Genetic Hearing Loss and Gene Therapy

Article information

Genomics Inform. 2018;16.e20
Publication date (electronic) : 2018 December 28
doi :
1Department of Otolaryngology-Head and Neck Surgery, Dankook University College of Medicine, Cheonan 31116, Korea
2Beckman Laser Institute Korea, Dankook University, Cheonan 31116, Korea
*Corresponding author: Tel: +82-41-550-1785, Fax: +82-41-550-1090, E-mail:
Received 2018 November 29; Revised 2018 December 3; Accepted 2018 December 4.


Genetic hearing loss crosses almost all the categories of hearing loss which includes the following: conductive, sensory, and neural; syndromic and nonsyndromic; congenital, progressive, and adult onset; high-frequency, low-frequency, or mixed frequency; mild or profound; and recessive, dominant, or sex-linked. Genes play a role in almost half of all cases of hearing loss but effective treatment options are very limited. Genetic hearing loss is considered to be extremely genetically heterogeneous. The advancements in genomics have been instrumental to the identification of more than 6,000 causative variants in more than 150 genes causing hearing loss. Identification of genes for hearing impairment provides an increased insight into the normal development and function of cells in the auditory system. These defective genes will ultimately be important therapeutic targets. However, the auditory system is extremely complex which requires tremendous advances in gene therapy including gene vectors, routes of administration, and therapeutic approaches. This review summarizes and discusses recent advances in elucidating the genomics of genetic hearing loss and technologies aimed at developing a gene therapy that may become a treatment option for in the near future.


The World Health Organization reported that 466 million people worldwide suffers from hearing loss and estimated to rise over 900 million by 2050 [1]. Hearing loss means not able to hear as well as someone with normal hearing or a hearing threshold of more than 25 decibels in one or both ears. Hearing loss can also be classified as either conductive, sensorineural or mixed hearing loss. Conductive hearing loss is when there is a problem conducting the sound waves along the outer ear, tympanic membrane (eardrum) and ossicular chain of the middle ear towards the cochlea. Sensorineural hearing loss (SNHL) is when there is problem translating the sound vibrations into electrical signals in the sensory hair cells (HCs) inside the cochlear or damage in transmitting the information involving the afferent nerves towards the brain. This communication between the ear and brain can be damaged by aging, acoustic overexposure and ototoxic drugs. Heredity also plays a big part wherein genes for hearing are mutated or genes may increase the susceptibility to ear damage or deterioration from aging.

Hearing loss causes an annual global deficit of US $750 billion [2] which offers a high demand for an effective solution. Conductive hearing loss can be surgically managed in most patients. In contrast, SNHL is mostly irreversible and results in permanent hearing loss. However, hearing rehabilitation is possible thru hearing devices that can either be worn externally or implanted. Despite the advances in hearing aid and cochlear implant technologies, the quality of perceived sound still cannot mimic that of the normal ear. Impaired speech perception in noisy environments and musical sound perception are the biggest hurdles of cochlear implants [3, 4].

Scientist around the world are working on genomics-based research and development in hearing science. In this review, we consolidated the genes that are currently identified to be associated with hearing loss. We reviewed ways in which genes are used to restore or protect hearing and ways to deliver the genes to their target cells such as viral and non-viral vectors. We also discussed the various strategies used in gene therapy such as gene replacement, slicing and editing.

Genetic Hearing Loss

Syndromic vs. nonsyndromic hearing loss

Clinically, hearing impairment may be associated with other disorders (syndromic) or it may only be a symptom (nonsyndromic). Syndromic hearing loss occurs with malformations of the external ear, together with other malformations in other organs or organ systems. Nonsyndromic hearing loss has no associated visible deformities or the external ear or any related medical conditions, but could be associated with problems of the middle or inner ear.

Deafness genes

Genes are responsible for hearing loss among 50%–60% of children born with hearing loss [5]. According to the Hereditary Hearing Loss Homepage [6] to date, there is a total of 112 non-syndromic hearing loss genes that has been identified (Fig. 1), 71 autosomal recessive (Table 1) [7125], 45 autosomal dominant (Table 2) [126207], and 5 X-linked and 1 non-syndromic genes (Table 3) [208218]. The most common cause of severe-to-profound nonsyndromic hearing loss in most populations is the autosomal recessive mutation of GJB2. While the most common cause of mild-to-moderate hearing loss is the autosomal recessive mutation on STRC [219]. On the other hand, About 30% of inherited hearing loss is associated with a syndrome [220]. Syndromic hearing impairment tends to be less genetically heterogeneous than nonsyndromic, but more than one locus has been identified for several syndromes. There are currently 11 syndromes (Table 4) [221265] associated with hearing loss with a total of 47 syndromic hearing loss genes with 27 autosomal recessive, 13 autosomal dominant, 4 autosomal dominant or recessive and 2 X-linked recessive pattern of inheritance.

Fig. 1

Inheritance pattern of identified genes for genetic hearing loss. Drawn with data adapted from Hereditary Hearing Loss Homepage [6].

Autosomal recessive non-syndromic hearing loss genes and loci according to Hereditary Hearing Loss Homepage [6]

Autosomal dominant non-syndromic hearing loss genes and loci according to Hereditary Hearing Loss Homepage [6]

Other non-syndromic hearing loss genes and loci according to Hereditary Hearing Loss Homepage

Syndromic hearing loss genes according to Hereditary Hearing Loss Homepage [6]

Relevance of genomics in hearing loss

With the rapid advancement of genomics, it became possible to establish high-resolution genetic and physical maps, genomic and cDNA libraries which made it easier to correlate the genes for hearing loss. The establishment of the human fetal cochlear cDNA library gave way to the cloning of majority of the genes identified related to hearing loss [266]. Screening strategies can be made in combination with next-generation sequencing platforms to study sets of deafness subjects who are likely to have the same defective gene to effectively diagnose patients with genetic hearing loss [267].

Gene Therapy

As mentioned above, genetic hearing loss can now be screened in utero. In principle, gene therapy can fix a genetic mutation like the ones involving hearing genes removing or replacing the defective gene or supplying the absent gene.

However, compared to other target organs for gene therapy, there are several obstacles related to the anatomy of the inner ear. The cochlea is a spiraled and fluid-filled cavity in a bony labyrinth that is very vulnerable to changes which affect the conversion of sound vibration into electrical signals. Consequently, maintaining this homeostasis is the biggest challenge in delivering any kind of therapeutic products into the inner ear. Different routes of administration have been explored with various purposes, such as efficiency in transduction and reduced cochlear toxicity. The most successful way to deliver therapeutic agents to the cochlea is an intracochlear approach through the round window membrane (RWM). The RWM is a semipermeable soft tissue separating the middle and inner ear. It allows low molecular weight molecules to up to molecules with molecular weight 45,000 under normal physiological conditions [268]. Direct injection through the RWM can also be done with a microsyringe and a narrow-gauge needle. Another option is to insert material inside the cochlear cavity to create an opening, in a procedure called a cochleostomy. This was the approach used by our group to inject material into the three cochlear cavities (scala vestibule, scala media, and scala tympani) [269, 270].

Viral vs. non-viral gene delivery

Gene transfection to inner ear cells have mostly utilized replication defective viral vectors (Table 5) [274280]. For example, adenoviruses were used to transfer gene markers such as β-galactosidase and red fluorescent protein as well as functional genes such as glial-derived neurotrophic factor (GDNF) to the auditory system [270, 281, 282]. Another example is the use of adeno-associated viral vectors (AAV), such as AAV1, 2, 6, 8, and Anc80L65, which showed greater transfection efficiency in inner ear delivery [283]. Recently, the USH1 protein network component harmonin (USH1C) gene delivery using synthetic Anc80L65 vectors to treat hearing loss in mice with Usher syndrome restored complex auditory and balance behaviour similar to near wild-type levels with up to 90% transduction efficiency [276]. AAV2/8 vectors that encode wild-type whirlin (WHRN) gene restored inner hair cells (IHC) but not outer hair cells (OHC) and auditory function [272]. AAV2/1 vectors were injected in transmembrane channel like 1 (TMC1) mutant mice restored moderate hearing function with minimal auditory-brainstem-response threshold [284]. A similar viral capsid and a promoter that restricted expression to IHCs partially restored auditory function in mice deficient in the IHC gene encoding for vesicular glutamate transporter 3 (VGluT3) [271]. Furthermore, the cellular tropism of a novel adeno-associated bovine virus vector efficiently transduced cochlear and vestibular HC and supporting cells without pathological effects outperforming other viral vectors [285].

Viral vectors used in gene therapy for genetic hearing loss studies

The concept of gene therapy seems straightforward, but numerous problems and risks exist that prevent gene therapy using viral vectors [286]. Even with all the potential benefits of gene therapy, the utilization of viral vectors in the clinical setup is hindered by the possibility of tumorigenesis and unexpected adverse effects from virus integration in human DNA. Therefore, non-viral delivery systems are developed as an alternative to harness gene therapy. These non-viral vectors include cationic liposomes and other non-liposomal polymers along with the use of biolistic materials and electroporation (Table 6) [287301].

Non-viral vectors used in gene therapy for genetic hearing loss studies

Cationic liposomes are phospholipid vesicles that fuses to the cellular membrane due to their cationic charge, thereby releasing the DNA to the cytoplasm [302]. Cationic liposomes can be easily prepared in large amounts, non-infectious and has a large gene capacity. Meanwhile, synthetic and naturally occurring polycationic polymers attract negatively charged phosphates of the DNA [303]. These include polyethylenimine, dextran, chitosan, PLGA and among others. Cationic polymers are also easy to prepare and non-immunogenic. However, both types have low transfection yields and may still provoke an acute immune response.

Another mode of gene transfection makes use of DNA-coated gold microparticles and bombarded into a targeted cellular surface by a pressure pulse of compressed helium gas [304]. These are not immunogenic and results in a very good in vivo activity. Electroporation is also used to create transient pores in the lipid membrane, allowing the transfection of plasmid DNA, using electric field pulses [305]. However, these methods may cause significant tissue damage during the procedure and need surgery for targeted internal organs. Gene transfer is also limited to the targeted area only.

Gene therapy strategies

Gene replacement using cDNA

Gene replacement is basically delivering a functional cDNA with the correct coding sequence to supplement a nonfunctional mutant gene of interest in specific cell types [306]. The ideal application of gene replacement is in genetic disorders caused by mutations leading to loss in phenotype, such as recessive diseases. However, effectivity of this gene therapy is limited by the duration in which gene is delivered during development of target organs. If the mutation begins during prenatal development, gene replacement may not be able to recover normal physiology after significant malformations. In addition, an extended expression of the exogenous sequence must be maintained if the mutated gene is expressed into adulthood. Dominant deafness mutations are less likely to be recovered with gene replacement strategies but other approaches can still be utilized.

Gene silencing using RNA interference

Dominant hearing loss mutations in heterozygous animals can be “silenced” or negatively regulated by suppressing the mutant allele while allowing expression of the wild-type allele to overcome the consequences of the mutation. Gene silencing can be achieved at the transcriptional level by preventing the mRNA from being transcribed. At the post-transcriptional level, gene silencing occurs with use of RNA interference (RNAi) to prevent mRNA translation [307]. The central role in RNAi is played by two types of short complementary small RNA—microRNA (miRNA) or small interfering RNA (siRNA). In an acoustic overexposure study in mouse, siRNA was found to be able to silence the expression of AMP-activated protein kinase which causes HC loss and cochlear synaptopathy [308]. The main advantage of this method its sequence specificity which makes it very suitable for silencing dominant mutations without affecting wild-type sequences or off target sequences [309].

