**1. Introduction**

The World Health Organization (WHO) defines hearing loss (HL) as the inability to perceive the sounds with different grades of impairment, from slight to profound including deafness [1].

Sound waves move from outer (or external) to middle and then to the inner ear, three anatomically distinct structures of the ear which transmit the sound to a signal into the brain. The sound waves travel down the cannel of the outer and middle ear until hitting the tympanic membrane. Vibrations from the middle ear create movement of the fluid in the inner ear. This movement of the fluid is transmitted through the tectorial membrane to the hair cells in the organ of Corti, then the stimulus is transmitted by electric signals up to the auditory nerve to the brain. The brain interprets the electrical signals as sound. **Figure 1** shows the different compartment of the ear as described above.

Depending on the compartment affected, hearing loss could be classified as *conductive* or *sensorineural*. Conductive hearing loss is when the outer and middle ear are affected, and it results in the inability to transmit sound waves to the inner ear [3]. On the other hand, impairments in the inner ear are known as sensorineural [4]. Conductive hearing loss could be treated by medication, surgery cochlear implants or hearing aids, meanwhile sensorineural is mostly irreversible because of the complexity of the structure, the limited regeneration and access to the sensory structures in the cochlea [5].

#### **Figure 1.**

*Scheme of hearing system from external ear to inner ear. Path of the sound waves (in blue) through outer, middle and inner ear is represented where Sw, sound waves; E, external ear; ec, ear canal; T, tympanic membrane; C, cochlea; N, auditory nerve. Magnification of the cochlea structures (adapted from Sanchez-Calderon et al. [2]) is shown framed in yellow where BC, border cells; CC, Claudius's cells; DC, Deiter's cells; HC, Hensen's cells; IC, intermediate cells; IHC, inner hair cells; IPC, inner phalangeal cells; Li, spiral limbus; N, cochlear neurons; MB, Basilar Membrane; OHC, outer hair cells; PC, pillar cells; RM, Reisner's membrane; SG, spiral ganglion; SL, spiral ligament; SV, stria vascularis and TM, tectorial membrane.*

#### **2. Hearing loss etiology**

There are several causes of hearing loss affecting over 500 million people worldwide [6]. Approximately 50% of the hearing impairment has a genetic etiology, the remaining cases are attributed to external factor such as noise or injury (acquired/ spontaneous). In addition, the contribution of both (genetic predisposition and environment) is very common as found in age-related hearing loss [7, 8].

Inherited hearing loss can be autosomal recessive or dominant, X-linked or mitochondrial-related. The autosomal recessive hearing loss is caused by pathogenic variant in both alleles (the child inherits them from both parents). Autosomal dominant inheritance occurs when variants in one single allele are able to cause hearing loss. Independent of the inheritance pattern, genetics of hearing loss are classified as syndromic when they are associated with pathologies in other organs or malformations of the external ear and non-syndromic [6]. Approximately 30% of hearing loss are syndromic whereas the 70% remaining are non-syndromic [9]. Each type of hearing loss (syndromic and non-syndromic) is further classified according to the mode of inheritance into autosomal recessive, autosomal dominant, X-linked and mitochondrial hearing loss.

#### **2.1 Syndromic hearing loss**

Syndromic hearing loss (SHL) is a form of hearing impairments in which it is associated with other diseases or symptoms. Most commonly SHL is associated with diseases that affect eyes, nervous system and skin. SHL accounts for 30% of hereditary hearing loss and can be inherited in an autosomal recessive, dominant and X-linked patterns. Moreover, several genes described in SHL are also causing non-syndromic hearing loss (NSHL) such as mutations in CDH23 gene causing either Usher syndrome type 1D and autosomal recessive NSHL (DFNB12) (OMIM: 605516) [10].

#### *2.1.1 Autosomal dominant SHL*

*Waardenburg syndrome* (WS) is first described in 1951 by Waardenburg. It is one of the most common congenital, sensorineural SHL [11]. Clinical symptoms include lateral displacement of the inner canthus of the eye (dystopia canthorum),

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pigmentations of the hair, eye and skin. It is estimated that WS is accounting for 2–5% of congenital hearing loss cases. According to the presence or absence of the clinical symptoms, Waardenburg syndrome is divided into four subtypes: WS1, WS2, WS3 and WS4. Patients with WS1, usually has dystopia canthorum, while patient with WS2 are not. WS3 also called Klein-Waardenburg syndrome characterized by dystopia canthorum and upper limb abnormalities. The last type WS4 also called Waardenburg-Shah syndrome is associated with Hirschsprung disease. Patients with WS4 are suffering from blockage of the large intestine and neurological defects. According to the hereditary hearing loss homepage, six genes are associated with WS (**Table 1**) [12]. These genes are essential for the development of

