; Arribat, Y.; Chatron, N.; Chrast, J.; Cocca, M.; Delprat, B.; et al. Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss. Hum. Mol. Genet. 2021, 30, 1785–1796. [Google Scholar] [CrossRef] [PubMed]
  122. Zhang, L.; Gao, Y.; Zhang, R.; Sun, F.; Cheng, C.; Qian, F.; Duan, X.; Wei, G.; Sun, C.; Pang, X.; et al. THOC1 deficiency leads to late-onset nonsyndromic hearing loss through p53-mediated hair cell apoptosis. PLOS Genet. 2020, 16, e1008953. [Google Scholar] [CrossRef] [PubMed]
  123. Su, X.; Feng, Y.; Rahman, S.A.; Wu, S.; Li, G.; Rüschendorf, F.; Zhao, L.; Cui, H.; Liang, J.; Fang, L.; et al. Phosphatidylinositol 4-kinase β mutations cause nonsyndromic sensorineural deafness and inner ear malformation. J. Genet. Genom. 2020, 47, 618–626. [Google Scholar] [CrossRef]
  124. Huang, S.; Ma, L.; Liu, X.; He, C.; Li, J.; Hu, Z.; Jiang, L.; Liu, Y.; Liu, X.; Feng, Y.; et al. A non-coding variant in 5’ untranslated region drove up-regulation of pseudo-kinase EPHA10 and caused non-syndromic hearing loss in humans. Hum. Mol. Genet. 2022, 32, 720–731. [Google Scholar] [CrossRef]
  125. Brownstein, Z.; Gulsuner, S.; Walsh, T.; Martins, F.T.; Taiber, S.; Isakov, O.; Lee, M.K.; Bordeynik-Cohen, M.; Birkan, M.; Chang, W.; et al. Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1. Clin. Genet. 2020, 98, 353–364. [Google Scholar] [CrossRef]
  126. 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. [Google Scholar] [CrossRef]
  127. 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. [Google Scholar] [CrossRef]
  128. 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. [Google Scholar]
  129. 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. [Google Scholar] [CrossRef] [PubMed]
  130. 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. [Google Scholar] [CrossRef] [PubMed]
  131. 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. [Google Scholar] [CrossRef] [PubMed]
  132. 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. [Google Scholar] [CrossRef]
  133. 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. [Google Scholar] [CrossRef]
  134. 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. [Google Scholar] [CrossRef]
  135. 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. [Google Scholar] [CrossRef]
  136. 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. [Google Scholar] [CrossRef]
  137. 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. [Google Scholar] [CrossRef]
  138. 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. [Google Scholar] [CrossRef]
  139. 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. [Google Scholar] [CrossRef] [PubMed]
  140. 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. [Google Scholar] [CrossRef] [PubMed]
  141. 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. [Google Scholar] [CrossRef] [PubMed]
  142. 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. [Google Scholar] [CrossRef]
  143. 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. [Google Scholar] [CrossRef]
  144. 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. [Google Scholar] [CrossRef]
  145. 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. [Google Scholar] [CrossRef]
  146. 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. [Google Scholar] [CrossRef]
  147. 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. [Google Scholar] [CrossRef]
  148. 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. [Google Scholar] [CrossRef]
  149. 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. [Google Scholar] [CrossRef] [PubMed]
  150. 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. [Google Scholar] [CrossRef]
  151. 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. [Google Scholar] [CrossRef]
  152. 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. [Google Scholar] [CrossRef]
  153. 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. [Google Scholar] [CrossRef]
  154. 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. [Google Scholar] [CrossRef] [PubMed]
  155. 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. [Google Scholar] [CrossRef] [PubMed]
  156. 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. [Google Scholar] [CrossRef]
  157. 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. [Google Scholar] [CrossRef]
  158. 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. [Google Scholar] [CrossRef]
  159. 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. [Google Scholar] [CrossRef] [PubMed]
  160. 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. [Google Scholar] [CrossRef] [PubMed]
  161. 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. [Google Scholar] [CrossRef] [PubMed]
  162. 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. [Google Scholar] [CrossRef] [PubMed]
  163. 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. [Google Scholar] [CrossRef]
  164. 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. [Google Scholar] [CrossRef]
  165. 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. [Google Scholar] [CrossRef]
  166. 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. [Google Scholar]
  167. 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. [Google Scholar] [CrossRef]
  168. 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. [Google Scholar] [CrossRef]