Gene editing using CRISPR/Cas9 system

Another gene therapy approach that recently gained much attention to edit genome sequences is the use of the CRISPE/Cas9 system. This approach is derived from prokaryotic immune systems for resistance to phages and plasmids [310]. It is the most recent and advanced programmable nuclease adapted for genome engineering which allows for the precise direct manipulation of genome sequences in the inner ear [311]. Engineered nuclease-based enzymes are used to find a target genome sequence and to introduce single- or double-strand DNA, which stimulate innate DNA repairing machinery.

CRISPR/Cas is considered as the most pervasive and easy-to-use system with multiple applications. Cas9 require the presence of a protospacer adjacent motif (PAM) immediately following the DNA target sequence which enables the system to be very specific but at the same time limits its clinical application [312]. To date, much effort has been directed toward the design of CRIPSR nucleases with altered PAM specificities and diminished off target activities allowing even more applications [313].

Clinical Application and Conclusions

Gene therapy is making a comeback after safety concerns during the late 1990s and early 2000s hampered research. Gene therapy for genetic hearing loss is also getting one step closer into being a clinical treatment after several clinical trials have been approved but yet to bear results. Although gene therapy is a promising treatment option, its application is currently limited by the risk of side effects and is still under study to ensure that it will be safe and effective. In the meantime, there are 2,597 clinical trials undertaken in 38 countries that have been either completed, are in progress, or approved involving gene therapy [314]. As we wait for preliminary results to ongoing clinical trials for gene therapy for hearing loss, there are already several syndromic hearing loss genes mentioned above wherein gene therapy trials have begun for their corresponding syndromes. These include the autosomal recessive gene MYO7A causing deaf-blindness in Usher syndrome [315]. Furthermore, lessons from different approaches in gene therapy in other systems can greatly influence the advancement in design and implementation of gene therapy for genetic hearing loss. Additional advances are expected in the coming years as the field of inner gene therapy moves toward the collective goal of developing novel and effective treatments for patients with genetic hearing loss.


This study was supported by the Ministry of Science, Information and Communications technology (ICT) and Future Planning grant funded by the Korean Government (NRF2016R1D1A1B03932624), and supported by Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) (NRF-2018K1A4 A3A02060572).


Authors’ contribution: Conceptualization: MYL

Funding Acquisition: MYL

Writing – original draft: NTC

Writing – review and editing: NTC, MYL

Conflict of interest

No potential conflicts of interest relevant to this article was reported.