*Branchio-Oto-Renal Syndrome* (BOR) is the second common autosomal dominant congenital SHL. It is characterized by malformations in the ears and is associated with different types of hearing loss: conductive, sensorineural and mixed hearing loss. Moreover, BOR syndrome is affecting kidneys structure and functions which results in renal abnormalities [13]. The frequency of BOR syndrome is estimated to be 1 in 40,000 individuals. Mutations in Eyes Absent homolog 1 (*EYA1*), Sine Oculis Homebox 5 (*SIX5*) and Sine Oculis Homebox 1 (*SIX1*) genes are found to be associated with BOR syndrome (**Table 1**). These genes are required for normal embryonic

**Syndrome Gene OMIM entry Inheritance** Alport syndrome *COL4A3* 120070 AR

Branchio-Oto-Renal syndrome *EYA1* 601653 AD

CHARGE syndrome *CHD7* 608892 AD

Jervell and Lange-Nielsen syndrome *KNCQ1* 607542 AR

Norrie disease *NDP* 300658 XL Pendred syndrome *SLC26A4* 605646 AR

Perrault syndrome *HSD17B4* 601860 AR

Stickler syndrome *COL2A1* 120140 AD

*COL4A4* 120131 AR *COL4A5* 303630 XL

*SIX5* 600963 AD *SIX1* 601205 AD

*SEMA3E* 608166 AD

*KCNE1* 176261 AR

*KCNJ10* 602208 AR *FOX11* 601093 AR

*HARS2* 600783 AR *CLPP* 601119 AR *LARS2* 604544 AR *TWNK* 606075 AR *ERAL1* 607435 AR

*COL11A1* 120280 AD *COL11A2* 120290 AD *COL9A1* 120210 AR *COL9A2* 120260 AR

melanocytes and have a major role in the function of the inner ear.

development of different organs including both the kidneys and the ears.

#### *Genetics and Acquired Hearing Loss DOI: http://dx.doi.org/10.5772/intechopen.86664*

*Geriatric Medicine and Gerontology*

**2. Hearing loss etiology**

**Figure 1.**

There are several causes of hearing loss affecting over 500 million people worldwide [6]. Approximately 50% of the hearing impairment has a genetic etiology, the remaining cases are attributed to external factor such as noise or injury (acquired/ spontaneous). In addition, the contribution of both (genetic predisposition and

*Scheme of hearing system from external ear to inner ear. Path of the sound waves (in blue) through outer, middle and inner ear is represented where Sw, sound waves; E, external ear; ec, ear canal; T, tympanic membrane; C, cochlea; N, auditory nerve. Magnification of the cochlea structures (adapted from Sanchez-Calderon et al. [2]) is shown framed in yellow where BC, border cells; CC, Claudius's cells; DC, Deiter's cells; HC, Hensen's cells; IC, intermediate cells; IHC, inner hair cells; IPC, inner phalangeal cells; Li, spiral limbus; N, cochlear neurons; MB, Basilar Membrane; OHC, outer hair cells; PC, pillar cells; RM, Reisner's membrane;* 

Inherited hearing loss can be autosomal recessive or dominant, X-linked or mitochondrial-related. The autosomal recessive hearing loss is caused by pathogenic variant in both alleles (the child inherits them from both parents). Autosomal dominant inheritance occurs when variants in one single allele are able to cause hearing loss. Independent of the inheritance pattern, genetics of hearing loss are classified as syndromic when they are associated with pathologies in other organs or malformations of the external ear and non-syndromic [6]. Approximately 30% of hearing loss are syndromic whereas the 70% remaining are non-syndromic [9]. Each type of hearing loss (syndromic and non-syndromic) is further classified according to the mode of inheritance into autosomal recessive, autosomal domi-

Syndromic hearing loss (SHL) is a form of hearing impairments in which it is associated with other diseases or symptoms. Most commonly SHL is associated with diseases that affect eyes, nervous system and skin. SHL accounts for 30% of hereditary hearing loss and can be inherited in an autosomal recessive, dominant and X-linked patterns. Moreover, several genes described in SHL are also causing non-syndromic hearing loss (NSHL) such as mutations in CDH23 gene causing either Usher syndrome type 1D and autosomal recessive NSHL (DFNB12) (OMIM:

*Waardenburg syndrome* (WS) is first described in 1951 by Waardenburg. It is one of the most common congenital, sensorineural SHL [11]. Clinical symptoms include lateral displacement of the inner canthus of the eye (dystopia canthorum),

environment) is very common as found in age-related hearing loss [7, 8].

*SG, spiral ganglion; SL, spiral ligament; SV, stria vascularis and TM, tectorial membrane.*

nant, X-linked and mitochondrial hearing loss.