  169. 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. [Google Scholar] [CrossRef] [PubMed]
  170. 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. [Google Scholar] [CrossRef] [PubMed]
  171. 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. [Google Scholar] [CrossRef]
  172. 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. [Google Scholar] [CrossRef] [PubMed]
  173. 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. [Google Scholar] [CrossRef] [PubMed]
  174. 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. [Google Scholar] [CrossRef]
  175. 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. [Google Scholar] [CrossRef]
  176. 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. [Google Scholar] [CrossRef]
  177. 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. [Google Scholar] [CrossRef]
  178. 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. [Google Scholar] [CrossRef]
  179. 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. [Google Scholar] [CrossRef] [PubMed]
  180. DeWan, A.; Parrado, A.; Leal, S. A second kindred linked to DFNA20 (17q25.3) reduces the genetic interval. Clin. Genet. 2002, 63, 39–45. [Google Scholar] [CrossRef] [PubMed]
  181. 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. [Google Scholar] [CrossRef]
  182. 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. [Google Scholar] [CrossRef]
  183. 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. [Google Scholar] [CrossRef] [PubMed]
  184. 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. [Google Scholar] [CrossRef]
  185. 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. [Google Scholar] [CrossRef]
  186. 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. [Google Scholar] [CrossRef]
  187. 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. [Google Scholar] [CrossRef]
  188. 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. [Google Scholar] [CrossRef]
  189. 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. [Google Scholar] [CrossRef] [PubMed]
  190. 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. [Google Scholar] [CrossRef]
  191. 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. [Google Scholar] [CrossRef]
  192. Vanderbilt Hereditary Deafness Study Group. Dominantly inherited low-frequency hearing loss. Arch. Otolaryngol. 1968, 88, 242–250. [Google Scholar] [CrossRef]
  193. Konigsmark, B.W.; Mengel, M.; Berlin, C.I. Familial Low Frequency Hearing Loss. Laryngoscope 1971, 81, 759–771. [Google Scholar] [CrossRef] [PubMed]
  194. 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. [Google Scholar] [CrossRef] [PubMed]
  195. 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. [Google Scholar] [CrossRef]
  196. 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. [Google Scholar] [CrossRef]
  197. 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. [Google Scholar] [CrossRef]
  198. 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. [Google Scholar] [CrossRef]
  199. 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. [Google Scholar] [CrossRef] [PubMed]
  200. 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. [Google Scholar] [CrossRef] [PubMed]
  201. 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. [Google Scholar] [CrossRef] [PubMed]
  202. 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. [Google Scholar] [CrossRef]
  203. 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. [Google Scholar] [CrossRef]
  204. 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. [Google Scholar] [CrossRef]
  205. 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. [Google Scholar] [CrossRef]
  206. 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. [Google Scholar] [CrossRef]
  207. 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. [Google Scholar] [CrossRef]
  208. 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. [Google Scholar] [CrossRef]
  209. 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. [Google Scholar] [CrossRef] [PubMed]
  210. 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. [Google Scholar] [CrossRef] [PubMed]
  211. 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. [Google Scholar] [CrossRef] [PubMed]
  212. 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. [Google Scholar] [CrossRef] [PubMed]
  213. 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. [Google Scholar] [CrossRef] [PubMed]
  214. 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. [Google Scholar] [CrossRef]
  215. 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. [Google Scholar] [CrossRef]
  216. 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. [Google Scholar] [CrossRef]
  217. Häkli, S.; Kytövuori, L.; Luotonen, M.; Sorri, M.; Majamaa, K. WFS1 mutations in hearing-impaired children. Int. J. Audiol. 2014, 53, 446–451. [Google Scholar] [CrossRef]
  218. 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. [Google Scholar] [CrossRef]
  219. 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. [Google Scholar] [CrossRef]
  220. 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. [Google Scholar] [CrossRef]
  221. 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. [Google Scholar] [CrossRef] [PubMed]
  222. 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. [Google Scholar] [CrossRef]