1. World Health Organization. Deafness and hearing loss Geneva: World Health Organization; 2018. Accessed 2018 Nov 20. Available from: .
2. Centers for Disease Control and Prevention. Hearing loss in children Atlanta: Center for Disease Control and Prevention; 2018. Accessed 2018 Nov 20. Available from: .
3. Bruns L, Murbe D, Hahne A. Understanding music with cochlear implants. Sci Rep 2016;6:32026.
4. Huang J, Sheffield B, Lin P, Zeng FG. Electro-tactile stimulation enhances cochlear implant speech recognition in noise. Sci Rep 2017;7:2196.
5. Morton CC, Nance WE. Newborn hearing screening: a silent revolution. N Engl J Med 2006;354:2151–2164.
6. Van Camp G, Smith RJ. Hereditary Hearing Loss Homepage The Authors: Hereditary Hearing Loss Homepage; 2018. Accessed 2018 Nov 20. Available from: .
7. Guilford P, Ben Arab S, Blanchard S, Levilliers J, Weissenbach J, Belkahia A, et al. A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nat Genet 1994;6:24–28.
8. Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 1997;387:80–83.
9. del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Alvarez A, Telleria D, et al. A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med 2002;346:243–249.
10. Guilford P, Ayadi H, Blanchard S, Chaib H, Le Paslier D, Weissenbach J, et al. A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene. Hum Mol Genet 1994;3:989–993.
11. Liu XZ, Walsh J, Mburu P, Kendrick-Jones J, Cope MJ, Steel KP, et al. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat Genet 1997;16:188–190.
12. Weil D, Kussel P, Blanchard S, Levy G, Levi-Acobas F, Drira M, et al. The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat Genet 1997;16:191–193.
13. Friedman TB, Liang Y, Weber JL, Hinnant JT, Barber TD, Winata S, et al. A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nat Genet 1995;9:86–91.
14. Wang A, Liang Y, Fridell RA, Probst FJ, Wilcox ER, Touchman JW, et al. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3 . Science 1998;280:1447–1451.
15. Baldwin CT, Weiss S, Farrer LA, De Stefano AL, Adair R, Franklyn B, et al. Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population. Hum Mol Genet 1995;4:1637–1642.
16. Li XC, Everett LA, Lalwani AK, Desmukh D, Friedman TB, Green ED, et al. A mutation in PDS causes non-syndromic recessive deafness. Nat Genet 1998;18:215–217.
17. Fukushima K, Ramesh A, Srisailapathy CR, Ni L, Chen A, O’Neill M, et al. Consanguineous nuclear families used to identify a new locus for recessive non-syndromic hearing loss on 14q. Hum Mol Genet 1995;4:1643–1648.
18. Fukushima K, Ramesh A, Srisailapathy CR, Ni L, Wayne S, O’Neill ME, et al. An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p-DFNB6. Genome Res 1995;5:305–308.
19. Naz S, Giguere CM, Kohrman DC, Mitchem KL, Riazuddin S, Morell RJ, et al. Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Am J Hum Genet 2002;71:632–636.
20. Jain PK, Fukushima K, Deshmukh D, Ramesh A, Thomas E, Lalwani AK, et al. A human recessive neurosensory nonsyndromic hearing impairment locus is potential homologue of murine deafness (dn) locus. Hum Mol Genet 1995;4:2391–2394.
21. Scott DA, Carmi R, Elbedour K, Yosefsberg S, Stone EM, Sheffield VC. An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds. Am J Hum Genet 1996;59:385–391.
22. Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, et al. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet 2002;30:277–284.
23. Veske A, Oehlmann R, Younus F, Mohyuddin A, Muller-Myhsok B, Mehdi SQ, et al. Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan. Hum Mol Genet 1996;5:165–168.
24. Bonne-Tamir B, DeStefano AL, Briggs CE, Adair R, Franklyn B, Weiss S, et al. Linkage of congenital recessive deafness (gene DFNB10) to chromosome 21q22.3. Am J Hum Genet 1996;58:1254–1259.
25. Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, et al. Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat Genet 2001;27:59–63.
26. Chaib H, Place C, Salem N, Chardenoux S, Vincent C, Weissenbach J, et al. A gene responsible for a sensorineural nonsyndromic recessive deafness maps to chromosome 2p22-23. Hum Mol Genet 1996;5:155–158.
27. Yasunaga S, Grati M, Cohen-Salmon M, El-Amraoui A, Mustapha M, Salem N, et al. A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet 1999;21:363–369.
28. Chaib H, Place C, Salem N, Dode C, Chardenoux S, Weissenbach J, et al. Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21-22. Hum Mol Genet 1996;5:1061–1064.
29. Bork JM, Peters LM, Riazuddin S, Bernstein SL, Ahmed ZM, Ness SL, et al. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet 2001;68:26–37.
30. Mustapha M, Chardenoux S, Nieder A, Salem N, Weissenbach J, el-Zir E, et al. A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36. Eur J Hum Genet 1998;6:245–250.
31. Mustapha M, Salem N, Weil D, el-Zir E, Loiselet J, Petit C. Identification of a locus on chromosome 7q31, DFNB14, responsible for prelingual sensorineural non-syndromic deafness. Eur J Hum Genet 1998;6:548–551.
32. Chen A, Wayne S, Bell A, Ramesh A, Srisailapathy CR, Scott DA, et al. New gene for autosomal recessive non-syndromic hearing loss maps to either chromosome 3q or 19p. Am J Med Genet 1997;71:467–471.
33. Charizopoulou N, Lelli A, Schraders M, Ray K, Hildebrand MS, Ramesh A, et al. Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat Commun 2011;2:201.
34. Rehman AU, Gul K, Morell RJ, Lee K, Ahmed ZM, Riazuddin S, et al. Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p. Hum Genet 2011;130:759–765.
35. Verpy E, Masmoudi S, Zwaenepoel I, Leibovici M, Hutchin TP, Del Castillo I, et al. Mutations in a new gene encoding a protein of the hair bundle cause non-syndromic deafness at the DFNB16 locus. Nat Genet 2001;29:345–349.
36. Greinwald JH Jr, Wayne S, Chen AH, Scott DA, Zbar RI, Kraft ML, et al. Localization of a novel gene for nonsyndromic hearing loss (DFNB17) to chromosome region 7q31. Am J Med Genet 1998;78:107–113.
37. Jain PK, Lalwani AK, Li XC, Singleton TL, Smith TN, Chen A, et al. A gene for recessive nonsyndromic sensorineural deafness (DFNB18) maps to the chromosomal region 11p14-p15.1 containing the Usher syndrome type 1C gene. Genomics 1998;50:290–292.
38. Ouyang XM, Xia XJ, Verpy E, Du LL, Pandya A, Petit C, et al. Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness. Hum Genet 2002;111:26–30.
39. Ahmed ZM, Smith TN, Riazuddin S, Makishima T, Ghosh M, Bokhari S, et al. Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC. Hum Genet 2002;110:527–531.
40. Schraders M, Ruiz-Palmero L, Kalay E, Oostrik J, del Castillo FJ, Sezgin O, et al. Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment. Am J Hum Genet 2012;91:883–889.
41. Green GE, Wayne S, Nishtala R, Chen AH, Ramesh A, Srisailapathy CR, et al. Identification of a novel locus (DFNB19) for non-syndromic autosomal-recessive hearing loss in a consanguineous family. In : Molecular Biology of Hearing and Deafness Meeting; 1998 Oct 8; Bathesda, MD.
42. Moynihan L, Houseman M, Newton V, Mueller R, Lench N. DFNB20: a novel locus for autosomal recessive, non-syndromal sensorineural hearing loss maps to chromosome 11q25-qter. Eur J Hum Genet 1999;7:243–246.
43. Mustapha M, Weil D, Chardenoux S, Elias S, El-Zir E, Beckmann JS, et al. An alpha-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21. Hum Mol Genet 1999;8:409–412.
44. Zwaenepoel I, Mustapha M, Leibovici M, Verpy E, Goodyear R, Liu XZ, et al. Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22. Proc Natl Acad Sci U S A 2002;99:6240–6245.
45. Ahmed ZM, Riazuddin S, Ahmad J, Bernstein SL, Guo Y, Sabar MF, et al. PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum Mol Genet 2003;12:3215–3223.
46. Khan SY, Ahmed ZM, Shabbir MI, Kitajiri S, Kalsoom S, Tasneem S, et al. Mutations of the RDX gene cause nonsyndromic hearing loss at the DFNB24 locus. Hum Mutat 2007;28:417–423.
47. Schraders M, Lee K, Oostrik J, Huygen PL, Ali G, Hoefsloot LH, et al. Homozygosity mapping reveals mutations of GRXCR1 as a cause of autosomal-recessive nonsyndromic hearing impairment. Am J Hum Genet 2010;86:138–147.
48. Yousaf R, Ahmed ZM, Giese APJ, Morell RJ, Lagziel A, Dabdoub A, Wilcox ER, Riazuddin S, Friedman TB, Riazuddin S. Modifier variant of METTL13 suppresses human GAB1-associated profound deafness. J Clin Invest 2018;128:1509–1522.
49. Pulleyn LJ, Jackson AP, Roberts E, Carridice A, Muxworthy C, Houseman M, et al. A new locus for autosomal recessive non-syndromal sensorineural hearing impairment (DFNB27) on chromosome 2q23-q31. Eur J Hum Genet 2000;8:991–993.
50. Shahin H, Walsh T, Sobe T, Abu Sa’ed J, Abu Rayan A, Lynch ED, et al. Mutations in a novel isoform of TRIOBP that encodes a filamentous-actin binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss. Am J Hum Genet 2006;78:144–152.
51. Riazuddin S, Khan SN, Ahmed ZM, Ghosh M, Caution K, Nazli S, et al. Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness. Am J Hum Genet 2006;78:137–143.
52. Wilcox ER, Burton QL, Naz S, Riazuddin S, Smith TN, Ploplis B, et al. Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell 2001;104:165–172.
53. Walsh T, Walsh V, Vreugde S, Hertzano R, Shahin H, Haika S, et al. From flies’ eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30. Proc Natl Acad Sci U S A 2002;99:7518–7523.
54. Mustapha M, Chouery E, Chardenoux S, Naboulsi M, Paronnaud J, Lemainque A, et al. DFNB31, a recessive form of sensorineural hearing loss, maps to chromosome 9q32-34. Eur J Hum Genet 2002;10:210–212.
55. Mburu P, Mustapha M, Varela A, Weil D, El-Amraoui A, Holme RH, et al. Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat Genet 2003;34:421–428.
56. Masmoudi S, Tlili A, Majava M, Ghorbel AM, Chardenoux S, Lemainque A, et al. Mapping of a new autosomal recessive nonsyndromic hearing loss locus (DFNB32) to chromosome 1p13.3–22.1. Eur J Hum Genet 2003;11:185–188.
57. Delmaghani S, Aghaie A, Bouyacoub Y, El Hachmi H, Bonnet C, Riahi Z, et al. Mutations in CDC14A, encoding a protein phosphatase involved in hair cell ciliogenesis, cause autosomal-recessive severe to profound deafness. Am J Hum Genet 2016;98:1266–1270.
58. Medlej-Hashim M, Mustapha M, Chouery E, Weil D, Parronaud J, Salem N, et al. Non-syndromic recessive deafness in Jordan: mapping of a new locus to chromosome 9q34.3 and prevalence of DFNB1 mutations. Eur J Hum Genet 2002;10:391–394.
59. Ansar M, Din MA, Arshad M, Sohail M, Faiyaz-Ul-Haque M, Haque S, et al. A novel autosomal recessive non-syndromic deafness locus (DFNB35) maps to 14q24.1-14q24.3 in large consanguineous kindred from Pakistan. Eur J Hum Genet 2003;11:77–80.
60. Collin RW, Kalay E, Tariq M, Peters T, van der Zwaag B, Venselaar H, et al. Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35. Am J Hum Genet 2008;82:125–138.
61. Naz S, Griffith AJ, Riazuddin S, Hampton LL, Battey JF Jr, Khan SN, et al. Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction. J Med Genet 2004;41:591–595.
62. Ahmed ZM, Morell RJ, Riazuddin S, Gropman A, Shaukat S, Ahmad MM, et al. Mutations of MYO6 are associated with recessive deafness, DFNB37. Am J Hum Genet 2003;72:1315–1322.
63. Ansar M, Ramzan M, Pham TL, Yan K, Jamal SM, Haque S, et al. Localization of a novel autosomal recessive non-syndromic hearing impairment locus (DFNB38) to 6q26-q27 in a consanguineous kindred from Pakistan. Hum Hered 2003;55:71–74.
64. Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, et al. Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am J Hum Genet 2009;85:25–39.
65. Delmaghani S, Aghaie A, Compain-Nouaille S, Ataie A, Lemainque A, Zeinali S, et al. DFNB40, a recessive form of sensorineural hearing loss, maps to chromosome 22q11. 21-12.1. Eur J Hum Genet 2003;11:816–818.
66. Aslam M, Wajid M, Chahrour MH, Ansar M, Haque S, Pham TL, et al. A novel autosomal recessive nonsyndromic hearing impairment locus (DFNB42) maps to chromosome 3q13.31-q22.3. Am J Med Genet A 2005;133A:18–22.
67. Borck G, Ur Rehman A, Lee K, Pogoda HM, Kakar N, von Ameln S, et al. Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42. Am J Hum Genet 2011;88:127–137.
68. Ansar M, Chahrour MH, Amin Ud Din M, Arshad M, Haque S, Pham TL, et al. DFNB44, a novel autosomal recessive non-syndromic hearing impairment locus, maps to chromosome 7p14.1-q11.22. Hum Hered 2004;57:195–199.
69. Santos-Cortez RL, Lee K, Giese AP, Ansar M, Amin-Ud-Din M, Rehn K, et al. Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. Hum Mol Genet 2014;23:3289–3298.
70. Bhatti A, Lee K, McDonald ML, Hassan MJ, Gutala R, Ansar M, et al. Mapping of a new autosomal recessive non-syndromic hearing impairment locus (DFNB45) to chromosome 1q43-q44. Clin Genet 2008;73:395–398.
71. Mir A, Ansar M, Chahrour MH, Pham TL, Wajid M, Haque S, et al. Mapping of a novel autosomal recessive nonsyndromic deafness locus (DFNB46) to chromosome 18p11.32-p11.31. Am J Med Genet A 2005;133A:23–26.
72. Hassan MJ, Santos RL, Rafiq MA, Chahrour MH, Pham TL, Wajid M, et al. A novel autosomal recessive non-syndromic hearing impairment locus (DFNB47) maps to chromosome 2p25.1-p24.3. Hum Genet 2006;118:605–610.
73. Ahmad J, Khan SN, Khan SY, Ramzan K, Riazuddin S, Ahmed ZM, et al. DFNB48, a new nonsyndromic recessive deafness locus, maps to chromosome 15q23-q25.1. Hum Genet 2005;116:407–412.
74. Ramzan K, Shaikh RS, Ahmad J, Khan SN, Riazuddin S, Ahmed ZM, et al. A new locus for nonsyndromic deafness DFNB49 maps to chromosome 5q12.3-q14.1. Hum Genet 2005;116:17–22.
