Open access peer-reviewed chapter

A Short Overview on Hearing Loss and Related Auditory Defects

Written By

Hina Khan, Hafiza Idrees, Zunaira Munir and Memoona Ramzan

Submitted: 27 April 2022 Reviewed: 09 May 2022 Published: 15 June 2022

DOI: 10.5772/intechopen.105222

From the Edited Volume

Auditory System - Function and Disorders

Edited by Sadaf Naz

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Abstract

Hearing is the ability of a person to recognize sound in the surroundings and it makes communication possible. Ear is the human organ serving as a transducer that perceives signals from the environment and converts it into detectable forms for interpretation by the brain. The auditory system is among one of the most highly studied systems. Researchers have described the physiological function of the system in detail but due to its complexity, the genetic mechanisms and genes implicated in auditory function are still being revealed. Numerous studies on the genetics of hearing indicate hearing loss as one of the most common and prevalent disorders as it affects approximately five million people worldwide. Besides hearing loss, there are several other pathologies of auditory system which are common and have an established genetic basis. In this chapter, we will introduce the genetics of some common auditory pathologies including syndromic and non-syndromic hearing loss, auditory neuropathy, age-related hearing loss, and tinnitus. These understandings will 1 day lead to better diagnosis, management, and cures.

Keywords

  • auditory neuropathy
  • hearing loss
  • tinnitus

1. Introduction

The medical condition which affects any process during sound transmission from ear to brain i.e. anywhere along the auditory pathway is termed hearing loss or deafness [1, 2]. The range of normal audible spectrum is 20–20,000 Hz. Hearing loss is the third most prevalent physical condition and one of the most common sensory disorders in humans [3, 4]. According to World Health Organization (WHO) (http://www.who.int/), around 466 million people (or 6.1% of the world’s population) are affected by deafness, including 34 million children under the age of 15 and 50% of all adults over the age of 75 [5]. By 2030, this figure is expected to increase to 630 million, and by 2050, it will be over 900 million [6].

Defective hearing can be categorized into a variety of types based on the damaged area of the auditory system, severity, type, age, mode of inheritance, and/or the involvement of other phenotypes. By severity, the hearing loss may be mild (20–40 dB HL), moderate (41–70 dB HL), severe (71–95 dB HL), and profound deafness that is greater than 95 dB HL [7]. Hearing loss can be classified on the basis of involved regions of the ear as well. Conductive hearing loss describes the phenotype due to the outer or middle ear defects. Sensorineural hearing loss involves inner ear defects. Mixed hearing loss indicates the presence of conductive and sensorineural hearing loss together [8]. With reference to age, hearing loss may be pre-lingual in which hearing loss occurs before speech development, or post-lingual in which hearing loss occurs after speech development [9].

Hearing loss can be genetic or caused by environmental factors. Environmental factors include high exposure to ototoxic agents, trauma, and bacterial or viral infections [10]. Genetic hearing loss can be inherited in different modes. It can include autosomal dominant, autosomal recessive, X-linked, or mitochondrial modes of inheritance. Mitochondrial hearing loss accounts for less than 1% of all instances of hereditary hearing loss. A human mitochondrion’s genome is 16,569-bp long and contains 22 tRNA and 2 rRNA genes and encodes 13 proteins. Mitochondrial hearing loss may be non-syndromic or syndromic as some other associated disorders can occur in addition to hearing [11]. X-linked hearing loss accounts for around 1–2% of cases of non-syndromic hearing loss, as well as many syndromic types. Approximately 80% of inherited hearing loss is autosomal recessive. Predominantly, it is a monogenic trait in each family. However, overall, it is heterogenetic [12]. Genetic hearing loss can be either in the form of syndromic or non-syndromic form. Approximately 30% of deafness comprises syndromic forms. It involves the presence of hearing loss in combination with other symptoms. More than 400 syndromes are known to be associated with deafness as one of the phenotypes and many of the causative genes involved in these syndromes have been identified [13]. Most common syndromes which are associated with hearing loss are Pendred syndrome and Usher syndrome [14].