**2.1 Syndromic hearing loss**

*2.1.1 Autosomal dominant SHL*

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605516) [10].

pigmentations of the hair, eye and skin. It is estimated that WS is accounting for 2–5% of congenital hearing loss cases. According to the presence or absence of the clinical symptoms, Waardenburg syndrome is divided into four subtypes: WS1, WS2, WS3 and WS4. Patients with WS1, usually has dystopia canthorum, while patient with WS2 are not. WS3 also called Klein-Waardenburg syndrome characterized by dystopia canthorum and upper limb abnormalities. The last type WS4 also called Waardenburg-Shah syndrome is associated with Hirschsprung disease. Patients with WS4 are suffering from blockage of the large intestine and neurological defects. According to the hereditary hearing loss homepage, six genes are associated with WS (**Table 1**) [12]. These genes are essential for the development of melanocytes and have a major role in the function of the inner ear.

*Branchio-Oto-Renal Syndrome* (BOR) is the second common autosomal dominant congenital SHL. It is characterized by malformations in the ears and is associated with different types of hearing loss: conductive, sensorineural and mixed hearing loss. Moreover, BOR syndrome is affecting kidneys structure and functions which results in renal abnormalities [13]. The frequency of BOR syndrome is estimated to be 1 in 40,000 individuals. Mutations in Eyes Absent homolog 1 (*EYA1*), Sine Oculis Homebox 5 (*SIX5*) and Sine Oculis Homebox 1 (*SIX1*) genes are found to be associated with BOR syndrome (**Table 1**). These genes are required for normal embryonic development of different organs including both the kidneys and the ears.



#### **Table 1.**

*List of syndromic hearing loss and its associated genes [12].*

*CHARGE syndrome* is another form of autosomal dominant hearing loss syndrome that affects several organs. Patients with CHARGE syndrome are characterized by different phenotypes, from which the name of the syndrome comes from, this includes: Coloboma, Heart defects, Atresia choanae, growth Retardation, Genital abnormalities and Ear abnormalities. The degree of abnormalities varies from one patient to another. It ranges from very severe and vital cases to minor phenotypes. The prevalence of CHARGE syndrome estimated to be 1 in 8500 to 10,000 newborns worldwide. Chromodomain helicase DNA-binding protein-7 (*CHD7*) is found to be the common cause of CHARGE syndrome. *CHD7* is a transcription factor protein that regulates chromatin [14].

### *2.1.2 Autosomal recessive SHL*

*Usher syndrome* is an autosomal recessive sensorineural hearing loss (SNHL) with retinitis [15]. According to the clinical phenotype, Usher syndrome is classified to three main types: Usher 1 (USH1), Usher 2 (USH2) and Usher 3 (USH3). USH1 is characterized by severe to profound SNHL, severe vestibular impairments and early onset retinitis pigmentosa. Mutations in several genes are found to be the cause of USH1 syndrome (**Table 1**). The most common genes causing USH1 are *MYO7A* and *CHD23*. Both genes are important for the development and function of inner ear hair cells. Patients with USH2 are found to suffer from moderate to severe SNHL with mid onset retinitis pigmentosa and no vestibular impairment. Usherin (*USH2A*) and Adhesion-G protein coupled receptor VI (*ADGRVI*) are found to be

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of the cases are).

*2.1.3 X-linked SHL*

syndrome are examples of X-Linked SHL.

*2.1.4 Mitochondrial-linked SHL*

functioning had been linked in MIDD [29].

*DOI: http://dx.doi.org/10.5772/intechopen.86664*

mutated in patients diagnosed with USH2. The last type is USH3 that is characterized by variable phenotypes of progressive hearing loss, vestibular impairment and late onset retinitis pigmentosa. The prevalence of Usher syndrome is estimated to be

The second common autosomal recessive SHL is *Pendred Syndrome* which is characterized by hearing loss and thyroid enlargement [16]. The hearing loss ranges from severe to profound are usually developed at early childhood [17]. A characteristic feature of Pendred syndrome is the Mondini malformation which is a combination of enlarged vestibular aqueduct and abnormal shape of the cochlea. The prevalence of Pendred syndrome is ranged from 1 to 7.5 per 100,000 newborns. Three genes are found to be mutated in patients with Pendred syndrome: *SLC26A4* which encodes for sodium-independent transporter of chloride iodide protein called Pendrin [18], *FOXI1* [19] and *KCNJ10* [20]. Approximately 50% of Pendred syndrome patients had mutations in *SLC26A4* gene, whereas the other two genes mutated in Pendred syndrome patients account for less than 2%

*Jervell and Lange-Nielsen Syndrome* is the third common autosomal recessive syndromic hearing loss. This condition is characterized by profound hearing loss with arrhythmia and long QT interval in the electrocardiogram that may result in heart failure and sudden death [21]. The prevalence of this syndrome is estimated to affect 1.6–6 per million people worldwide [22]. Genes found to be mutated in patients with this syndrome are potassium channel voltage-gated KQT-like subfamily member 1 (*KCNQ1*) [23] and potassium channel voltage-gated ISK-related subfamily member 1 (*KCNE1*) [24] with majority of the mutations (90%) occurs in *KCNQ1*. These channels are important for the movement of the potassium ions in order to maintain the normal function of the inner ear and cardiac muscle.