75. Riazuddin S, Ahmed ZM, Fanning AS, Lagziel A, Kitajiri S, Ramzan K, et al. Tricellulin is a tight-junction protein necessary for hearing. Am J Hum Genet 2006;79:1040–1051.
76. Girotto G, Abdulhadi K, Buniello A, Vozzi D, Licastro D, d’Eustacchio A, et al. Linkage study and exome sequencing identify a BDP1 mutation associated with hereditary hearing loss. PLoS One 2013;8:e80323.
77. Shaikh RS, Ramzan K, Nazli S, Sattar S, Khan SN, Riazuddin S, et al. A new locus for nonsyndromic deafness DFNB51 maps to chromosome 11p13-p12. Am J Med Genet A 2005;138:392–395.
78. Chen W, Kahrizi K, Meyer NC, Riazalhosseini Y, Van Camp G, Najmabadi H, et al. Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus. J Med Genet 2005;42:e61.
79. Irshad S, Santos RL, Muhammad D, Lee K, McArthur N, Haque S, et al. Localization of a novel autosomal recessive non-syndromic hearing impairment locus DFNB55 to chromosome 4q12-q13.2. Clin Genet 2005;68:262–267.
80. Delmaghani S, del Castillo FJ, Michel V, Leibovici M, Aghaie A, Ron U, et al. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet 2006;38:770–778.
81. Ben Said M, Grati M, Ishimoto T, Zou B, Chakchouk I, Ma Q, et al. A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60. Hum Genet 2016;135:513–524.
82. Liu XZ, Ouyang XM, Xia XJ, Zheng J, Pandya A, Li F, et al. Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum Mol Genet 2003;12:1155–1162.
83. Ali G, Santos RL, John P, Wambangco MA, Lee K, Ahmad W, et al. The mapping of DFNB62, a new locus for autosomal recessive non-syndromic hearing impairment, to chromosome 12p13.2-p11.23. Clin Genet 2006;69:429–433.
84. Du X, Schwander M, Moresco EM, Viviani P, Haller C, Hildebrand MS, et al. A catechol-O-methyltransferase that is essential for auditory function in mice and humans. Proc Natl Acad Sci U S A 2008;105:14609–14614.
85. Ahmed ZM, Masmoudi S, Kalay E, Belyantseva IA, Mosrati MA, Collin RW, et al. Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans. Nat Genet 2008;40:1335–1340.
86. Tariq A, Santos RL, Khan MN, Lee K, Hassan MJ, Ahmad W, et al. Localization of a novel autosomal recessive nonsyndromic hearing impairment locus DFNB65 to chromosome 20q13.2-q13.32. J Mol Med (Berl) 2006;84:484–490.
87. Grati M, Chakchouk I, Ma Q, Bensaid M, Desmidt A, Turki N, et al. A missense mutation in DCDC2 causes human recessive deafness DFNB66, likely by interfering with sensory hair cell and supporting cell cilia length regulation. Hum Mol Genet 2015;24:2482–2491.
88. Tlili A, Mannikko M, Charfedine I, Lahmar I, Benzina Z, Ben Amor M, et al. A novel autosomal recessive non-syndromic deafness locus, DFNB66, maps to chromosome 6p21.2-22.3 in a large Tunisian consanguineous family. Hum Hered 2005;60:123–128.
89. Shabbir MI, Ahmed ZM, Khan SY, Riazuddin S, Waryah AM, Khan SN, et al. Mutations of human TMHS cause recessively inherited non-syndromic hearing loss. J Med Genet 2006;43:634–640.
90. Kalay E, Li Y, Uzumcu A, Uyguner O, Collin RW, Caylan R, et al. Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss. Hum Mutat 2006;27:633–639.
91. Santos RL, Hassan MJ, Sikandar S, Lee K, Ali G, Martin PE Jr, et al. DFNB68, a novel autosomal recessive non-syndromic hearing impairment locus at chromosomal region 19p13.2. Hum Genet 2006;120:85–92.
92. Santos-Cortez RL, Faridi R, Rehman AU, Lee K, Ansar M, Wang X, et al. Autosomal-recessive hearing impairment due to rare missense variants within S1PR2 . Am J Hum Genet 2016;98:331–338.
93. Chishti MS, Lee K, McDonald ML, Hassan MJ, Ansar M, Ahmad W, et al. Novel autosomal recessive non-syndromic hearing impairment locus (DFNB71) maps to chromosome 8p22-21.3. J Hum Genet 2009;54:141–144.
94. Riazuddin S, Anwar S, Fischer M, Ahmed ZM, Khan SY, Janssen AG, et al. Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. Am J Hum Genet 2009;85:273–280.
95. Waryah AM, Rehman A, Ahmed ZM, Bashir ZH, Khan SY, Zafar AU, et al. DFNB74, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 12q14.2-q15. Clin Genet 2009;76:270–275.
96. Ahmed ZM, Yousaf R, Lee BC, Khan SN, Lee S, Lee K, et al. Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74. Am J Hum Genet 2011;88:19–29.
97. Horn HF, Brownstein Z, Lenz DR, Shivatzki S, Dror AA, Dagan-Rosenfeld O, et al. The LINC complex is essential for hearing. J Clin Invest 2013;123:740–750.
98. Grillet N, Schwander M, Hildebrand MS, Sczaniecka A, Kolatkar A, Velasco J, et al. Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans. Am J Hum Genet 2009;85:328–337.
99. Rehman AU, Morell RJ, Belyantseva IA, Khan SY, Boger ET, Shahzad M, et al. Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79. Am J Hum Genet 2010;86:378–388.
100. Ali Mosrati M, Schrauwen I, Ben Saiid M, Aifa-Hmani M, Fransen E, Mneja M, et al. Genome-wide analysis reveals a novel autosomal-recessive hearing loss locus DFNB80 on chromosome 2p16.1-p21. J Hum Genet 2013;58:98–101.
101. Shahin H, Walsh T, Rayyan AA, Lee MK, Higgins J, Dickel D, et al. Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families. Eur J Hum Genet 2010;18:407–413.
102. Schraders M, Oostrik J, Huygen PL, Strom TM, van Wijk E, Kunst HP, et al. Mutations in PTPRQ are a cause of autosomal-recessive nonsyndromic hearing impairment DFNB84 and associated with vestibular dysfunction. Am J Hum Genet 2010;86:604–610.
103. Yariz KO, Duman D, Zazo Seco C, Dallman J, Huang M, Peters TA, et al. Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss. Am J Hum Genet 2012;91:872–882.
104. Ali RA, Rehman AU, Khan SN, Husnain T, Riazuddin S, Friedman TB, et al. DFNB86, a novel autosomal recessive non-syndromic deafness locus on chromosome 16p13.3. Clin Genet 2012;81:498–500.
105. Rehman AU, Santos-Cortez RL, Morell RJ, Drummond MC, Ito T, Lee K, et al. Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. Am J Hum Genet 2014;94:144–152.
106. Jaworek TJ, Richard EM, Ivanova AA, Giese AP, Choo DI, Khan SN, et al. An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans. PLoS Genet 2013;9:e1003774.
107. Basit S, Lee K, Habib R, Chen L, Umm e K, Santos-Cortez RL, et al. DFNB89, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 16q21-q23.2. Hum Genet 2011;129:379–385.
108. Ali G, Lee K, Andrade PB, Basit S, Santos-Cortez RL, Chen L, et al. Novel autosomal recessive nonsyndromic hearing impairment locus DFNB90 maps to 7p22.1-p15.3. Hum Hered 2011;71:106–112.
109. Sirmaci A, Erbek S, Price J, Huang M, Duman D, Cengiz FB, et al. A truncating mutation in SERPINB6 is associated with autosomal-recessive nonsyndromic sensorineural hearing loss. Am J Hum Genet 2010;86:797–804.
110. Tabatabaiefar MA, Alasti F, Shariati L, Farrokhi E, Fransen E, Nooridaloii MR, et al. DFNB93, a novel locus for autosomal recessive moderate-to-severe hearing impairment. Clin Genet 2011;79:594–598.
111. Simon M, Richard EM, Wang X, Shahzad M, Huang VH, Qaiser TA, et al. Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. PLoS Genet 2015;11:e1005097.
112. Ansar M, Lee K, Naqvi SK, Andrade PB, Basit S, Santos-Cortez RL, et al. A new autosomal recessive nonsyndromic hearing impairment locus DFNB96 on chromosome 1p36.31-p36.13. J Hum Genet 2011;56:866–868.
113. Mujtaba G, Schultz JM, Imtiaz A, Morell RJ, Friedman TB, Naz S. A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss. J Med Genet 2015;52:548–552.
114. Delmaghani S, Aghaie A, Michalski N, Bonnet C, Weil D, Petit C. Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness. Hum Mol Genet 2012;21:3835–3844.
115. Li J, Zhao X, Xin Q, Shan S, Jiang B, Jin Y, et al. Whole-exome sequencing identifies a variant in TMEM132E causing autosomal-recessive nonsyndromic hearing loss DFNB99. Hum Mutat 2015;36:98–105.
116. Yousaf R, Gu C, Ahmed ZM, Khan SN, Friedman TB, Riazuddin S, et al. Mutations in diphosphoinositol-pentakisphosphate kinase PPIP5K2 are associated with hearing loss in human and mouse. PLoS Genet 2018;14:e1007297.
117. Imtiaz A, Kohrman DC, Naz S. A frameshift mutation in GRXCR2 causes recessively inherited hearing loss. Hum Mutat 2014;35:618–624.
118. Behlouli A, Bonnet C, Abdi S, Bouaita A, Lelli A, Hardelin JP, et al. EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness. Orphanet J Rare Dis 2014;9:55.
119. Seco CZ, Oonk AM, Dominguez-Ruiz M, Draaisma JM, Gandia M, Oostrik J, et al. Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. Eur J Hum Genet 2015;23:189–194.
120. Diaz-Horta O, Subasioglu-Uzak A, Grati M, DeSmidt A, Foster J 2nd, Cao L, et al. FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing. Proc Natl Acad Sci U S A 2014;111:9864–9868.
121. Dahmani M, Ammar-Khodja F, Bonnet C, Lefevre GM, Hardelin JP, Ibrahim H, et al. EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss. Orphanet J Rare Dis 2015;10:96.
122. Diaz-Horta O, Abad C, Sennaroglu L, Foster J 2nd, DeSmidt A, Bademci G, et al. ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. Proc Natl Acad Sci U S A 2016;113:5993–5998.
123. Walsh T, Shahin H, Elkan-Miller T, Lee MK, Thornton AM, Roeb W, et al. Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. Am J Hum Genet 2010;87:90–94.
124. Diaz-Horta O, Sirmaci A, Doherty D, Nance W, Arnos K, Pandya A, et al. GPSM2 mutations in Chudley-McCullough syndrome. Am J Med Genet A 2012;158A:2972–2973.
125. Doherty D, Chudley AE, Coghlan G, Ishak GE, Innes AM, Lemire EG, et al. GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. Am J Hum Genet 2012;90:1088–1093.
126. Leon PE, Raventos H, Lynch E, Morrow J, King MC. The gene for an inherited form of deafness maps to chromosome 5q31. Proc Natl Acad Sci U S A 1992;89:5181–5184.
127. Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King MC. Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science 1997;278:1315–1318.
128. Coucke P, Van Camp G, Djoyodiharjo B, Smith SD, Frants RR, Padberg GW, 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.
129. Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, et al. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 1999;96:437–446.
130. Xia JH, Liu CY, Tang BS, Pan Q, Huang L, Dai HP, et al. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat Genet 1998;20:370–373.
131. Gao X, Yuan YY, Lin QF, Xu JC, Wang WQ, Qiao YH, 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.
132. Chaib H, Lina-Granade G, Guilford P, Plauchu H, Levilliers J, Morgon A, et al. A gene responsible for a dominant form of neurosensory non-syndromic deafness maps to the NSRD1 recessive deafness gene interval. Hum Mol Genet 1994;3:2219–2222.
133. Denoyelle F, Lina-Granade G, Plauchu H, Bruzzone R, Chaib H, Levi-Acobas F, et al. Connexin 26 gene linked to a dominant deafness. Nature 1998;393:319–320.
134. Grifa A, Wagner CA, D’Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, et al. Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet 1999;23:16–18.
135. Chen AH, Ni L, Fukushima K, Marietta J, O’Neill M, Coucke P, et al. Linkage of a gene for dominant non-syndromic deafness to chromosome 19. Hum Mol Genet 1995;4:1073–1076.
136. Donaudy F, Snoeckx R, Pfister M, Zenner HP, Blin N, Di Stazio M, et al. Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4). Am J Hum Genet 2004;74:770–776.
137. Zheng J, Miller KK, Yang T, Hildebrand MS, Shearer AE, DeLuca AP, et al. Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with alpha-tectorin and is mutated in autosomal dominant hearing loss (DFNA4). Proc Natl Acad Sci U S A 2011;108:4218–4223.
138. van Camp G, Coucke P, Balemans W, van Velzen D, van de Bilt C, van Laer L, et al. Localization of a gene for non-syndromic hearing loss (DFNA5) to chromosome 7p15. Hum Mol Genet 1995;4:2159–2163.
139. Van Laer L, Huizing EH, Verstreken M, van Zuijlen D, Wauters JG, Bossuyt PJ, et al. Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat Genet 1998;20:194–197.
140. Lesperance MM, Hall JW 3rd, Bess FH, Fukushima K, Jain PK, Ploplis B, et al. A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. Hum Mol Genet 1995;4:1967–1972.
141. Van Camp G, Kunst H, Flothmann K, McGuirt W, Wauters J, Marres 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.
142. Bespalova IN, Van Camp G, Bom SJ, Brown DJ, Cryns K, DeWan AT, 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.
143. Young TL, Ives E, Lynch E, Person R, Snook S, MacLaren L, et al. Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Hum Mol Genet 2001;10:2509–2514.
144. Fagerheim T, Nilssen O, Raeymaekers P, Brox V, Moum T, Elverland HH, et al. Identification of a new locus for autosomal dominant non-syndromic hearing impairment (DFNA7) in a large Norwegian family. Hum Mol Genet 1996;5:1187–1191.
145. Wesdorp M, de Koning Gans PA, Schraders M, Oostrik J, Huynen MA, Venselaar H, et al. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction. Hum Genet 2018;May. 12. [Epub]. .
146. Manolis EN, Yandavi N, Nadol JB Jr, Eavey RD, McKenna M, Rosenbaum S, et al. A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13. Hum Mol Genet 1996;5:1047–1050.
147. Robertson NG, Lu L, Heller S, Merchant SN, Eavey RD, McKenna M, et al. Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nat Genet 1998;20:299–303.
148. O’Neill ME, Marietta J, Nishimura D, Wayne S, Van Camp G, Van Laer L, et al. A gene for autosomal dominant late-onset progressive non-syndromic hearing loss, DFNA10, maps to chromosome 6. Hum Mol Genet 1996;5:853–856.
149. Wayne S, Robertson NG, DeClau F, Chen N, Verhoeven K, Prasad S, et al. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet 2001;10:195–200.
150. Tamagawa Y, Kitamura K, Ishida T, Ishikawa K, Tanaka H, Tsuji S, et al. A gene for a dominant form of non-syndromic sensorineural deafness (DFNA11) maps within the region containing the DFNB2 recessive deafness gene. Hum Mol Genet 1996;5:849–852.