  223. Panigrahi, I.; Kumari, D.; Kumar, B.N.A. Single gene variants causing deafness in Asian Indians. J. Genet. 2021, 100, 35. [Google Scholar] [CrossRef]
  224. 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. [Google Scholar] [CrossRef]
  225. 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. [Google Scholar] [CrossRef]
  226. Avraham, K. DFNA15. Adv Otorhinolaryngol. 2000, 56, 107–115. [Google Scholar] [CrossRef]
  227. Gottfried, I.; Huygen, P.L.M.; Avraham, K.B. The Clinical Presentation of DFNA15/POU4F3. Adv. Otorhinolaryngol. 2002, 61, 92–97. [Google Scholar] [CrossRef]
  228. 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. [Google Scholar] [CrossRef]
  229. 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. [Google Scholar] [CrossRef] [PubMed]
  230. 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. [Google Scholar] [CrossRef] [PubMed]
  231. 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. [Google Scholar] [CrossRef] [PubMed]
  232. 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. [Google Scholar] [CrossRef]
  233. 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. [Google Scholar] [CrossRef]
  234. 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. [Google Scholar] [CrossRef]
  235. 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. [Google Scholar] [CrossRef]
  236. 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. [Google Scholar] [CrossRef]
  237. 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. [Google Scholar] [CrossRef]
  238. 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. [Google Scholar] [CrossRef]
  239. 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. [Google Scholar] [CrossRef] [PubMed]
  240. 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. [Google Scholar] [CrossRef] [PubMed]
  241. 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. [Google Scholar] [CrossRef] [PubMed]
  242. 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. [Google Scholar] [CrossRef]
  243. 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. [Google Scholar] [CrossRef]
  244. 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. [Google Scholar] [CrossRef]
  245. 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. [Google Scholar] [CrossRef]
  246. 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. [Google Scholar] [CrossRef]
  247. 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. [Google Scholar] [CrossRef]
  248. 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. [Google Scholar] [CrossRef]
  249. 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. [Google Scholar] [CrossRef]
  250. 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. [Google Scholar] [CrossRef] [PubMed]
  251. 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. [Google Scholar] [CrossRef] [PubMed]
  252. 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. [Google Scholar] [CrossRef]
  253. 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. [Google Scholar] [CrossRef]
  254. 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. [Google Scholar] [CrossRef]
  255. 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. [Google Scholar] [CrossRef]
  256. 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. [Google Scholar] [CrossRef]
  257. 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. [Google Scholar] [CrossRef]
  258. 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. [Google Scholar] [CrossRef]
  259. 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. [Google Scholar] [CrossRef]
  260. 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. [Google Scholar] [PubMed]
  261. 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. [Google Scholar] [CrossRef] [PubMed]
  262. 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. [Google Scholar] [CrossRef] [PubMed]
  263. 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. [Google Scholar] [CrossRef]
  264. 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. [Google Scholar] [CrossRef]
  265. 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. [Google Scholar] [CrossRef]
  266. 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. [Google Scholar] [CrossRef]
  267. 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. [Google Scholar] [CrossRef]
  268. 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. [Google Scholar] [CrossRef]
  269. 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. [Google Scholar] [CrossRef] [PubMed]
  270. 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. [Google Scholar] [CrossRef] [PubMed]
  271. 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. [Google Scholar] [CrossRef] [PubMed]
  272. 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. [Google Scholar] [CrossRef]
  273. 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. [Google Scholar] [CrossRef]
  274. 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. [Google Scholar] [CrossRef]
  275. 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. [Google Scholar] [CrossRef]
  276. 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. [Google Scholar] [CrossRef]
  277. 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. [Google Scholar] [CrossRef]
  278. 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. [Google Scholar] [CrossRef]
  279. 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. [Google Scholar] [CrossRef]