Hearing loss conditions inherited with an X-linked pattern are rare. Only few syndromes with few patients were reported. Norrie disease and Mohr-Tranebjaerg

*Norrie disease* is a rare X-linked recessive disorder characterized by progressive visual impairment. One-third of males with Norrie disease will develop progressive hearing loss and other phenotype-like intellectual disabilities. Mutation in *NDP* gene is the cause of 95% of the affected individuals. *NDP* is a gene that encodes

*Mohr-Tranebjaerg syndrome* also called deafness dystonia optic atrophy syndrome is another X-linked recessive syndrome that is associated with early onset hearing loss, movement disability and visual impairment. Less than 70 cases of this syndrome were reported worldwide. *TIMM8A* is the causative gene for this syndrome which encodes the Translocase of Inner Mitochondrial Membrane 8 homolog A protein. This protein is important for the development of nervous system [26].

*Maternally inherited diabetes and deafness* (MIDD) is a mitochondrial disorder causing a syndromic form of diabetes accompanied by sensorineural hearing loss and some cases include renal problems, pigmentary retinopathy, ptosis, myopathy, cardiomyopathy and/or neuro-psychiatric symptoms (OMIM: 520000) [27, 28]. Mutations in MT-TL1, MT-TK or MT-TE mitochondrial genes coding for mtRNAs, which participate in the protein production in mitochondria and impair their

Norrin protein which regulates vascularization of the retina [25].

1 in 6000 to 10,000 with USH1 and USH2 being the most common types.

#### *Genetics and Acquired Hearing Loss DOI: http://dx.doi.org/10.5772/intechopen.86664*

*Geriatric Medicine and Gerontology*

*CHARGE syndrome* is another form of autosomal dominant hearing loss syndrome that affects several organs. Patients with CHARGE syndrome are characterized by different phenotypes, from which the name of the syndrome comes from, this includes: Coloboma, Heart defects, Atresia choanae, growth Retardation, Genital abnormalities and Ear abnormalities. The degree of abnormalities varies from one patient to another. It ranges from very severe and vital cases to minor phenotypes. The prevalence of CHARGE syndrome estimated to be 1 in 8500 to 10,000 newborns worldwide. Chromodomain helicase DNA-binding protein-7 (*CHD7*) is found to be the common cause of CHARGE syndrome. *CHD7* is a transcription

**Syndrome Gene OMIM entry Inheritance** Treacher Collins syndrome *TCOF1* 606847 AD

Usher syndrome *MYO7A* 276903 AD

Waardenburg syndrome *PAX3* 606597 AD

*POLR1D* 613715 AD *POLR1C* 610060 AD

*USH1C* 605242 AR *CDH23* 605516 AR *PCDH15* 605514 AR *SANS* 607696 AR *USH2A* 608400 AR *ADGRV1* 602851 AR *WHRN* 607928 AR *CLRN1* 606397 AR *HARS* 142810 AR

*MITF* 156845 AD *SNAI2* 602150 AD *SOX10* 602229 AD *PAX3* 606597 AD *EDNRB* 131244 AR *EDN3* 131242 AR *SOX10* 602229 AR

*Usher syndrome* is an autosomal recessive sensorineural hearing loss (SNHL) with retinitis [15]. According to the clinical phenotype, Usher syndrome is classified to three main types: Usher 1 (USH1), Usher 2 (USH2) and Usher 3 (USH3). USH1 is characterized by severe to profound SNHL, severe vestibular impairments and early onset retinitis pigmentosa. Mutations in several genes are found to be the cause of USH1 syndrome (**Table 1**). The most common genes causing USH1 are *MYO7A* and *CHD23*. Both genes are important for the development and function of inner ear hair cells. Patients with USH2 are found to suffer from moderate to severe SNHL with mid onset retinitis pigmentosa and no vestibular impairment. Usherin (*USH2A*) and Adhesion-G protein coupled receptor VI (*ADGRVI*) are found to be

factor protein that regulates chromatin [14].

*List of syndromic hearing loss and its associated genes [12].*

*2.1.2 Autosomal recessive SHL*

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**Table 1.**

mutated in patients diagnosed with USH2. The last type is USH3 that is characterized by variable phenotypes of progressive hearing loss, vestibular impairment and late onset retinitis pigmentosa. The prevalence of Usher syndrome is estimated to be 1 in 6000 to 10,000 with USH1 and USH2 being the most common types.