Predominantly, 70% of deafness is non-syndromic i.e. hearing loss is the only phenotype. Approximately, 80% of all non-syndromic deafness cases are autosomal recessive (DFNB), 15–20% are autosomal dominant (DFNA), 1–2% cases are X-linked (DFN) and less than 1% of hearing loss is Y linked (DFNY) or mitochondrial [15]. More than 115 non-syndromic hearing loss genes have been identified (https://hereditaryhearingloss.org, accessed April 2022). More than 100 loci have been mapped to different chromosomal positions for non-syndromic autosomal recessive hearing loss in humans. It was originally estimated that approximately 1% of human protein-coding genes are involved in audition [16], but this number has already been exceeded. New research indicates that up to a thousand genes may be involved in hearing. Therefore, additional genes remain to be discovered that cause hearing loss.

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2. Syndromic hearing loss

Syndromic hearing loss is defined as hearing loss accompanying other clinical features in at least one other body system [17]. Up to 30% of hereditary deafness is syndromic and more than 400 genetic disorders have been associated with hearing loss [18]. There are many syndromes associated with hearing loss, but the most common hearing loss-linked syndromes are Pendred syndrome, Usher syndrome, and Waardenburg syndrome [19]. Pendred and Usher syndrome are often confused with non-syndromic cases due to delayed onset of subtle manifestation of other phenotypes.

Pendred syndrome is a condition typically associated with sensorineural deafness, goiter (an enlargement of the thyroid gland), and/or enlarged vestibular aqueduct. It is the most common autosomal recessive sensorineural hearing loss with an estimated incidence of 10 in 100,000 individuals [20, 21, 22]. The hearing impairment is usually congenital or has early-onset while goiter appears in the later years of life. Pendred syndrome is mainly caused by the biallelic variants in SLC26A4 gene, which encodes Pendrin, a transmembrane exchanger of anions and bases. Until now, numerous missense, deletions, and truncating variants in SLC26A4 for Pendred syndrome have been reported [23]. Splice-site, as well as a few missense variants, are described in association with non-syndromic hearing impairment, DFNB4 [24]. Additionally, there are some variants, which may cause non-syndromic deafness DFNB4 or syndromic PDS in a few cases [25].

Usher syndrome is a condition characterized by deafness/hearing loss and vision/an eye disease called retinitis pigmentosa (RP); sometimes also affecting balance. It is the second most syndrome associated with hearing loss with a frequency of 6 in 100,000 individuals, and is often misdiagnosed and presented as a non-syndromic disorder [26]. Usher syndrome has three main clinical types based on the age of onset and audiovestibular features. Usher syndrome presents significant genetic heterogeneity, which means more than one gene can cause the same type of the syndrome [17]. Usher type I (USH1) is the most severe subtype, characterized by profound congenital sensorineural deafness, progressive retinitis pigmentosa, and vestibular dysfunction. To date, five USH1 genes have been identified; MYO7A (the most common), CDH23 (second most common), PCDH15 (third most common), USH1C, and USH1G (minor effects) which are implicated at the loci USH1B, USH1D, USH1F, USH1C, and USH1G respectively [27].

Usher type II (USH2) is characterized by moderate to severe hearing loss, later onset of retinal pigmentosa and normal vestibular function. Three genetic loci have been involved in USH2, namely, USH2A, USH2C, and USH2D along with the corresponding genes. In Usher type III (USH3), hearing loss is progressive, postlingual, and retinal pigmentosa and the vestibular dysfunction are more variable [26]. Some atypical genes and loci have been related to the disease; however, their roles are not very well studied, for example, ESPN (USH1M), HARS (USH3), CEP78 (atypical Usher), CEP250 (atypical Usher), ABDH12 (USH3), and ARSG (atypical Usher, USH4), and three loci, namely, USH1E, USH1H, and USH1K [28]. As the Usher type II and III are usually associated with moderate to severe hearing loss and retinitis pigmentosa developed in later stages of life, these two types of Usher syndrome are often misdiagnosed as non-syndromic moderate to severe hearing loss [29].