  280. 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. [Google Scholar] [CrossRef]
  281. 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. [Google Scholar] [CrossRef] [PubMed]
  282. 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. [Google Scholar] [CrossRef] [PubMed]
  283. 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. [Google Scholar] [CrossRef]
  284. 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. [Google Scholar] [CrossRef] [PubMed]
  285. 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. [Google Scholar] [CrossRef]
  286. 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. [Google Scholar] [CrossRef]
  287. 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. [Google Scholar] [CrossRef]
  288. 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. [Google Scholar] [CrossRef]
  289. 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. [Google Scholar] [CrossRef] [PubMed]
  290. 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. [Google Scholar] [CrossRef] [PubMed]
  291. 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. [Google Scholar] [CrossRef] [PubMed]
  292. 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. [Google Scholar] [CrossRef]
  293. 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. [Google Scholar]
  294. 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. [Google Scholar] [CrossRef]
  295. 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. [Google Scholar] [CrossRef]
  296. 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. [Google Scholar] [CrossRef]
  297. 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. [Google Scholar] [CrossRef]
  298. 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. [Google Scholar] [CrossRef]
  299. 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. [Google Scholar] [CrossRef]
  300. 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. [Google Scholar] [CrossRef]
  301. 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. [Google Scholar] [CrossRef] [PubMed]
  302. Usami, S.; Nishio, S.; Moteki, H.; Miyagawa, M.; Yoshimura, H. Cochlear Implantation from the Perspective of Genetic Background. Anat. Rec. 2019, 303, 563–593. [Google Scholar] [CrossRef] [PubMed]
  303. 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. [Google Scholar] [CrossRef] [PubMed]
  304. Vona, B.; Doll, J.; Hofrichter, M.A.H.; Haaf, T. Non-syndromic hearing loss: Clinical and diagnostic challenges. Med. Genet. 2020, 32, 117–129. [Google Scholar] [CrossRef]
  305. 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. [Google Scholar] [CrossRef]
  306. Thorpe, R.K.; Smith, R.J.H. Future directions for screening and treatment in congenital hearing loss. Precis. Clin. Med. 2020, 3, 175–186. [Google Scholar] [CrossRef]
  307. Delmaghani, S.; El-Amraoui, A. Inner Ear Gene Therapies Take off: Current Promises and Future Challenges. J. Clin. Med. 2020, 9, 2309. [Google Scholar] [CrossRef]
  308. 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. [Google Scholar] [CrossRef]
Table
Table 1. Autosomal dominant non-syndromic hearing loss: loci, genes and clinical manifestations.
Table 1. Autosomal dominant non-syndromic hearing loss: loci, genes and clinical manifestations.
LocusCytogenetic LocationGeneProtein FunctionHL OnsetAudiometric ConfigurationHL TrendComments
DFNA15q31.3DIAPH1Cytoskeletal organization of inner ear hair cells.Childhood (1st decade)RisingProgressiveHL may be associated with thrombocytopenia or auditory neuropathy and tends to progress to a profound degree by the 4th decade of life [18,19,20].
DFNA2A1p34.2KCNQ4Potassium channel in the cochlear sensory cells.Childhood/Adolescence (1st–2nd decade)SlopingProgressiveAt younger ages, HL is mild in the low frequencies and moderate in the high frequencies. Over the years, hearing progressively deteriorates in all frequencies [21,22].
DFNA2B1p34.3GJB3Gap junction
(connexin 31).		Adulthood (4th decade)SlopingProgressiveHL tends to be milder in females [23,24].
DFNA2C1p36.11IFNLR1Cytokine receptor.Adulthood (3rd-4th decade)SlopingProgressiveHearing is initially normal in the low frequencies, but it progressively deteriorates in all frequencies [25].
DFNA3A13q12.11GJB2Gap junction
(connexin 26).		Congenital/Childhood (1st decade) Sloping ProgressiveThe degree of HL can range from mild to profound [26].
DFNA3B13q12.11GJB6Gap junction
(connexin 30).		Congenital/Childhood (1st decade)SlopingProgressiveThe degree of HL can range from mild to profound [27].
DFNA4A19q13.33MYH14Regulation of cytokinesis, cell motility, and polarity. Childhood to adulthood (1st–3rd decade)FlatProgressiveThe initial audiogram may be slightly sloping or U-shaped, but it becomes flat over the years [28,29].
DFNA4B19q13.31–q13.32CEACAM16Connection between the outer hair cells stereocilia and tectorial membrane.Childhood/Adolescence (1st–2nd decade)FlatProgressiveHL may initially be limited to high frequencies but progressively involves all frequencies [30].
DFNA57p15.3GSDMERegulation of apoptosis.Childhood to adulthood (1st–6th decade) SlopingProgressiveHL may initially be limited to high frequencies but progressively involves all frequencies [31,32].
DFNA6/14/384p16.1WFS1Cation-selective ion channel.Congenital to adulthood (1st–3rd decade)RisingProgressiveHearing worsens over time but does not progress to profound HL [33].