151. Liu XZ, Walsh J, Tamagawa Y, Kitamura K, Nishizawa M, Steel KP, et al. Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene. Nat Genet 1997;17:268–269.
152. Brown MR, Tomek MS, Van Laer L, Smith S, Kenyon JB, Van Camp G, et al. A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA13, maps to chromosome 6p. Am J Hum Genet 1997;61:924–927.
153. McGuirt WT, Prasad SD, Griffith AJ, Kunst HP, Green GE, Shpargel KB, et al. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat Genet 1999;23:413–419.
154. Vahava O, Morell R, Lynch ED, Weiss S, Kagan ME, Ahituv N, et al. Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science 1998;279:1950–1954.
155. Fukushima K, Kasai N, Ueki Y, Nishizaki K, Sugata K, Hirakawa S, 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.
156. Lalwani AK, Luxford WM, Mhatre AN, Attaie A, Wilcox ER, Castelein CM. A new locus for nonsyndromic hereditary hearing impairment, DFNA17, maps to chromosome 22 and represents a gene for cochleosaccular degeneration. Am J Hum Genet 1999;64:318–323.
157. Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM, Mhatre AN. Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9 . Am J Hum Genet 2000;67:1121–1128.
158. Bonsch D, Scheer P, Neumann C, Lang-Roth R, Seifert E, Storch P, et al. 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.
159. Green GE, Whitehead S, Van Camp G, Smith RJ. Identification of a new locus-DFNA19-for dominant hearing impairment. In : Molecular Biology of Hearing and Deafness Meeting; 1998 Oct 8; Bathesda, MD.
160. Morell RJ, Friderici KH, Wei S, Elfenbein JL, Friedman TB, Fisher RA. A new locus for late-onset, progressive, hereditary hearing loss DFNA20 maps to 17q25. Genomics 2000;63:1–6.
161. Zhu M, Yang T, Wei S, DeWan AT, Morell RJ, Elfenbein JL, et al. Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26). Am J Hum Genet 2003;73:1082–1091.
162. van Wijk E, Krieger E, Kemperman MH, De Leenheer EM, Huygen PL, Cremers CW, et al. A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26). J Med Genet 2003;40:879–884.
163. Kunst H, Marres H, Huygen P, van Duijnhoven G, Krebsova A, van der Velde S, et al. 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.
164. Melchionda S, Ahituv N, Bisceglia L, Sobe T, Glaser F, Rabionet R, 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.
165. Salam AA, Hafner FM, Linder TE, Spillmann T, Schinzel AA, Leal SM. 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.
166. Mosrati MA, Hammami B, Rebeh IB, Ayadi L, Dhouib L, Ben Mahfoudh K, et al. A novel dominant mutation in SIX1, affecting a highly conserved residue, result in only auditory defects in humans. Eur J Med Genet 2011;54:e484–488.
167. Hafner FM, Salam AA, Linder TE, Balmer D, Baumer A, Schinzel AA, et al. 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.
168. Greene CC, McMillan PM, Barker SE, Kurnool P, Lomax MI, Burmeister M, et al. DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24. Am J Hum Genet 2001;68:254–260.
169. Ruel J, Emery S, Nouvian R, Bersot T, Amilhon B, Van Rybroek JM, et al. Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice. Am J Hum Genet 2008;83:278–292.
170. Nakano Y, Kelly MC, Rehman AU, Boger ET, Morell RJ, Kelley MW, et al. Defects in the alternative splicing-dependent regulation of REST cause deafness. Cell 2018;174:536–548.e521.
171. Peters LM, Fridell RA, Boger ET, San Agustin TB, Madeo AC, Griffith AJ, et al. A locus for autosomal dominant progressive non-syndromic hearing loss, DFNA27, is on chromosome 4q12-13.1. Clin Genet 2008;73:367–372.
172. Peters LM, Anderson DW, Griffith AJ, Grundfast KM, San Agustin TB, Madeo AC, et al. Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28. Hum Mol Genet 2002;11:2877–2885.
173. Mangino M, Flex E, Capon F, Sangiuolo F, Carraro E, Gualandi F, et al. Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26. Eur J Hum Genet 2001;9:667–671.
174. Snoeckx RL, Kremer H, Ensink RJ, Flothmann K, de Brouwer A, Smith RJ, et al. A novel locus for autosomal dominant non-syndromic hearing loss, DFNA31, maps to chromosome 6p21.3. J Med Genet 2004;41:11–13.
175. 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.
176. Bonsch D, Schmidt CM, Scheer P, Bohlender J, Neumann C, Am Zehnhoff-Dinnesen A, et al. 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.
177. Nakanishi H, Kawashima Y, Kurima K, Chae JJ, Ross AM, Pinto-Patarroyo G, et al. NLRP3 mutation and cochlear auto-inflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy. Proc Natl Acad Sci U S A 2017;114:E7766–E7775.
178. Booth KT, Askew JW, Talebizadeh Z, Huygen PLM, Eudy J, Kenyon J, et al. Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37. Genet Med 2018;Sep. 24. [Epub]. .
179. Xia J, Deng H, Feng Y, Zhang H, Pan Q, Dai H, 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.
180. Abe S, Katagiri T, Saito-Hisaminato A, Usami S, Inoue Y, Tsunoda T, et al. 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.
181. Blanton SH, Liang CY, Cai MW, Pandya A, Du LL, Landa B, et al. A novel locus for autosomal dominant non-syndromic deafness (DFNA41) maps to chromosome 12q24-qter. J Med Genet 2002;39:567–570.
182. Yan D, Zhu Y, Walsh T, Xie D, Yuan H, Sirmaci A, et al. Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise. Proc Natl Acad Sci U S A 2013;110:2228–2233.
183. Flex E, Mangino M, Mazzoli M, Martini A, Migliosi V, Colosimo A, et al. Mapping of a new autosomal dominant non-syndromic hearing loss locus (DFNA43) to chromosome 2p12. J Med Genet 2003;40:278–281.
184. Modamio-Hoybjor S, Moreno-Pelayo MA, Mencia A, del Castillo I, Chardenoux S, Armenta D, et al. A novel locus for autosomal dominant nonsyndromic hearing loss (DFNA44) maps to chromosome 3q28-29. Hum Genet 2003;112:24–28.
185. Modamio-Hoybjor S, Mencia A, Goodyear R, del Castillo I, Richardson G, Moreno F, et al. A mutation in CCDC50, a gene encoding an effector of epidermal growth factor-mediated cell signaling, causes progressive hearing loss. Am J Hum Genet 2007;80:1076–1089.
186. 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.
187. D’Adamo P, Pinna M, Capobianco S, Cesarani A, D’Eustacchio A, Fogu P, et al. A novel autosomal dominant non-syndromic deafness locus (DFNA48) maps to 12q13-q14 in a large Italian family. Hum Genet 2003;112:319–320.
188. Donaudy F, Ferrara A, Esposito L, Hertzano R, Ben-David O, Bell RE, et al. Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. Am J Hum Genet 2003;72:1571–1577.
189. Moreno-Pelayo MA, Modamio-Hoybjor S, Mencia A, del Castillo I, Chardenoux S, Fernandez-Burriel M, et al. 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.
190. Modamio-Hoybjor S, Moreno-Pelayo MA, Mencia A, del Castillo I, Chardenoux S, Morais D, et al. 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.
191. Mencia A, Modamio-Hoybjor S, Redshaw N, Morin M, Mayo-Merino F, Olavarrieta L, et al. Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat Genet 2009;41:609–613.
192. Walsh T, Pierce SB, Lenz DR, Brownstein Z, Dagan-Rosenfeld O, Shahin H, 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.
193. Yan D, Ke X, Blanton SH, Ouyang XM, Pandya A, Du LL, et al. A novel locus for autosomal dominant non-syndromic deafness, DFNA53, maps to chromosome 14q11.2-q12. J Med Genet 2006;43:170–174.
194. Gurtler N, Kim Y, Mhatre A, Schlegel C, Mathis A, Lalwani AK. DFNA54, a third locus for low-frequency hearing loss. J Mol Med (Berl) 2004;82:775–780.
195. Zhao Y, Zhao F, Zong L, Zhang P, Guan L, Zhang J, 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.
196. Bonsch D, Schmidt CM, Scheer P, Bohlender J, Neumann C, am Zehnhoff-Dinnesen A, et al. 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.
197. Lezirovitz K, Braga MC, Thiele-Aguiar RS, Auricchio MT, Pearson PL, Otto PA, et al. A novel autosomal dominant deafness locus (DFNA58) maps to 2p12-p21. Clin Genet 2009;75:490–493.
198. Ouyang XM, Yan D, Du LL. A novel locus for autosomal dominant non-syndromic hearing loss maps to chromosome 2q213-q241. In : Midwinter Meeting for the Association for Research in Otolaryngology; 2007 Feb 11–15; Denver, CO.
199. Cheng J, Zhu Y, He S, Lu Y, Chen J, Han B, 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.
200. Azaiez H, Booth KT, Bu F, Huygen P, Shibata SB, Shearer AE, et al. TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum Mutat 2014;35:819–823.
201. Nyegaard M, Rendtorff ND, Nielsen MS, Corydon TJ, Demontis D, Starnawska A, 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.
202. Thoenes M, Zimmermann U, Ebermann I, Ptok M, Lewis MA, Thiele H, 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.
203. Azaiez H, Decker AR, Booth KT, Simpson AC, Shearer AE, Huygen PL, et al. HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice. PLoS Genet 2015;11:e1005137.
204. Zazo Seco C, Serrao de Castro L, van Nierop JW, Morin M, Jhangiani S, Verver EJ, 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.
205. 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.
206. Eisenberger T, Di Donato N, Decker C, Delle Vedove A, Neuhaus C, Nurnberg G, et al. A C-terminal nonsense mutation links PTPRQ with autosomal-dominant hearing loss, DFNA73. Genet Med 2018;20:614–621.
207. Eisenberger T, Di Donato N, Baig SM, Neuhaus C, Beyer A, Decker E, et al. Targeted and genomewide NGS data disqualify mutations in MYO1A, the “DFNA48 gene”, as a cause of deafness. Hum Mutat 2014;35:565–570.
208. Liu X, Han D, Li J, Han B, Ouyang X, Cheng J, et al. Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2. Am J Hum Genet 2010;86:65–71.
209. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, et al. Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4 . Science 1995;267:685–688.
210. Schraders M, Haas SA, Weegerink NJ, Oostrik J, Hu H, Hoefsloot LH, et al. Next-generation sequencing identifies mutations of SMPX, which encodes the small muscle protein, X-linked, as a cause of progressive hearing impairment. Am J Hum Genet 2011;88:628–634.
211. Huebner AK, Gandia M, Frommolt P, Maak A, Wicklein EM, Thiele H, et al. Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss. Am J Hum Genet 2011;88:621–627.
212. del Castillo I, Villamar M, Sarduy M, Romero L, Herraiz C, Hernandez FJ, et al. A novel locus for non-syndromic sensorineural deafness (DFN6) maps to chromosome Xp22. Hum Mol Genet 1996;5:1383–1387.
213. Zong L, Guan J, Ealy M, Zhang Q, Wang D, Wang H, et al. Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder. J Med Genet 2015;52:523–531.
214. Rost S, Bach E, Neuner C, Nanda I, Dysek S, Bittner RE, et al. Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6 . Eur J Hum Genet 2014;22:208–215.
215. Wang QJ, Lu CY, Li N, Rao SQ, Shi YB, Han DY, et al. Y-linked inheritance of non-syndromic hearing impairment in a large Chinese family. J Med Genet 2004;41:e80.
216. Bykhovskaya Y, Estivill X, Taylor K, Hang T, Hamon M, Casano RA, et al. Candidate locus for a nuclear modifier gene for maternally inherited deafness. Am J Hum Genet 2000;66:1905–1910.
217. Schoen CJ, Emery SB, Thorne MC, Ammana HR, Sliwerska E, Arnett J, et al. Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila. Proc Natl Acad Sci U S A 2010;107:13396–13401.
218. Kim TB, Isaacson B, Sivakumaran TA, Starr A, Keats BJ, Lesperance MM. A gene responsible for autosomal dominant auditory neuropathy (AUNA1) maps to 13q14-21. J Med Genet 2004;41:872–876.
219. Sloan-Heggen CM, Bierer AO, Shearer AE, Kolbe DL, Nishimura CJ, Frees KL, et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet 2016;135:441–450.
220. Hilgert N, Smith RJ, Van Camp G. Function and expression pattern of nonsyndromic deafness genes. Curr Mol Med 2009;9:546–564.
221. Mochizuki T, Lemmink HH, Mariyama M, Antignac C, Gubler MC, Pirson Y, et al. Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 1994;8:77–81.
222. Barker DF, Hostikka SL, Zhou J, Chow LT, Oliphant AR, Gerken SC, et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 1990;248:1224–1227.
223. Abdelhak S, Kalatzis V, Heilig R, Compain S, Samson D, Vincent C, et al. A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nat Genet 1997;15:157–164.
224. Hoskins BE, Cramer CH, Silvius D, Zou D, Raymond RM, Orten DJ, et al. Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am J Hum Genet 2007;80:800–804.
225. Ruf RG, Berkman J, Wolf MT, Nurnberg P, Gattas M, Ruf EM, et al. A gene locus for branchio-otic syndrome maps to chromosome 14q21.3-q24.3. J Med Genet 2003;40:515–519.
226. Lalani SR, Safiullah AM, Molinari LM, Fernbach SD, Martin DM, Belmont JW. SEMA3E mutation in a patient with CHARGE syndrome. J Med Genet 2004;41:e94.
227. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955–957.
228. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 1997;15:186–189.
229. Tyson J, Tranebjaerg L, Bellman S, Wren C, Taylor JF, Bathen J, et al. IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum Mol Genet 1997;6:2179–2185.
230. Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, et al. KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nat Genet 1997;17:267–268.
231. Berger W, van de Pol D, Warburg M, Gal A, Bleeker-Wagemakers L, de Silva H, et al. Mutations in the candidate gene for Norrie disease. Hum Mol Genet 1992;1:461–465.
232. Chen ZY, Hendriks RW, Jobling MA, Powell JF, Breakefield XO, Sims KB, et al. Isolation and characterization of a candidate gene for Norrie disease. Nat Genet 1992;1:204–208.
233. Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997;17:411–422.
234. Yang T, Vidarsson H, Rodrigo-Blomqvist S, Rosengren SS, Enerback S, Smith RJ. Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4). Am J Hum Genet 2007;80:1055–1063.
235. Yang T, Gurrola JG 2nd, Wu H, Chiu SM, Wangemann P, Snyder PM, et al. Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome. Am J Hum Genet 2009;84:651–657.
236. Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, et al. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet 2010;87:282–288.
237. Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K, Morell RJ, et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 2013;92:605–613.
238. Pierce SB, Gersak K, Michaelson-Cohen R, Walsh T, Lee MK, Malach D, et al. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet 2013;92:614–620.
239. Morino H, Pierce SB, Matsuda Y, Walsh T, Ohsawa R, Newby M, et al. Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features. Neurology 2014;83:2054–2061.
240. Chatzispyrou IA, Alders M, Guerrero-Castillo S, Zapata Perez R, Haagmans MA, Mouchiroud L, et al. A homozygous missense mutation in ERAL1, encoding a mitochondrial rRNA chaperone, causes Perrault syndrome. Hum Mol Genet 2017;26:2541–2550.
241. Ahmad NN, Ala-Kokko L, Knowlton RG, Jimenez SA, Weaver EJ, Maguire JI, et al. Stop codon in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy). Proc Natl Acad Sci U S A 1991;88:6624–6627.
242. Richards AJ, Yates JR, Williams R, Payne SJ, Pope FM, Scott JD, et al. A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen. Hum Mol Genet 1996;5:1339–1343.
243. Vikkula M, Mariman EC, Lui VC, Zhidkova NI, Tiller GE, Goldring MB, et al. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 1995;80:431–437.
244. Van Camp G, Snoeckx RL, Hilgert N, van den Ende J, Fukuoka H, Wagatsuma M, et al. A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am J Hum Genet 2006;79:449–457.
245. Baker S, Booth C, Fillman C, Shapiro M, Blair MP, Hyland JC, et al. A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome. Am J Med Genet A 2011;155A:1668–1672.
246. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. The Treacher Collins Syndrome Collaborative Group. Nat Genet 1996;12:130–136.
247. Dauwerse JG, Dixon J, Seland S, Ruivenkamp CA, van Haeringen A, Hoefsloot LH, et al. Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nat Genet 2011;43:20–22.
248. Weil D, Blanchard S, Kaplan J, Guilford P, Gibson F, Walsh J, et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 1995;374:60–61.
249. Verpy E, Leibovici M, Zwaenepoel I, Liu XZ, Gal A, Salem N, et al. A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat Genet 2000;26:51–55.
250. Bolz H, von Brederlow B, Ramirez A, Bryda EC, Kutsche K, Nothwang HG, et al. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet 2001;27:108–112.
251. Ahmed ZM, Riazuddin S, Bernstein SL, Ahmed Z, Khan S, Griffith AJ, et al. Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am J Hum Genet 2001;69:25–34.
252. Weil D, El-Amraoui A, Masmoudi S, Mustapha M, Kikkawa Y, Laine S, et al. Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin. Hum Mol Genet 2003;12:463–471.
253. Ahmed ZM, Riazuddin S, Khan SN, Friedman PL, Riazuddin S, Friedman TB. USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22-23. Clin Genet 2009;75:86–91.
254. Eudy JD, Weston MD, Yao S, Hoover DM, Rehm HL, Ma-Edmonds M, et al. Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa. Science 1998;280:1753–1757.
255. Weston MD, Luijendijk MW, Humphrey KD, Moller C, Kimberling WJ. Mutations in the VLGR1 gene implicate G-protein signaling in the pathogenesis of Usher syndrome type II. Am J Hum Genet 2004;74:357–366.
256. Ebermann I, Scholl HP, Charbel Issa P, Becirovic E, Lamprecht J, Jurklies B, et al. A novel gene for Usher syndrome type 2: mutations in the long isoform of whirlin are associated with retinitis pigmentosa and sensorineural hearing loss. Hum Genet 2007;121:203–211.
257. Joensuu T, Hamalainen R, Yuan B, Johnson C, Tegelberg S, Gasparini P, et al. Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3. Am J Hum Genet 2001;69:673–684.
258. Bondurand N, Kuhlbrodt K, Pingault V, Enderich J, Sajus M, Tommerup N, et al. A molecular analysis of the yemenite deaf-blind hypopigmentation syndrome: SOX10 dysfunction causes different neurocristopathies. Hum Mol Genet 1999;8:1785–1789.
259. Tassabehji M, Newton VE, Read AP. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet 1994;8:251–255.
260. Sanchez-Martin M, Rodriguez-Garcia A, Perez-Losada J, Sagrera A, Read AP, Sanchez-Garcia I. SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum Mol Genet 2002;11:3231–3236.
261. Bondurand N, Dastot-Le Moal F, Stanchina L, Collot N, Baral V, Marlin S, et al. Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4. Am J Hum Genet 2007;81:1169–1185.
262. Zlotogora J, Lerer I, Bar-David S, Ergaz Z, Abeliovich D. Homozygosity for Waardenburg syndrome. Am J Hum Genet 1995;56:1173–1178.
263. Attie T, Till M, Pelet A, Amiel J, Edery P, Boutrand L, et al. Mutation of the endothelin-receptor B gene in Waardenburg-Hirschsprung disease. Hum Mol Genet 1995;4:2407–2409.
264. Edery P, Attie T, Amiel J, Pelet A, Eng C, Hofstra RM, et al. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 1996;12:442–444.
265. Pingault V, Bondurand N, Kuhlbrodt K, Goerich DE, Prehu MO, Puliti A, et al. SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat Genet 1998;18:171–173.
266. Robertson NG, Khetarpal U, Gutierrez-Espeleta GA, Bieber FR, Morton CC. Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening. Genomics 1994;23:42–50.
267. Sakuma N, Moteki H, Takahashi M, Nishio SY, Arai Y, Yamashita Y, et al. An effective screening strategy for deafness in combination with a next-generation sequencing platform: a consecutive analysis. J Hum Genet 2016;61:253–261.
268. Liu H, Hao J, Li KS. Current strategies for drug delivery to the inner ear. Acta Pharm Sin B 2013;3:86–96.
269. Lee MY, Kurioka T, Nelson MM, Prieskorn DM, Swiderski DL, Takada Y, et al. Viral-mediated Ntf3 overexpression disrupts innervation and hearing in nondeafened guinea pig cochleae. Mol Ther Methods Clin Dev 2016;3:16052.
270. Takada Y, Takada T, Lee MY, Swiderski DL, Kabara LL, Dolan DF, et al. Ototoxicity-induced loss of hearing and inner hair cells is attenuated by HSP70 gene transfer. Mol Ther Methods Clin Dev 2015;2:15019.
271. Akil O, Seal RP, Burke K, Wang C, Alemi A, During M, et al. Restoration of hearing in the VGLUT3 knockout mouse using virally mediated gene therapy. Neuron 2012;75:283–293.
272. Chien WW, Isgrig K, Roy S, Belyantseva IA, Drummond MC, May LA, et al. Gene therapy restores hair cell stereocilia morphology in inner ears of deaf whirler mice. Mol Ther 2016;24:17–25.
273. Geschwind MD, Hartnick CJ, Liu W, Amat J, Van De Water TR, Federoff HJ. Defective HSV-1 vector expressing BDNF in auditory ganglia elicits neurite outgrowth: model for treatment of neuron loss following cochlear degeneration. Hum Gene Ther 1996;7:173–182.
274. Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL, Dolan DF, et al. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 2005;11:271–276.
275. Kawamoto K, Ishimoto S, Minoda R, Brough DE, Raphael Y. Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. J Neurosci 2003;23:4395–4400.
276. Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian AA, et al. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol 2017;35:264–272.
277. Pietola L, Aarnisalo AA, Joensuu J, Pellinen R, Wahlfors J, Jero J. HOX-GFP and WOX-GFP lentivirus vectors for inner ear gene transfer. Acta Otolaryngol 2008;128:613–620.
278. Schlecker C, Praetorius M, Brough DE, Presler RG Jr, Hsu C, Plinkert PK, et al. Selective atonal gene delivery improves balance function in a mouse model of vestibular disease. Gene Ther 2011;18:884–890.
279. Shibata SB, Di Pasquale G, Cortez SR, Chiorini JA, Raphael Y. Gene transfer using bovine adeno-associated virus in the guinea pig cochlea. Gene Ther 2009;16:990–997.
280. Staecker H, Liu W, Malgrange B, Lefebvre PP, Van De Water TR. Vector-mediated delivery of bcl-2 prevents degeneration of auditory hair cells and neurons after injury. ORL J Otorhinolaryngol Relat Spec 2007;69:43–50.
281. Raphael Y, Frisancho JC, Roessler BJ. Adenoviral-mediated gene transfer into guinea pig cochlear cells in vivo. Neurosci Lett 1996;207:137–141.
282. Yagi M, Magal E, Sheng Z, Ang KA, Raphael Y. Hair cell protection from aminoglycoside ototoxicity by adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor. Hum Gene Ther 1999;10:813–823.
283. Landegger LD, Pan B, Askew C, Wassmer SJ, Gluck SD, Galvin A, et al. A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol 2017;35:280–284.
284. Askew C, Rochat C, Pan B, Asai Y, Ahmed H, Child E, et al. Tmc gene therapy restores auditory function in deaf mice. Sci Transl Med 2015;7:295ra108.
285. Di Pasquale G, Rzadzinska A, Schneider ME, Bossis I, Chiorini JA, Kachar B. A novel bovine virus efficiently transduces inner ear neuroepithelial cells. Mol Ther 2005;11:849–855.
286. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 2003;4:346–358.
287. Wareing M, Mhatre AN, Pettis R, Han JJ, Haut T, Pfister MH, et al. Cationic liposome mediated transgene expression in the guinea pig cochlea. Hear Res 1999;128:61–69.
288. Jero J, Mhatre AN, Tseng CJ, Stern RE, Coling DE, Goldstein JA, et al. Cochlear gene delivery through an intact round window membrane in mouse. Hum Gene Ther 2001;12:539–548.
289. Jero J, Tseng CJ, Mhatre AN, Lalwani AK. A surgical approach appropriate for targeted cochlear gene therapy in the mouse. Hear Res 2001;151:106–114.
290. Staecker H, Li D, O’Malley BW Jr, Van De Water TR. Gene expression in the mammalian cochlea: a study of multiple vector systems. Acta Otolaryngol 2001;121:157–163.
291. Zhang W, Zhang Y, Sood R, Ranjan S, Surovtseva E, Ahmad A, et al. Visualization of intracellular trafficking of Math1 protein in different cell types with a newly-constructed non-viral gene delivery plasmid. J Gene Med 2011;13:134–144.
292. Toyama K, Ozeki M, Hamajima Y, Lin J. Expression of the integrin genes in the developing cochlea of rats. Hear Res 2005;201:21–26.
293. Zhang W, Zhang Y, Lobler M, Schmitz KP, Ahmad A, Pyykko I, et al. Nuclear entry of hyperbranched polylysine nanoparticles into cochlear cells. Int J Nanomedicine 2011;6:535–546.
294. Tan BT, Foong KH, Lee MM, Ruan R. Polyethylenimine-mediated cochlear gene transfer in guinea pigs. Arch Otolaryngol Head Neck Surg 2008;134:884–891.
295. Tamura T, Kita T, Nakagawa T, Endo T, Kim TS, Ishihara T, et al. Drug delivery to the cochlea using PLGA nanoparticles. Laryngoscope 2005;115:2000–2005.
296. Belyantseva IA, Boger ET, Friedman TB. Myosin XVa localizes to the tips of inner ear sensory cell stereocilia and is essential for staircase formation of the hair bundle. Proc Natl Acad Sci U S A 2003;100:13958–13963.
297. Belyantseva IA, Boger ET, Naz S, Frolenkov GI, Sellers JR, Ahmed ZM, et al. Myosin-XVa is required for tip localization of whirlin and differential elongation of hair-cell stereocilia. Nat Cell Biol 2005;7:148–156.
298. Woods C, Montcouquiol M, Kelley MW. Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nat Neurosci 2004;7:1310–1318.
299. Zheng JL, Gao WQ. Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nat Neurosci 2000;3:580–586.
300. Brigande JV, Gubbels SP, Woessner DW, Jungwirth JJ, Bresee CS. Electroporation-mediated gene transfer to the developing mouse inner ear. Methods Mol Biol 2009;493:125–139.
301. Gubbels SP, Woessner DW, Mitchell JC, Ricci AJ, Brigande JV. Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer. Nature 2008;455:537–541.
302. Wrobel I, Collins D. Fusion of cationic liposomes with mammalian cells occurs after endocytosis. Biochim Biophys Acta 1995;1235:296–304.
303. Gao X, Kim KS, Liu D. Nonviral gene delivery: what we know and what is next. AAPS J 2007;9:E92–E104.
304. Belyantseva IA. Helios Gene Gun-mediated transfection of the inner ear sensory epithelium. Methods Mol Biol 2009;493:103–123.
305. Heller LC, Ugen K, Heller R. Electroporation for targeted gene transfer. Expert Opin Drug Deliv 2005;2:255–268.
306. Ahmed H, Shubina-Oleinik O, Holt JR. Emerging gene therapies for genetic hearing loss. J Assoc Res Otolaryngol 2017;18:649–670.
307. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 2001;411:494–498.
308. Hill K, Yuan H, Wang X, Sha SH. Noise-induced loss of hair cells and cochlear synaptopathy are mediated by the activation of AMPK . J Neurosci 2016;36:7497–7510.
309. Shibata SB, Ranum PT, Moteki H, Pan B, Goodwin AT, Goodman SS, et al. RNA interference prevents autosomal-dominant hearing loss. Am J Hum Genet 2016;98:1101–1113.
310. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013;339:819–823.
311. Lee MY, Park YH. Potential of gene and cell therapy for inner ear hair cells. Biomed Res Int 2018;20188137614.
312. Zou B, Mittal R, Grati M, Lu Z, Shu Y, Tao Y, et al. The application of genome editing in studying hearing loss. Hear Res 2015;327:102–108.
313. Hirano S, Nishimasu H, Ishitani R, Nureki O. Structural basis for the altered PAM specificities of engineered CRISPR-Cas9. Mol Cell 2016;61:886–894.
314. Ginn SL, Amaya AK, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2017: An update . J Gene Med 2018;20:e3015.
315. Lopes VS, Williams DS. Gene therapy for the retinal degeneration of Usher syndrome caused by mutations in MYO7A. Cold Spring Harb Perspect Med 2015;5:a017319.