Waardenburg syndrome (WS) is also known as an auditory-pigmentary disorder as it is characterized by hearing loss along with pigmentation abnormalities in skin, hair, and eyes. WS is the most common type of autosomal dominant sensorineural hearing loss with an occurrence of 1 in 40,000 individuals. Based on clinical features, WS has 4 subtypes; Type I, II, III, and IV and six genes PAX3, MITF, SNAI2, EDN3, EDNRB, and SOX10 have been identified. Type II patients present typical hearing loss and pigment abnormalities while types I, III, and IV are associated with some additional symptoms affecting face, limb, and/or gastrointestinal system [30, 31].

Variants of many genes are involved in both syndromic and non-syndromic hearing loss. The phenotypic variability caused by the same variant can be due to the influence of genetic or environmental modifiers. Some of the syndromic deafness phenotypes are age-dependent and cannot be diagnosed in children; for example, retinitis pigmentosa development in Usher syndrome. The list of syndromes associated with hearing loss is large but here we have listed only the most common ones [32].

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3. Non-syndromic hearing loss

Non-syndromic hearing loss, deafness without any other defects, is highly heterogeneous [33]. Genetic studies and linkage analysis have been helpful in identifying genes involved in hearing loss. Reports till 2021 indicate a total of 124 genes that have been identified for non-syndromic hearing loss. Among these, 78 genes are involved in autosomal recessive non-syndromic hearing loss while 51 genes cause autosomal dominant non-syndromic hearing loss (Figure 1). About 5 genes are known to cause non-syndromic deafness in an X-linked manner [34] (https://hereditaryhearingloss.org/, accessed April 2022).

Figure 1.

Frequency of various inheritance patterns for non-syndromic hearing loss.

3.1 Autosomal recessive non-syndromic hearing loss (ARNSHL)

Worldwide data, with the prominence of Caucasian populations, indicate that GJB2 variants account for the maximal cases of autosomal recessive non-syndromic deafness with the rate exceeding 50% of reported cases. SLC26A4 is the second in line causative gene followed by MYO15A, OTOF, CDH23, and TMC1 [35].

In this section, we will shed light on the most common genes involved in autosomal recessive non-syndromic hearing loss (ARNSHL).

DFNB1 is the first deafness locus that was mapped in 1994 [36]. GJB2 encoding connexin26 (Cx26) was assigned to this locus during the study on three autosomal recessive non-syndromic sensorineural deaf families with nonsense variants in the gene. Connexin26 plays an important role in human ear development. The immuno-histochemical staining of human cochlear cells has revealed high levels of GJB2 expression [37]. Cx26 being a gap junction protein regulates intracellular communication and plays an important role in maintaining potassium levels in the inner ear. This potassium balance is crucial to normal auditory function [38]. Over the years, several studies have been conducted for the development of efficient therapy targeting hereditary hearing loss. A study showed that introducing normal GJB2 gene through bacterial artificial chromosome (BAC) in GJB2 deleted mice resulted in normal hearing and Auditory Brain Response (ABR) score [39]. Variants in GJB2 cause approximately 16% of deafness in Iran [40]. In Pakistan, GJB2-related deafness frequency ranges from 6 to 7% for profound deafness [41] to 9.5% for moderate to severe hearing loss [42]. The variant c.35delG is the most common bi-allelic GJB2 mutation worldwide with allele frequency up to 100% in European, North African, and Middle Eastern populations [43]. However, different variants are more common in other populations.