DFNA71q23.3LMX1ATranscription factor.Congenital to adulthood (1st–6th decade)SlopingProgressiveHL is characterized by high variability in age of onset and severity. HL can be associated with vertigo [34].
DFNA8/1211q23.3TECTANon-collagenous component of the tectorial membrane.Congenital/Childhood (1st–2nd decade)U-shaped/
Sloping		Stable/
Progressive		Missense mutations in the zona pellucida domain of TECTA cause moderate HL in the middle frequencies, while missense mutations in the zonadhesin region cause mild-to- moderate HL in the high frequencies. HL is progressive if cysteine residues are affected [35].
DFNA914q12COCHStructural support to the cochlea and interaction with other molecules in the extracellular matrix.Adolescence/Adulthood (2nd–3rd decade)SlopingProgressiveHL is associated with variable vestibular dysfunction and tends to progress to anacusis by the 5th decade of life [36,37].
DFNA106q23.2EYA4Transcriptional activator.Adolescence/Adulthood (1st–5th decade)Flat/Gently slopingProgressiveTruncating variants tend to cause flat-type HL that deteriorates at all frequencies, while non-truncating variants tend to cause high-frequency HL [38,39].
DFNA1111q13.5MYO7AUnconventional myosin that serves in intracellular movements.Childhood to adulthood (1st–5th decade)Flat/Gently sloping/RisingProgressiveHL may be associated with mild vestibular dysfunctions and is gradually progressive [40,41].
DFNA136p21.32 COL11A2Fibril-forming collagen found mainly in the cartilage extracellular matrix.Congenital to adulthood (1st–4th decade)U-shapedStable HL is generally non-progressive and limited to middle frequencies [42,43].
DFNA155q32POU4F3Transcription factor.Adolescence/Adulthood (2nd–6th decade)Sloping/FlatProgressiveHL may be associated with vestibular dysfunction and is characterized by intrafamilial variability. It tends to progress to a profound degree over the years [44,45].
DFNA162q23–q24.3Unknown Unknown.Childhood (1st decade)Sloping FluctuatingHL may be associated with vertigo. In women, hearing may worsen immediately after delivery. Treatment with oral steroids can restore hearing during episodes of acute HL [46].
DFNA1722q12.3MYH9Homeostasis of the organ of Corti, spiral ligament, and Reissner membrane.Childhood to adulthood (1st–5th decade)SlopingProgressiveHL is associated with cochleosaccular dysplasia and organ of Corti degeneration [47].
DFNA183q22UnknownUnknown.Childhood (1st decade)SlopingProgressiveHL initially involves only the high frequencies, but over the years, it also affects the middle and low frequencies [48].
DFNA1910 centromicUnknownUnknown.CongenitalFlatStableHL is mild-to-moderate and non-progressive [49].
DFNA20/2617q25.3ACTG1Cytoskeletal organization of inner ear hair cells and stereocilia maintenance.Childhood/Adolescence (1st–2nd decade)SlopingProgressiveHL tends to progress to a profound degree by the 6th decade of life [50,51].
DFNA216p24.1–p22.3RIPOR2Essential component of hair cell stereocilia.Childhood to adulthood (1st–5th decade)SlopingProgressiveHL is gradually sloping and progressive [52].
DFNA226q14.1MYO6Manteinance of hair cell stereocilia.Childhood to adulthood (1st–3rd decade)Sloping/FlatProgressiveHL may be associated with mild hypertrophic cardiomyopathy. It tends to progress to a profound degree by the 5th decade of life [53].
DFNA2314q23.1SIX1Control of genes involved in ear development.CongenitalSlopingStableHL is generally non-progressive and may be associated with preauricular pits, hypodysplastic kidneys, and vesicoureteral reflux [54].
DFNA244q35-qterUnknown Unknown.CongenitalSlopingStableThe degree of HL can range from mild to profound [55].
DFNA2512q23.1SLC17A8Vesicular glutamate transporter.Childhood to adulthood (1st–6th decade)Sloping ProgressiveHL is slowly progressive [56].
DFNA274q12RESTTranscriptional repressor.Congenital to adulthood (1st–3rd decade)FlatProgressiveHL tends to progress to a profound degree by the 5th decade of life [57,58].
DFNA288q22.3GRHL2Transcription factor.Childhood (1st decade)Flat/Gently SlopingProgressive HL tends to progress to a severe degree at higher frequencies by the 5th decade [59].