Article information Continued

Fig. 1

Inheritance pattern of identified genes for genetic hearing loss. Drawn with data adapted from Hereditary Hearing Loss Homepage [6].

Table 1

Autosomal recessive non-syndromic hearing loss genes and loci according to Hereditary Hearing Loss Homepage [6]

Locus (OMIM) Location Gene (OMIM) Key references (PubMed)
DFNB1A 13q12 GJB2 [7, 8]
DFNB1B 13q12 GJB6 [9]
DFNB2 11q13.5 MYO7A [1012]
DFNB3 17p11.2 MYO15A [13, 14]
DFNB4 7q31 SLC26A4 [15, 16]
DFNB5 (see note 1) 14q12 Unknown [17]
DFNB6 3p14 p21 TMIE [18, 19]
DFNB7/11 9q13 q21 TMC1 [2022]
DFNB8/10 21q22 TMPRSS3 [2325]
DFNB9 (see note 2) 2p22-p23 OTOF [26, 27]
DFNB10 See DFNB8 - -
DFNB11 See DFNB7 - -
DFNB12 10q21 q22 CDH23 [28, 29]
DFNB13 7q34 36 Unknown [30]
DFNB14 7q31 Unknown [31]
DFNB15/72/95 3q21 q25,19p13 GIPC3 [3234]
DFNB16 15q21 q22 STRC [35]
DFNB17 7q31 Unknown [36]
DFNB18 11p14 15.1 USH1C [3739]
DFNB18B 11p15.1 OTOG [40]
DFNB19 18p11 Unknown [41]
DFNB20 11q25-qter Unknown [42]
DFNB21 11q TECTA [43]
DFNB22 16p12.2 OTOA [44]
DFNB23 10p11.2 q21 PCDH15 [45]
DFNB24 11q23 RDX [46]
DFNB25 4p13 GRXCR1 [47]
DFNB26 (see note 3) 4q31 Unknown [48]
DFNB27 2q23 q31 Unknown [49]
DFNB28 22q13 TRIOBP [50, 51]
DFNB29 21q22 CLDN14 [52]
DFNB30 10p11.1 MYO3A [53]
DFNB31 9q32 q34 WHRN [54, 55]
DFNB32/105 1p13.3 22.1 CDC14A [56, 57]
DFNB33 9q34.3 Unknown [58]
DFNB35 14q24.1 24.3 ESRRB [59, 60]
DFNB36 1p36.3 ESPN [61]
DFNB37 6q13 MYO6 [62]
DFNB38 6q26 q27 Unknown [63]
DFNB39 7q21.1 HGF [64]
DFNB40 22q Unknown [65]
DFNB42 3q13.31 q22.3 ILDR1 [66, 67]
DFNB44 7p14.1 q11.22 ADCY1 [68, 69]
DFNB45 1q43 q44 Unknown [70]
DFNB46 18p11.32 p11.31 Unknown [71]
DFNB47 2p25.1 p24.3 Unknown [72]
DFNB48 15q23 q25.1 CIB2 [73]
DFNB49 5q12.3 q14.1. MARVELD2/BDP1 [7476]
DFNB51 11p13 p12 Unknown [77]
DFNB53 6p21.3 COL11A2 [78]
DFNB55 4q12 q13.2 Unknown [79]
DFNB59 2q31.1 q31.3 PJVK [80]
DFNB60 5q23.2 q31.1 SLC22A4 [81]
DFNB61 7q22.1 SLC26A5 [82]
DFNB62 12p13.2 p11.23 Unknown [83]
DFNB63 11q13.2 q13.4 LRTOMT/COMT2 [84, 85]
DFNB65 20q13.2 q13.32 Unknown [86]
DFNB66 6p21.2 22.3 DCDC2 [87]
DFNB66/67 6p21.31 LHFPL5 [8890]
DFNB68 19p13.2 S1PR2 [91, 92]
DFNB71 8p2221.3 Unknown [93]
DFNB72 See DFNB15 - -
DFNB73 1p32.3 BSND [94]
DFNB74 12q14.2 q15 MSRB3 [95, 96]
DFNB76 19q13.12 SYNE4 [97]
DFNB77 18q12q 21 LOXHD1 [98]
DFNB79 9q34.3 TPRN [99]
DFNB80 2p16.1 p21 Unknown [100]
DFNB81 19p Unknown [34]
DFNB82 1p13.1 (see note 4) [101]
DFNB83 See DFNA47 - -
DFNB84 12q21.2 PTPRQ/OTOGL [102, 103]
DFNB85 17p12 q11.2 Unknown [101]
DFNB86 16p13.3 TBC1D24 [104, 105]
DFNB88 2p12 p11.2 ELMOD3 [106]
DFNB89 16q21 q23.2 KARS [107]
DFNB90 7p22.1 p15.3 Unknown [108]
DFNB91 6p25 SERPINB6 [109]
DFNB93 11q12.311 q13.2 CABP2 [110]
DFNB94 - NARS2 [111]
DFNB95 See DFNB15 - -
DFNB96 1p36.31 p36.13 Unknown [112]
DFNB97 7q31.2q31.31 MET [113]
DFNB98 21q22.3-qter TSPEAR [114]
DFNB99 17q12 TMEM132E [115]
DFNB100 5q13.2 q23.2 PPIP5K2 [116]
DFNB101 5q32 GRXCR2 [117]
DFNB102 12p12.3 EPS8 [118]
DFNB103 6p21.1 CLIC5 [119]
DFNB104 6p22.3 FAM65B [120]
DFNB105 See DFNB32 - [57]
DFNB106 11p15.5 EPS8L2 [121]
DFNB108 1p31.3 ROR1 [122]

Note 1: DFNB5 was reported originally as DFNB4.