The second common autosomal recessive SHL is *Pendred Syndrome* which is characterized by hearing loss and thyroid enlargement [16]. The hearing loss ranges from severe to profound are usually developed at early childhood [17]. A characteristic feature of Pendred syndrome is the Mondini malformation which is a combination of enlarged vestibular aqueduct and abnormal shape of the cochlea. The prevalence of Pendred syndrome is ranged from 1 to 7.5 per 100,000 newborns. Three genes are found to be mutated in patients with Pendred syndrome: *SLC26A4* which encodes for sodium-independent transporter of chloride iodide protein called Pendrin [18], *FOXI1* [19] and *KCNJ10* [20]. Approximately 50% of Pendred syndrome patients had mutations in *SLC26A4* gene, whereas the other two genes mutated in Pendred syndrome patients account for less than 2% of the cases are).

*Jervell and Lange-Nielsen Syndrome* is the third common autosomal recessive syndromic hearing loss. This condition is characterized by profound hearing loss with arrhythmia and long QT interval in the electrocardiogram that may result in heart failure and sudden death [21]. The prevalence of this syndrome is estimated to affect 1.6–6 per million people worldwide [22]. Genes found to be mutated in patients with this syndrome are potassium channel voltage-gated KQT-like subfamily member 1 (*KCNQ1*) [23] and potassium channel voltage-gated ISK-related subfamily member 1 (*KCNE1*) [24] with majority of the mutations (90%) occurs in *KCNQ1*. These channels are important for the movement of the potassium ions in order to maintain the normal function of the inner ear and cardiac muscle.

### *2.1.3 X-linked SHL*

Hearing loss conditions inherited with an X-linked pattern are rare. Only few syndromes with few patients were reported. Norrie disease and Mohr-Tranebjaerg syndrome are examples of X-Linked SHL.

*Norrie disease* is a rare X-linked recessive disorder characterized by progressive visual impairment. One-third of males with Norrie disease will develop progressive hearing loss and other phenotype-like intellectual disabilities. Mutation in *NDP* gene is the cause of 95% of the affected individuals. *NDP* is a gene that encodes Norrin protein which regulates vascularization of the retina [25].

*Mohr-Tranebjaerg syndrome* also called deafness dystonia optic atrophy syndrome is another X-linked recessive syndrome that is associated with early onset hearing loss, movement disability and visual impairment. Less than 70 cases of this syndrome were reported worldwide. *TIMM8A* is the causative gene for this syndrome which encodes the Translocase of Inner Mitochondrial Membrane 8 homolog A protein. This protein is important for the development of nervous system [26].

#### *2.1.4 Mitochondrial-linked SHL*

*Maternally inherited diabetes and deafness* (MIDD) is a mitochondrial disorder causing a syndromic form of diabetes accompanied by sensorineural hearing loss and some cases include renal problems, pigmentary retinopathy, ptosis, myopathy, cardiomyopathy and/or neuro-psychiatric symptoms (OMIM: 520000) [27, 28]. Mutations in MT-TL1, MT-TK or MT-TE mitochondrial genes coding for mtRNAs, which participate in the protein production in mitochondria and impair their functioning had been linked in MIDD [29].

#### **2.2 Non-syndromic hearing loss**

Hearing loss which is not associated with any other disease or symptoms is called non-syndromic hearing loss (NSHL). It accounts for more than 70% of hereditary hearing loss. According to the hereditary hearing loss homepage, there are more than 100 genes associated with NSHL and more than 6000 causative variants are identified so far which makes it extremely heterogeneous [30].

According to the mode of inheritance, NSHL can be classified as autosomal recessive (75–85%), autosomal dominant (20–25%) and X-linked or mitochondrial (1–2%). The loci responsible for NSHL are named DEN which stands for Deafness. Letter "A" is added, if the mode of inheritance is autosomal dominant (DFNA), "B" if the inheritance is recessive (DFNB) and "X" if the inheritance is X-linked (DFNX). The numbers indicate the chronological order of gene discovery.

#### *2.2.1 Autosomal dominant NSHL genes (DFNA)*

Autosomal dominant forms account for 20–25% of NSHL and are characterized by post-lingual progressive hearing loss [31]. More than 40 genes are associated with autosomal dominant NSHL. *DIAPH1* gene which is located in the DFNA1 locus is one of the first loci described for autosomal dominant NSHL. It encodes protein that is important for polymerization with actin which plays major role in cytoskeletal of hair cells in the inner ear. Mutations in *DIAPH1* are associated with early onset progressive hearing loss and some patients may have mild thrombocytopenia without bleeding tendencies [32].