DFNA3015q25-q26UnknownUnknown.Congenital to adulthood (1st–4th decade)SlopingProgressiveHL is initially limited to high frequencies but progressively involves the middle frequencies [60].
DFNA316p21.3Unknown Unknown.Childhood to adulthood (1st–4th decade)U-shaped/FlatProgressiveHL is characterized by high variability in age of onset, audiometric configuration, and progression [61].
DFNA3211p15Unknown Unknown.//ProgressiveThis locus was reported only as an abstract [62].
DFNA3313q34-qterUnknownUnknown.Adolescence/Adulthood (2nd–3rd decade)SlopingProgressiveHL is initially limited to high frequencies but progressively involves all frequencies [63].
DFNA341q44NLRP3Critical component of the NLRP3 inflammasome that is activated in innate immune responses.Childhood to adulthood (1st–4th decade)SlopingProgressiveHL is slowing progressive and may be associated with autoinflammatory disorders (e.g., oral ulcers, arthralgia, arthritis, urticaria, periodic fever, and lymphadenopathy) [64].
DFNA369q21.13TMC1Component of mechanotransduction channels in hair cells of the inner ear.Childhood to adulthood (1st–3rd decade)Sloping/FlatProgressiveHL tends rapidly to involve all frequencies and progress to a profound degree. It may be associated with vertigo [65,66].
DFNA371p21.1COL11A1Essential for skeletal, ocular and auditory functions. Congenital/Childhood (1st decade)U-shaped/Flat/Gently slopingProgressive HL is generally in the mild-to-moderate range and tends to a slow progression [67].
DFNA394q22.1DSPPDentin mineralization and inner ear homeostasis.Adulthood (3rd decade)SlopingProgressiveHL is associated with dentinogenesis imperfecta [68].
DFNA4016p12.2CRYMThyroid hormone binding for possible regulatory roles.Congenital/Childhood (1st decade)SlopingProgressive/
Stable		HL is generally in the moderate-to-severe range [69].
DFNA4112q24.33P2RX2Ligand-gated ion channel.Childhood/Adolescence (1st–2nd decade)SlopingProgressiveHL is exacerbated by noise exposure and tends to be severe by the 3rd decade of life [70,71].
DFNA42/525q31.1–q32Unknown Unknown.Adulthood (2nd–3rd decade)SlopingProgressiveHL is initially limited to high frequencies but progressively involves all frequencies, resulting in profound HL [72,73].
DFNA432p12UnknownUnknown.Adulthood (2nd–3rd decade)SlopingProgressiveHL is slowly progressive, extending to all frequencies by the 5th/6th decade of life [74].
DFNA443q28CCDC50Effector of epidermal growth factor-mediated cell signaling.Childhood (1st decade)RisingProgressiveHL is initially limited to low and mild frequencies but gradually involves all frequencies, progressing to profound HL in the 6th decade of life [75].
DFNA479p21–p22UnknownUnknown.Adulthood (2nd–3rd decade)SlopingProgressiveHL is initially limited to high frequencies but progressively involves all frequencies, reaching the moderate-to-severe range by the 5th decade of life [76].
DFNA4812q13.3–q14MYO1AUnconventional myosin.Childhood to adulthood (1st–3rd decade)FlatProgressiveHL is slowly progressive. The degree of HL can range from moderate to severe [77,78].
DFNA491q21–q23Unknown Unknown.Childhood (1st decade)RisingProgressiveHL is initially limited to low and middle frequencies. By the 4th decade of life, audiometric configuration reaches a U shape (severe HL for middle frequencies and moderate HL for low and high frequencies) [79].
DFNA507q32.2MIR96Essential for differentiation and function of the inner ear.Adolescence (2nd decade)FlatProgressiveHL is initially mild and progresses to a severe-to-profound range by the 7th decade of life [80,81].
DFNA519q21.11TJP2Organization of epithelial and endothelial intercellular junctions. Adulthood (4th decade)SlopingProgressiveHL progressively involves all frequencies, resulting in profound HL [82].
DFNA5314q11.2–q12UnknownUnknown.Adolescence (2nd decade)SlopingProgressiveHL is initially mild and limited to high frequencies but gradually involves all frequencies and progresses to a profound degree by the 4th/5th decade of life [83].