DFNB4 is caused by variants in SLC26A4, causing both autosomal recessive Pendred syndrome as well as non-syndromic deafness. It was first identified as a Pendred syndrome gene (PDS) using a positional cloning strategy. A year later, the gene was found to cause non-syndromic autosomal recessive deafness when a consanguineous family in southwest India was studied having a variant in the Pendred gene with no symptoms of goiter [44, 45]. Up till now 641 variants in SLC26A4 have been reported in public databases (http://www.hgmd.cf.ac.uk/ac/search.php). SLC26A4 encodes pendrin, an exchange of bicarbonate/chloride ions in the inner ear maintaining the homeostasis of endolymph [46]. The role of pendrin in normal hearing is elucidated by the fact that knockout mice Slc26a4−/− are completely deaf with vestibular dysfunction [47]. In knockout mice, reduced pH and utricular endolymphatic potential along with an increased level of Ca2+ are key factors leading to deafness. As it seems obvious, low Ca2+ concentration in human ear endolymph is crucial to the normal hearing process [48]. In a cohort of patients, single allele variants in SLC26A4 fail to account for DFNB4 or Pendred syndrome. Digenic variants for some genes along with SLC26A4 have been reported to be causative in such cases. KCNJ10 an inwardly rectifying K+ channel gene is important for maintaining endocochlear potential. Heterozygous variants in both SLC26A4 and KCNJ10 result in digenic non-syndromic hearing loss associated with enlarged vestibular aqueduct syndrome [49]. Similarly, missense EPHA2 variant in patients with mono-allelic SLC26A4 variations has been reported in patients with Pendred syndrome. EPHA2 controls pendrin localization by forming a complex with it and faulty EPHA2 causes mislocalization of pendrin in the inner ear [50].

DFNB3, a non-syndromic deafness locus maps to chromosome 17p11.2. MYO15A pertaining to this locus causes congenital profound deafness in humans and shaker2 (sh2) phenotype with vestibular defects in mice [51, 52, 53]. MYO15A encoded by this gene is an unconventional Myosin; tail homology 4—protein 4.1, ezrin, radixin, and moesin (MyTH4-FERM) myosin [54]. MYO15A is localized at the tips of both the outer hair cells (OHCs) and the inner hair cells (IHCs) and has a developmental role in the formation of stereocilia and thus, is indispensable to the hearing process [55]. Although, identified as a gene for profound deafness, less severe cases of hearing loss due to MYO15A variants are well known. The severity of deafness due to variants in this gene is in accordance with the protein domain being affected [56]. Frequency of MYO15A-related deafness is 5.71% in the Iranian population [57] and about 7.2% in the Vietnamese population [58].

Deafness autosomal recessive non-syndromic deafness, DFNB9 is caused by OTOF gene encoding otoferlin protein [59]. Otoferlin is essential to human hearing as it plays a role in inner hair cell formation and exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse [60]. Otoferlin converts low-intensity stimuli at the synapse between inner hair cells and auditory nerve fiber [61]. OTOF variants cause auditory neuropathy (discussed later in this chapter) manifested as severe to profound non-syndromic deafness in most individuals. Cochlear implants in patients with OTOF-related deafness have shown promising results [62, 63].

CDH23 was identified in families with Usher syndrome (USH1D) mapping to DFNB12 locus [64]. Immuno-histochemical studies on rodent models showed localization of cadherin to upper and lower tip-links. These tip-links lie near stereocilia of hair cells and gate mechanoelectrical transduction [65]. The phenotype due to mutations in CDH23 depends upon the type of variants in the gene. Missense variants with residual protein function are thought to cause DFNB12 while homozygous nonsense, frameshift, splice site, and a few missense variants with total loss of function cause USH1D [66]. Cochlear implants in children aged 11–36 months with CDH23 mutations improved their hearing, speech, and performance necessitating the need for early diagnosis and possible improvement in hearing following implants [67].

TMC1 variants are responsible for both dominant form of deafness DFNA36 as well as non-syndromic recessive hearing loss DFNB7/B11 [68]. Most of the TMC1 variants cause autosomal recessive non-syndromic deafness while only a few are involved in dominantly inherited hearing loss. TMC1 is a transmembrane channel protein that forms the pore of mechanosensory transduction channels (MET) in vertebrate inner ear hair cells [69]. In Pakistani population, 3.4% of autosomal recessive non-syndromic hearing loss (ARSNHL) is caused by TMC1 variants [70]. The TMC1-related ARSNHL is 3.1% of diagnosed cases in the western European population [71] while 4.3–8.1% in the Turkish population [72, 73].

In countries like Pakistan where consanguinity rate is high, gene variants of HGF, MYO7A, TMPRSS3, CIB2, and CLDN14 along with the ones mentioned above also contribute to large cases of profound and moderate to severe hearing loss [74, 75]. HGF within DFNB39 locus 7q21.11 encodes hepatocyte growth factor. The variants of HGF, responsible for autosomal-recessive, non-syndromic hearing loss are located in intron 4. Also, indels in a highly conserved 3′ untranslated region (3′UTR) affect splicing of HGF exons resulting in deafness [76].