Note 2: DFNB9 was reported originally as DFNB6.

Note 3: DFNB26 is suppressed by dominant modifier DFNM1.

Note 4: The gene at the DFNB82 locus was initially reported as GPSM2 [123], but this gene was later determined to cause Chudley-McCullough syndrome [124, 125].

Table 2

Autosomal dominant non-syndromic hearing loss genes and loci according to Hereditary Hearing Loss Homepage [6]

Locus (OMIM) Location Gene (OMIM) Key references (PubMed)
DFNA1 5q31 DIAPH1 [126, 127]
DFNA2A 1p34 KCNQ4 [129, 130]
DFNA2B 1p35.1 GJB3 [132]
DFNA2C - IFNLR1 [134]
DFNA3A 13q11 q12 GJB2 [8, 135, 136]
DFNA3B 13q12 GJB6 [138]
DFNA4A 19q13 MYH14 [139, 140]
DFNA4B 19q13.32 CEACAM16 [142]
DFNA5 7p15 GSDME [144, 145]
DFNA6 4p16.3 WFS1 [148151]
DFNA7 1q21-q23 LMX1A [152, 153]
DFNA8 See DFNA12 - -
DFNA9 14q12 q13 COCH [157, 158]
DFNA10 6q22 q23 EYA4 [160, 161]
DFNA11 11q12.3 q21 MYO7A [164, 165]
DFNA12 11q2224 TECTA -
DFNA13 6p21 COL11A2 [169, 170]
DFNA14 See DFNA6 - -
DFNA15 5q31 POU4F3 [172]
DFNA16 2q24 Unknown [174]
DFNA17 22q MYH9 [176, 177]
DFNA18 3q22 Unknown [179]
DFNA19 10(pericentr.) Unknown [181]
DFNA20 17q25 ACTG1 [183185]
DFNA21 6p21 Unknown [187]
DFNA22 6q13 MYO6 [189]
DFNA23 14q21 q22 SIX1 [191, 192]
DFNA24 4q Unknown [194]
DFNA25 12q21 24 SLC17A8 [196, 197]
DFNA26 See DFNA20 - -
DFNA27 4q12 REST [199, 200]
DFNA28 8q22 GRHL2 [202]
DFNA30 15q25 26 Unknown [204]
DFNA31 6p21.3 Unknown [206]
DFNA32 11p15 Unknown [128]
DFNA33 13q34-qter Unknown [131]
DFNA34 1q44 NLRP3 [133]
DFNA36 9q13 q21 TMC1 [22]
DFNA37 1p21 COL11A1 [137]
DFNA38 See DFNA6 - -
DFNA39 (see note 1) 4q21.3 DSPP [141]
DFNA40 16p12.2 CRYM [143]
DFNA41 12q24-qter P2RX2 [146, 147]
DFNA42 5q31.1 q32 Unknown [141]
DFNA43 2p12 Unknown [154]
DFNA44 3q28 29 CCDC50 [155, 156]
DFNA47 9p21 22 Unknown [159]
DFNA48 12q13 q14 MYO1A [162, 163]
DFNA49 1q21 q23 Unknown [166]
DFNA50 7q32.2 MIRN96 [167, 168]
DFNA51 9q21 TJP2 [171]
DFNA52 4q28 Unknown [141]
DFNA53 14q11.2 q12 Unknown [173]
DFNA54 5q31 Unknown [175]
DFNA56 9q31.3 q34.3 TNC [178]
DFNA57 19p13.2 Unknown [180]
DFNA58 2p12 p21 Unknown [182]
DFNA59 11p14.2 q12.3 Unknown [186]
DFNA60 2q21.3 q24.1 Unknown [188]
DFNA64 12q24.31 q24.32 SMAC/DIABLO [190]
DFNA65 16p13.3 TBC1D24 [193]
DFNA66 6q15 21 CD164 [195]
DFNA67 20q13.33 OSBPL2 [175]
DFNA68 15q25.2 HOMER2 [198]
DFNA69 12q21.32 q23.1 KITLG [201]
DFNA70 3q21.3 MCM2 [203]
DFNA73 12q21.31 PTPRQ [205]

Note 1: Mutations in DSPP dentinogenesis imperfect associated with hearing impairment in some families.

Note 2: MYO1A has been called in to question as the causative gene for DFNA48 [207].

Table 3

Other non-syndromic hearing loss genes and loci according to Hereditary Hearing Loss Homepage

Locus (OMIM) Location Gene (OMIM) Key references (PubMed)
 DFNX1a Xq22 PRPS1 [208]
 DFNX2 Xq21.1 POU3F4 [209]
 DFNX3 Xp21.2 Unknown [210, 211]
 DFNX4 Xp22 SMPX [212]
 DFNX5 Xq26.1 AIFM1 [213]
 DFNX6 Xp22.3 COL4A6 [214]

 DFNY1 Y Unknown [215]

 DFNM1 1q24 Unknown [48]
 DFNM2 8q23 Unknown [216]

AUNA-Auditory Neuropathy [217, 218]
 AUNA1 13q14-21 DIAPH3

Previous nomenclature designated X-linked loci as DFN but this has been changed to DFNX.

Table 4

Syndromic hearing loss genes according to Hereditary Hearing Loss Homepage [6]

Gene (OMIM) Location Inheritance Key references (PubMed)
Alport syndrome
COL4A3 2q36.3 Autosomal recessive [221]
COL4A4 2q36.3 Autosomal recessive [221]
COL4A5 Xq22.3 X-linked recessive [222]

Branchio-Oto-Renal syndrome
EYA1 8q13.3 Autosomal dominant [223]
SIX5 19q13.32 Autosomal dominant [224]
SIX1 14q23.1 Autosomal dominant [225]

CHARGE syndrome
SEMA3E 7q21.11 Autosomal dominant [226]
CHD7 8q12.2 Autosomal dominant [227]

Jervell & Lange-Nielsen syndrome
KNCQ1 11p15.5-15.4 Autosomal recessive [228]
KCNE1 21q22.12 Autosomal recessive [229, 230]

Norrie disease
NDP Xp11.3 X-linked recessive [231, 232]

Pendred syndrome
SLC26A4 7q22.3 Autosomal recessive [233]
FOXI1 5q35.1 Autosomal recessive [234]
KCNJ10 1q23.2 Autosomal recessive [235]

Perrault syndrome
HSD17B4 5q23.1 Autosomal recessive [236]
HARS2 5q31.3 Autosomal recessive [236]
CLPP 19p13.3 Autosomal recessive [237]
LARS2 3p21.31 Autosomal recessive [238]
TWNK 10q24.21 Autosomal recessive [239]
ERAL1 17q11.2 Autosomal recessive [240]

Stickler syndrome
COL2A1 12q13.11 Autosomal dominant [241]
COL11A1 1p21 Autosomal dominant [242]
COL11A2 6p21.32 Autosomal recessive/dominant [243]
COL9A1 6q13 Autosomal recessive [244]
COL9A2 1p34.2 Autosomal recessive [245]

Treacher Collins syndrome
TCOF1 5q32-q33.1 Autosomal dominant [246]
POLR1D 13q12.2 Autosomal dominant [247]
POLR1C 6p21.1 Autosomal recessive [247]

Usher syndrome
MYO7A 11q13.5 Autosomal recessive [248]
USH1C 11p15.1 Autosomal recessive [249]
CDH23 10q22.1 Autosomal recessive [250]
PCDH15 10q21.1 Autosomal recessive [251]
SANS/USH1G 17q25.1 Autosomal recessive [252]
 See Note A 15q25.1 Autosomal recessive [253]
USH2A 1q41 Autosomal recessive [254]
ADGRV1/VLGR1/GPR98 5q14.3 Autosomal recessive [255]
WHRN 9q32 Autosomal recessive [256]
CLRN1 3q25.1 Autosomal recessive [257]

Waardenburg syndrome
PAX3 2q36.1 Autosomal dominant [258]
MITF 3p13 Autosomal dominant [259]
SNAI2 8q11 Autosomal recessive [260]
SOX10 22q13.1 Autosomal dominant [261]
PAX3 2q36.1 Autosomal dominant or recessive [262]
EDNRB 13q22.3 Autosomal dominant or recessive [263]
EDN3 20q13.32 Autosomal dominant or recessive [264]
SOX10 22q13.1 Autosomal dominant [265]

Table 5

Viral vectors used in gene therapy for genetic hearing loss studies

Viral vector Example Load Animal Route of administration Reference
Adenovirus Ad5-CMV-Atoh1-GFP Atoh1 Guinea pig Cochleostomy (scala media) [274]
Ad5-CMV-Math1.11D Math1 Guinea pig Cochleostomy (scala media) [275]
Ad28-CMV-GFP + Ad28-GFAP-Atoh1 Atoh1 Mouse Round window (scala tympani) [278]

Adeno-associated virus AAV-mVGLUT3 VGLUT3 Mouse Round window (scala tympani) [271]
AAV8-CMV-whirlin-GFP WHRN Mouse Round window (scala tympani) [272]
AAV2/Anc80L65.CMV.trunc-harm USH1C Mouse Round window (scala tympani) [276]
BAAV-β-actin-GFP β-actin Rat Cochleostomy (scala media) [279]

Herpes simplex virus pHSV-blc-2 BCL2 Rats Organ of Corti explants [280]
pHSV-BDNF-LacZ BDNF Rat Spiral ganglia explant [273]

Lentivirus Lenti-HOX-GFP GFP Mouse Round window (scala tympani) [277]

Table 6

Non-viral vectors used in gene therapy for genetic hearing loss studies

Non-viral vector Example Load Animal Route of administration Reference
Cationic liposomes Liposomes β-gal plasmid Guinea pig RWM after cochleostomy [287]
Liposomes eGFP plasmid Mouse Gelfoam on RWM [288290]
Lipofectamine 2000 Math1 Rat OC-derived cell line [291]

Cationic non-liposomal polymers Polybrene Integrin antisense oligonucleotide Rats OC-derived cell line [292]
Dendritic polymers (HPNP) eGFP plasmid Rat Sponge on RWM/cochlear explants [293]
Polyethylenimine (PEI) eGFP plasmid Guinea pig Scala tympani injection [294]
PLGA nanoparticles Fluorescent dye (Rhodamine) Guinea pig Gelfoam on RWM [295]

Biolistic Gold particles using Gene gun MyoXVa Mouse OC explants [296, 297]

Electroporation Electroporation Math1 Rat OC explants [298, 299]
Electroporation Math1 Mouse In utero [300, 301]

RWM, round window membrane; eGFP, enhanced green fluorescent protein; OC, organ of Corti; PLGA, poly(lactic-co-glycolic acid).