DFNA545q31UnknownUnknown.Childhood to adulthood (1st–3rd decade)Rising ProgressiveHL slowly progresses to a severe degree and may be associated with vertigo [84].
DFNA559p13.2–p13.3Unknown Unknown.///This locus was reported only in a Chinese journal [85].
DFNA569q33.1TNCGuidance of migrating neurons during development.Childhood to adulthood (1st-3rd decade)RisingProgressiveHL is initially mild and limited to low frequencies but gradually involves all frequencies, progressing to a severe degree [86].
DFNA5719p13.2UnknownUnknown.Childhood (1st decade)RisingProgressiveHL is initially limited to low frequencies but gradually involves all frequencies and progresses to the moderate-to-severe range by the 5th/6th decade of life [87].
DFNA582p12–p21UnknownUnknown.Adolescence/Adulthood (2nd–4th decade)SlopingProgressiveHL is initially mild and limited to high frequencies but gradually involves all frequencies, progressing to a severe degree [88].
DFNA5911p14.2–q12.3Unknown Unknown.CongenitalSlopingStableHL is severe-to-profound and non-progressive [89].
DFNA602q21.3–q24.1UnknownUnknown.Adolescence/Adulthood (2nd–3rd decade)/ProgressiveThis locus was reported only as an abstract [90].
DFNA633q25.1–q25.2UnknownUnknown.///This locus was assigned by the HUGO nomenclature committee, but no information is available [91].
DFNA6412q24.31DIABLORegulation of apoptosis.Adolescence/Adulthood (2nd–3rd decade)Flat ProgressiveHigh-frequency tinnitus is often present at the onset of HL [92].
DFNA6516p13.3TBC1D24Regulation of membrane trafficking.Adulthood (3rd decade)SlopingProgressiveHL is initially limited to high frequencies, but slowly progresses to all frequencies, reaching the severe-to-profound range in the 7th decade of life [93,94].
DFNA666q15–21CD164Transmembrane sialomucin and cell adhesion molecule. Congenital to adulthood (1st–3rd decade)Flat/U-shapedStable/
Progressive		HL is characterized by high variability in the age of onset and progression [95].
DFNA6720q13.33OSBPL2Intracellular lipid receptor.Childhood to adulthood (1st–4th decade)SlopingProgressiveHL is initially limited to high frequencies but rapidly progresses to all frequencies [96].
DFNA6815q25.2HOMER2Intracellular calcium homeostasis and cytoskeletal organization.Childhood/Adolescence (1st–2nd decade)SlopingProgressiveHL is initially limited to high frequencies but gradually progresses to all frequencies [97,98].
DFNA6912q21.32KITLGLigand of the tyrosine-kinase receptor.CongenitalFlat/Sloping/
Rising		StableHL is unilateral or bilateral asymmetric. HL may be associated with subclinical vestibular dysfunctions [99].
DFNA703q21.3MCM2Important role in the onset of DNA replication and cell division.Adolescence/Adulthood (≥2nd decade)Sloping/Flat ProgressiveHL is slowly progressive, resulting in a mild to profound degree [100,101].
DFNA7115q21.2DMXL2Participation in signal transduction pathways.Congenital to adolescence (1st–2nd decade)FlatProgressiveHL gradually progresses to a severe-to-profound degree in the 5th decade of life [102,103].
DFNA726p21.33SLC44A4Choline transporter plays a role in the choline–acetylcholine system.Adulthood (3rd decade)U-shapedProgressiveHL is initially limited to middle frequencies but gradually progresses to all frequencies [104].
DFNA7312q21.31PTPRQRegulation of cellular proliferation and differentiation.Childhood to adulthood (1st–3rd decade)SlopingProgressiveThe degree of HL can range from mild to severe [105,106].
DFNA747p14.3PDE1CProliferation of vascular smooth muscle cells and neointimal hyperplasia.Adulthood (3rd decade)SlopingProgressiveHL gradually progresses from a mild to profound degree [107].
DFNA757q22.1TRRAPImportant role in transcription and DNA repair.Adulthood (2nd decade) SlopingProgressiveHL is initially limited to middle and high frequencies, but gradually involves all frequencies [108].
DFNA763q23PLS1Actin-bundling protein of the stereocilia.Childhood to adulthood (1st–4th decade)Sloping Stable/
Progressive		HL tends to be more severe at higher frequencies, ranging from a mild to profound degree [109,110].