MYO7A mapping to 11q13.5 causes non-syndromic hearing loss both in recessive and dominant fashion and Usher syndrome (USH1B). MYO7A the unconventional myosin is required for the normal function of cochlear hair cells [77, 78].

TMPRSS3 variants cause pre-lingual hearing impairment i.e. DFNB10 and late-onset DFNB8-associated hearing impairment. The severity of phenotype depends upon the combination of two mutant alleles. The type II transmembrane protease 3 encoded by TMPRSS3 regulates epithelial sodium channels and potassium calcium-activated channel subfamily M alpha 1 (KCNMA1). Enac (Epithelial Amiloride Sensitive Sodium Channel) in turn controls the signaling pathway in inner ear essential to hearing. In the human ear, TMPRSS3 variants lead to hair cell apoptosis and disruption of intracellular homeostasis [79, 80, 81, 82, 83].

3.2 Autosomal dominant non-syndromic hearing loss

In the case of autosomal dominant non-syndromic hearing loss, frequently reported genes in literature include WFS1, KCNQ4, COCH, and GJB2 although dominant hearing loss does not account for a large number of cases as compared to autosomal recessive deafness [35].

DFNA2 (Deafness autosomal dominant 2A) locus was assigned to cause autosomal dominant non-syndromic hearing loss (ADNSHL) by Kubisch et al. [84]. KCNQ4 mapping to this locus encodes Potassium Voltage-Gated Channel Subfamily Q Member 4 protein expressed in OHCs in cochlea. Variants of KCNQ4 implicated in ADNSHL disrupt the channel’s ability to differentiate between K+ and Na+ ions and exert a strong dominant-negative effect on K+ currents in the inner ear [84].

Interestingly, KCNQ4 variant has also been reported to cause hearing loss in a pseudo-dominant fashion. In a family with genetic heterogeneity, pathogenic variant c.872C > T in a homozygous state caused early-onset moderate to profound or moderate to severe deafness that progressed to profound deafness in a patient. This variant in heterozygous state caused mild to moderate hearing loss in the carrier [85]. In another study, KCNQ4 gene variant c.1044_1051del8 was identified to be responsible for causing autosomal recessive hearing loss with a severe phenotype [86]. KCNQ4 variants c.211delC, c.725G > A, and c.1044_1051del8 induce cell death in heterologous expression systems in a dominant manner [87]. Recent studies propose possible contribution of KCNQ4 to age-related deafness as well [88].

COCH mapping to 14q12 was described to cause DFNA9 with vestibular dysfunction in three unrelated families [89]. In DFNA9, pathogenic variants of COCH lead to the accumulation of acellular deposits in the inner ear due to gain of function of mutant cochlin. Cochlin protein is the major component of interossicular joints and tympanic membrane of middle ear [90]. For many years, it was thought to be a gene implicated only for autosomal dominant hearing loss, when in 2018 a homozygous nonsense variant in COCH was identified to cause congenital pre-lingual recessive deafness DFNB110 [91].

WSF1 was identified as a gene for Wolfram syndrome; an autosomal recessive disorder, by a positional cloning approach [92]. In 2001, Bespalova et al. defined families associated with autosomal dominant non-syndromic low-frequency sensorineural hearing loss (NSLFHL), DFNA6/14/38 having variants in WSF1 gene [93].

GJB2 has already been described for autosomal recessive non-syndromic hearing loss. The dominant mode of inheritance for GJB2 was proposed in deaf families with palmoplantar keratoderma [37, 94]. The role of GJB2 for autosomal dominant deafness 3A (DFNA3) was defined in a study on GJB2 variants in the Austrian population [95].

3.3 X-linked non-syndromic hearing loss

The prevalence of X-linked non-syndromic deafness is 1–3%. As males are hemizygous for X-chromosome, they are predominantly affected by X-linked deafness [11].