*WFS1* encodes for Wolframin protein which plays role in regulating cellular Ca2 + homeostasis and is involved in the process of sensory perception of sound. Mutations in *WFS1* are found to be associated with DFNA6, DFNA14 and DFNA38 in which they are characterized by hearing loss in low frequency [33, 34]. Some missense mutations in this gene are also associated with congenital profound hearing loss, progressive optic atrophy and diabetes. The above-mentioned phenotypes are a form of autosomal recessive hearing loss condition known as Wolfram syndrome [35].

The *TECTA* gene that encodes the tectorin-alpha protein forms the tectorial membrane in the cochlea and the otolithic membrane in the vestibular system. Mutations in *TECTA* are found in families with DFNA8/12 in which hearing loss could be pre- or post-lingual [36]. The severity of hearing loss varies depending on the domain where the mutation occurs. Some mutations in *TECTA* are also associated with DFNB21 hearing loss in which hearing loss is prelingual with severe to profound phenotype [37].

Deafness autosomal dominant 5 (*DFNA5*) gene that encodes for the Gasdermin-E protein is another gene associated with autosomal dominant nonsyndromic hearing loss [38]. Gasdermin-E plays essential role in cellular response to DNA damage by regulating TP53.

Other genes associated with autosomal dominant hearing loss are listed in **Table 2**.

#### *2.2.2 Autosomal recessive NSHL*

Autosomal recessive hearing loss account for majority (75–85%) forms of nonsyndromic hearing loss in which the hearing loss is prelingual and severe to profound. The most common gene causing autosomal recessive NSHL is *GJB2* accounts for 50% of the cases. The other 50% of the autosomal recessive NSHL resulted from mutations in 70 genes (**Table 2**).

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**Gene Locus OMIM entry Inheritance** *ACTG1* DFNA20/26 102560 AD *ADCY1* DFNB44 103072 AR *AIFM1* DFNX5 300169 XL *BDP1* DFNB49 607012 AR *BSND* DFNB73 606412 AR *CABP2* DFNB93 607314 AR *CCDC50* DFNA44 611051 AD *CD164* DFNA66 603356 AD *CDC14A* DFNB32/105 601728 AR *CDH23* DFNB12 605516 AR *CEACAM16* DFNA4B 614591 AD *CIB2* DFNB48 605564 AR *CLDN14* DFNB29 605608 AR *CLIC5* DFNB103 607293 AR *COCH* DFNA9 603196 AD *COL11A1* DFNA37 120280 AD *COL11A2* DFNB53, DFNA13 120290 AR, AD *COL4A6* DFNX6 303631 XL *CRYM* DFNA40 123740 AD *DCDC2* DFNB66 605755 AR *DIAPH1* DFNA1 602121 AD *DMXL2* 612186 AD *ELMOD3* DFNB88 615427 AR *EPS8* DFNB102 600206 AR *EPS8L2* DFNB106 614988 AR *ESPN* DFNB36 606351 AR *ESRP1* 609245 AR *ESRRB* DFNB35 602167 AR *EYA4* DFNA10 603550 AD *FAM65B* DFNB104 611410 AR *GIPC3* DFNB15/72/95 608792 AR *GJB2* DFNB1A, DFNA3A 121011 AR, AD *GJB3* DFNA2B 603324 AD *GJB6* DFNB1B, DFNA3B 604418 AR, AD *GPSM2* DFNB82 609245 AR *GRHL2* DFNA28 608576 AD *GRXCR1* DFNB25 613283 AR *GRXCR2* DFNB101 615762 AR *GSDME/DFNA5* DFNA5 608798 AD *HGF* DFNB39 142409 AR *HOMER2* DFNA68 604799 AD *IFNLR1* DFNA2C 607404 AD *ILDR1* DFNB42 609739 AR

#### *Genetics and Acquired Hearing Loss DOI: http://dx.doi.org/10.5772/intechopen.86664*

*Geriatric Medicine and Gerontology*

**2.2 Non-syndromic hearing loss**

Hearing loss which is not associated with any other disease or symptoms is called non-syndromic hearing loss (NSHL). It accounts for more than 70% of hereditary hearing loss. According to the hereditary hearing loss homepage, there are more than 100 genes associated with NSHL and more than 6000 causative variants are

According to the mode of inheritance, NSHL can be classified as autosomal recessive (75–85%), autosomal dominant (20–25%) and X-linked or mitochondrial (1–2%). The loci responsible for NSHL are named DEN which stands for Deafness. Letter "A" is added, if the mode of inheritance is autosomal dominant (DFNA), "B" if the inheritance is recessive (DFNB) and "X" if the inheritance is X-linked (DFNX). The numbers indicate the chronological order of gene discovery.