DFNA7716p13.11ABCC1Transport various molecules across extra- and intra-cellular membranes.Adulthood (2nd–3rd decade)Sloping ProgressiveHL is initially limited to high frequencies but progresses to all frequencies by the 4th–5th decade of life [111].
DFNA785q23.3SLC12A2Membrane protein important in maintaining proper ionic balance and cell volume. CongenitalFlatStableHL is generally profound and may be associated with motor delay due to vestibular dysfunctions. Motor delay often resolves with age [112,113].
DFNA794q21.22SCD5Membrane protein of the endoplasmic reticulum that catalyzes the formation of monounsaturated fatty acids.Adulthood (3rd-7th decade)SlopingProgressiveHL is generally milder in female patients [114].
DFNA8018q11.1–q11.2GREB1LPredicted to be involved in retinoic acid signaling.CongenitalFlatStableHL is generally profound and associated with absent or malformed cochleae (incomplete partition type I) and eighth cranial nerves [115,116].
DFNA812p11.2ELMOD3GTPase-activating protein. Adulthood (3rd decade)SlopingProgressive HL is slowly progressive and ranges from a severe to profound degree [117].
DFNA823p25.3ATP2B2P-type primary ion transport ATPase.Childhood to adulthood (1st–6th decade)Sloping ProgressiveHL is rapidly progressive and may be associated with mild vestibular abnormalities [118].
DFNA835q13.2MAP1BImportant for axonal growth and synapse maturation during brain development. Adolescence to adulthood (2nd–3rd decade)SlopingProgressiveHL ranges from a mild to profound degree. Distortion product otoacoustic emissions (DPOAE) are usually present, indicating the normal function of outer hair cells [119].
DFNA8413q34ATP11AP4-ATPase. Congenital to adulthood (1st–3rd decade)SlopingProgressiveHL is slowly progressive and is characterized by intrafamilial variation in disease severity [120].
DFNA851p36.12USP48Involved in the processing of poly-ubiquitin precursors.Childhood to adulthood (1st–3rd decade)FlatProgressiveHL may be asymmetric [121].
DFNA8618p11.32THOC1Participatation in apoptotic pathways. Adulthood (4th decade)Sloping ProgressiveHL gradually progresses to all frequencies, reaching the severe-to-profound degree in the 7th/8th decades of life [122].
DFNA871q21.3PI4KBInvolved in Golgi-to-plasma membrane trafficking.CongenitalFlatProgressiveHL is generally profound and associated with inner ear malformations, such as incomplete cochlea partition and enlarged vestibular aqueduct [123].
DFNA881p34.3EPHA10Mediators of cell–cell communication, regulating cell attachment, shape, and mobility in neuronal and epithelial cells.Adulthood (3rd–4th decade)SlopingProgressiveHL gradually progresses to a profound degree [124].
DFNA894q22.2ATOH1Transcriptional regulator.Congenital/Childhood (1st decade)FlatProgressiveOnset of HL is at birth or in early childhood [125].
HL = Hearing loss. * DFNA29, DFNA35, DFNA45, DFNA46, DFNA61, and DFNA62 are reserved by the HUGO Gene Nomenclature Committee (HGNC).
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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 (DFNA): A Comprehensive Narrative Review. Biomedicines 2023, 11, 1616. https://doi.org/10.3390/biomedicines11061616

AMA Style

Aldè M, Cantarella G, Zanetti D, Pignataro L, La Mantia I, Maiolino L, Ferlito S, Di Mauro P, Cocuzza S, Lechien JR, et al. Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review. Biomedicines. 2023; 11(6):1616. https://doi.org/10.3390/biomedicines11061616

Chicago/Turabian Style

Aldè, Mirko, Giovanna Cantarella, Diego Zanetti, Lorenzo Pignataro, Ignazio La Mantia, Luigi Maiolino, Salvatore Ferlito, Paola Di Mauro, Salvatore Cocuzza, Jérôme René Lechien, and et al. 2023. "Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review" Biomedicines 11, no. 6: 1616. https://doi.org/10.3390/biomedicines11061616

APA Style

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). Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review. Biomedicines, 11(6), 1616. https://doi.org/10.3390/biomedicines11061616

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