Loss of function variants in PRPS1 encoding phosphoribosyl pyrophosphate (PRPP) synthetase 1 enzyme was assigned to non-syndromic X-linked sensorineural deafness, DFNX1, in a Chinese family [96]. Another gene for X-linked non-syndromic deafness, POU3F4 was defined by De kok et al. Nonsense mutations in SMPX, c.109G > T in a German family and c.175G > T in a Spanish family were assigned to DFNX4 locus for X-linked non-syndromic deafness [97]. AIFM1 pathogenic variants are involved in familial and sporadic cases of X-linked recessive auditory neuropathy spectrum disorder [98]. Single mutations in COL4A6 were linked to a genetic disorder when a pathogenic variant c.1771G > A was found to cause X-linked non-syndromic hearing loss DFNX6 with cochlear malformation in a Hungarian family [99].

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4. Auditory neuropathy

Auditory Neuropathy was first defined by Arnold and his colleagues in 1996 while working on individuals with hearing loss. These individuals had normal outer hair cells in the cochlea, and preserved otoacoustic emissions while the ABRs were either absent or severely abnormal due to malfunction in eight cranial nerves. Auditory neuropathy may occur alone or as part of generalized neuropathic process [100].

Auditory neuropathy is divided into two categories according to the cause of neuropathy. In auditory neuropathy type I (AN type I) demyelination and axonal loss of auditory nerve is the predominant cause, while auditory neuropathy type II (AN type II) occurs due to lesions in eight cranial nerves either at inner hair cells (IHCs) or synapses between IHCs and auditory nerve dendrites or at both [100, 101, 102, 103].

Auditory neuropathy can be inherited as either non-syndromic or with accompanying clinical features as a syndrome. Syndromic auditory neuropathy can be due to dominant syndromes like Charcot-Marie-Tooth and Leber’s Hereditary Optic Neuropathy (LHON) or recessive syndromes like Fredreich’s Ataxia [104]. Mitochondrially inherited case of auditory neuropathy was reported by Deltenre et al. [105].

Non-syndromic auditory neuropathy can be dominant, recessive, or X-linked. AUNA1 was the first locus to be studied for autosomal dominant auditory neuropathy [106]. Pathogenic variants in OTOF cause non-syndromic recessive auditory neuropathy (NSRAN) [107]. Deafness due to OTOF gene variants is manifested in two ways:

  1. non-syndromic auditory neuropathy spectrum disorder ANSD causing severe to profound bilateral deafness with congenital/prelingual onset.

  2. temperature-sensitive auditory neuropathy spectrum disorder (TS-ANSD) with normal hearing at baseline body temperature and bilateral hearing loss on rising body temperature of 0.5°C or more with subsequent revival of hearing a few hours from achieving basal body temperature [108].

Some studies suggest variants in GJB2 can cause non-syndromic recessive ANSD [109, 110]. X-linked pattern for NSRAN was identified when it was reported that AUNX1 gene variant is responsible for causing auditory neuropathy and progressive peripheral sensory neuropathy in X- linked manner [111].

Since the discovery of auditory neuropathy scientists has been trying to pinpoint the underlying reason. A study has shown that more than 40% of cases of ANSD are due to hereditary neurological disorders [112]. Although majority of cases of ANSD are sporadic in nature, familial cases have also been reported [113].

The frequency of auditory neuropathy among patients with hearing loss has remained underestimated. In a recent study on Saudi Arabian children diagnosed with NSHL (non-syndromic hearing loss), 9.85% were identified to have ANSD [114]. Thus, the disorder is more prevalent than it was once thought. Other than genetic cause, one of the prominent reasons of auditory neuropathy is bilirubin toxicity, as it damages the auditory nerve and brainstem auditory nuclei [115].

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5. Age-related hearing loss (ARHL)

Age-related hearing loss (ARHL) which is also known as presbycusis, is defined as a progressive, bilateral, and symmetrical sensorineural hearing loss which is mostly observed at high sound frequencies. It is the most common sensory deficit occurring in individuals over the age of 75, severely affecting their communication, cognitive abilities, and social activities [116]. ARHL is the third most prevalent health condition in the world, affecting older adults after heart disease and arthritis [117]. In estimation by the World Health Organization (WHO) 580 million people worldwide over the age of 65 are experiencing hearing loss. It is anticipated that by the next decade over one billion people over the age of 60 will be affected by ARHL (http://www.who.int/en/).