Autosomal dominant forms account for 20–25% of NSHL and are characterized by post-lingual progressive hearing loss [31]. More than 40 genes are associated with autosomal dominant NSHL. *DIAPH1* gene which is located in the DFNA1 locus is one of the first loci described for autosomal dominant NSHL. It encodes protein that is important for polymerization with actin which plays major role in cytoskeletal of hair cells in the inner ear. Mutations in *DIAPH1* are associated with early onset progressive hearing loss and some patients may have mild thrombocytopenia

*WFS1* encodes for Wolframin protein which plays role in regulating cel-

 homeostasis and is involved in the process of sensory perception of sound. Mutations in *WFS1* are found to be associated with DFNA6, DFNA14 and DFNA38 in which they are characterized by hearing loss in low frequency [33, 34]. Some missense mutations in this gene are also associated with congenital profound hearing loss, progressive optic atrophy and diabetes. The above-mentioned phenotypes are a form of autosomal recessive hearing loss condition known as Wolfram

The *TECTA* gene that encodes the tectorin-alpha protein forms the tectorial membrane in the cochlea and the otolithic membrane in the vestibular system. Mutations in *TECTA* are found in families with DFNA8/12 in which hearing loss could be pre- or post-lingual [36]. The severity of hearing loss varies depending on the domain where the mutation occurs. Some mutations in *TECTA* are also associated with DFNB21 hearing loss in which hearing loss is prelingual with severe to

Other genes associated with autosomal dominant hearing loss are listed in **Table 2**.

Autosomal recessive hearing loss account for majority (75–85%) forms of nonsyndromic hearing loss in which the hearing loss is prelingual and severe to profound. The most common gene causing autosomal recessive NSHL is *GJB2* accounts for 50% of the cases. The other 50% of the autosomal recessive NSHL resulted from

Deafness autosomal dominant 5 (*DFNA5*) gene that encodes for the Gasdermin-E protein is another gene associated with autosomal dominant nonsyndromic hearing loss [38]. Gasdermin-E plays essential role in cellular response to

identified so far which makes it extremely heterogeneous [30].

*2.2.1 Autosomal dominant NSHL genes (DFNA)*

without bleeding tendencies [32].

lular Ca2

+

syndrome [35].

profound phenotype [37].

DNA damage by regulating TP53.

*2.2.2 Autosomal recessive NSHL*

mutations in 70 genes (**Table 2**).

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**121**

**Table 2.**

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*DOI: http://dx.doi.org/10.5772/intechopen.86664*

found to cause DFNB1 and DFNA3 [39].

*mitochondrial (MIT) non-syndromic hearing loss (NSHL) [12].*

tion also carry mutation in *GJB6* [40].

pathways to the brain [41].

*GJB2* gene is one of the gap junction proteins that are expressed in the inner ear, which encodes connexin 26. This protein allows the exchange of potassium ions between the cells in the inner ear. More than 100 mutations identified in *GJB2* were

*List of genes associated with autosomal dominant (AD), autosomal recessive (AR), X-linked (XL) and* 

**Gene Locus OMIM entry Inheritance** *SIX1* DFNA23 601205 AD *SLC17A8* DFNA25 607557 AD *SLC22A4* DFNB60 604943 AR *SLC26A4* DFNB4 605646 AR *SLC26A5* DFNB61 604943 AR *SMAC/DIABLO* DFNA64 605219 AD *SMPX* DFNX4 300226 XL *STRC* DFNB16 606440 AR *SYNE4* DFNB76 615535 AR *TBC1D24* DFNB86, DFNA65 613577 AR, AD *TECTA* DFNB21, DFNA8/12 602574 AR, AD *TJP2* DFNA51 607709 AD *TMC1* DFNB7/11, DFNA36 606706 AR, AD *TMEM132E* DFNB99 616178 AR *TMIE* DFNB6 607237 AR *TMPRSS3* DFNB8/10 605511 AR *TNC* DFNA56 187380 AD *TPRN* DFNB79 613354 AR *TRIOBP* DFNB28 609761 AR *TSPEAR* DFNB98 612920 AR *Unknown* DFNY1 400043 YL *USH1C* DFNB18 605242 AR *WBP2* 606962 AR *WFS1* DFNA6/14/38 606201 AD *WHRN* DFNB31 607928 AR

Other gene related to *GJB2* is *GJB6* that encodes for connexin 30 protein. Studies show that both genes can be inherited together and 8% of patients with *GJB2* muta-

*OTOF* gene encodes otoferlin protein that is responsible for the neural transmission at the synaptic cleft of the inner hair cell. Mutations in this gene cause prelingual, profound autosomal recessive hearing loss (DFNB9) and will result in damage of the neural receptors of the inner ear that will result on interruption of the nerve

Conventional and unconventional myosins are group of genes that are functioning as actin-binding proteins. Conventional myosins regulate contractility of actin filaments, while unconventional myosins are essential for vesicle trafficking and endocytosis [42]. Mutations in some unconventional myosins are associated with NSHL. *MYO6* is an example of unconventional myosins that is expressed in the

*Genetics and Acquired Hearing Loss DOI: http://dx.doi.org/10.5772/intechopen.86664*

*Geriatric Medicine and Gerontology*

**Gene Locus OMIM entry Inheritance** *KARS* DFNB89 601421 AR *KCNQ4* DFNA2A 603537 AD *KITLG* DFNA69 184745 AD *LHFPL5* DFNB66/67 609427 AR *LMX1A* DFNA7 600298 AD *LOXHD1* DFNB77 613072 AR *LRTOMT/COMT2* DFNB63 612414 AR *MARVELD2* DFNB49 610572 AR *MCM2* DFNA70 116945 AD *MET* DFNB97 164860 AR *MIRN96* DFNA50 611606 AD *MPZL2* 604873 AR *MSRB3* DFNB74 613719 AR *MTRNR1* 561000 MIT *MTTS1* 590080 MIT *MYH14* DFNA4A 608568 AD *MYH9* DFNA17 160775 AD *MYO15A* DFNB3 602666 AR *MYO3A* DFNB30 606808 AR, AD *MYO6* DFNB37, DFNA22 600970 AR, AD *MYO7A* DFNB2, DFNA11 276903 AR, AD *NARS2* DFNB94 612803 AR *NLRP3* DFNA34 606416 AD *OSBPL2* DFNA67 606731 AD *OTOA* DFNB22 607038 AR *OTOF* DFNB9 603681 AR *OTOG* DFNB18B 604487 AR *OTOGL* DFNB84 614925 AR *P2RX2* DFNA41 600844 AD *PCDH15* DFNB23 605514 AR *PDE1C* 602987 AD *PDZD7* DFNB57 612971 AR *PJVK* DFNB59 610219 AR *PNPT1* DFNB70 610316 AR *POU3F4* DFNX2 300039 XL *POU4F3* DFNA15 602460 AD *PPIP5K2* DFNB100 611648 AR *PRPS1* DFNX1 311850 XL *PTPRQ* DFNB84, DFNA73 603317 AR, AD *RDX* DFNB24 179410 AR *REST* DFNA27 600571 AD *ROR1* DFNB108 612959 AR *S1PR2* DFNB68 609427 AR *SERPINB6* DFNB91 173321 AR

**120**


#### **Table 2.**

*List of genes associated with autosomal dominant (AD), autosomal recessive (AR), X-linked (XL) and mitochondrial (MIT) non-syndromic hearing loss (NSHL) [12].*

*GJB2* gene is one of the gap junction proteins that are expressed in the inner ear, which encodes connexin 26. This protein allows the exchange of potassium ions between the cells in the inner ear. More than 100 mutations identified in *GJB2* were found to cause DFNB1 and DFNA3 [39].

Other gene related to *GJB2* is *GJB6* that encodes for connexin 30 protein. Studies show that both genes can be inherited together and 8% of patients with *GJB2* mutation also carry mutation in *GJB6* [40].

*OTOF* gene encodes otoferlin protein that is responsible for the neural transmission at the synaptic cleft of the inner hair cell. Mutations in this gene cause prelingual, profound autosomal recessive hearing loss (DFNB9) and will result in damage of the neural receptors of the inner ear that will result on interruption of the nerve pathways to the brain [41].

Conventional and unconventional myosins are group of genes that are functioning as actin-binding proteins. Conventional myosins regulate contractility of actin filaments, while unconventional myosins are essential for vesicle trafficking and endocytosis [42]. Mutations in some unconventional myosins are associated with NSHL. *MYO6* is an example of unconventional myosins that is expressed in the

inner hair cell of the cochlea. Mutation in *MYO6* causes DFNB37, a form of nonsyndromic deafness characterized by prelingual severe to profound hearing loss [43]. Other genes are listed in **Table 2**.

### *2.2.3 X-linked NSHL*

This form of hearing loss is very rare and only few genes are associated with non-syndromic hearing loss (**Table 2**). This form of hearing loss is characterized by progressive, conductive and sensorineural hearing loss. Mutations in *POU3F4* gene which cause DFNX2, account for 50% of the cases [44]. *POU3F4* gene encode for POU domain class 3 transcription factor 4 protein, which regulates the proliferation of neural cells in middle and inner ear early during development. Because this form of hearing loss is X-linked, the severity of hearing loss differs from male to female. In males, hearing loss is prelingual and range from severe to profound while in females hearing loss is post-lingual and less severe.