5.1 Etiology and classification

ARHL is a complex disorder which has both genetic and environmental causative factors [118]. In general, there are four major classes of ARHL each having a different cochlear biology and hearing phenotype. First type is the sensory presbycusis which is a progressive degeneration or loss of the inner and outer hair cells in cochlea. Individuals with sensory presbycusis usually have a steep sloping audiogram at high frequencies. The second type is the strial presbycusis which is characterized by the atrophy of stria vascularis. Individuals with strial presbycusis have relatively flat audiograms indicating loss of hearing over all the sound frequencies. Neural presbycusis is the third type which is defined by the degeneration of nerve fibers and patients with this type of pathology are unable to understand and distinguish speech. The fourth form of presbycusis is the cochlear-conductive or mechanical presbycusis which is caused by the changes in stiffness of basilar membrane in cochlea due to aging. Although microscopic findings are negligible in this type however, individuals exhibit gradual down sloping audiograms [119, 120].

5.2 Genetics of ARHL

Most people lose hearing acuity with age; however, it has been shown that genetic heritability also affects the susceptibility, time of onset, and severity of ARHL [118, 121, 122]. Although the biomolecular mechanisms of ARHL have been well defined but due to the complex pathology along with highly significant and variable environmental factors associated with ARHL, it has become difficult to identify the genetic contributors underlying ARHL. So far, researchers have investigated the genes involved in ARHL using familial and cohort-based approaches. However, genome wide association studies (GWAS), exome sequencing (ES) and genome sequencing (GS) on large cohorts have been more helpful revealing the genetic susceptibilities underlying ARHL. There are variants and Single Neucleotide Polymorphisms (SNPs) in more than 15 genes which are found responsible and have been well-studied for presbycusis in human or mouse models. In addition, ultra-rare heterozygous variants of known deafness genes have also been shown to cause severe form of ARHL [123].

Following is the detail of these genes which account for ARHL studied in different populations.

5.3 Genes involved in membrane transport and cellular adhesion

5.3.1 Solute carrier family 12 member 2 (SLC12A2)

SLC12A2 also referred to as Na+K+2xCl co-transporter (NKCC1) is a member of solute carrier family 12 which is involved in the transport of sodium, potassium, and chloride ions across the secretory and absorptive epithelia [124]. It is found to be expressed in the basolateral membrane of marginal strial cells and in the lateral wall fibrocytes in cochlea of rodents and non-human primates. Fibrocytes take up K+ from perilymph through SLC12A2 and ATP1A2 (α2-Na+K+ATPase) [125, 126] and pass it to intermediate cells and strial basal cells through gap junctions [127]. It also transports K+ from the intra-strial space into the marginal cells [128]. In mice, it has been shown that heterozygous variants in Slc12a2 can result in progressive ARHL without causing any damage to the cochlear morphology [129]. However, the role of this gene for ARHL in humans has not been tested yet.

5.3.2 Voltage gated potassium channel KQT like subfamily member 4 (KCNQ4)

Potassium channels play an important role in maintaining ionic composition and electrical signaling in biological fluids. Cochlear hair cells and vestibular structures have voltage-gated potassium channels encoded by KCNQ4 to maintain ionic balance in cochlear fluid [130]. Missense variants in KCNQ4 are commonly known to cause non-syndromic autosomal dominant hearing loss, DFNA2 [131, 132, 133, 134]. However, in a study of two Caucasian populations, several SNPs were found associated with ARHL, all of which were localized to a 13 kb region in the middle of the KCNQ4 [135].

5.3.3 Wolframin (WFS1)

WFS1 encodes Wolframin which is a transmembrane protein and is thought to be a large cation-selective ion channel [136]. Variants in WFS1 commonly cause Wolfram syndrome [137], and non-syndromic autosomal dominant low frequency sensorineural hearing loss [138, 139, 140]. In 2017, a study comprising 518 Finnish adults showed a heterozygous variant p.(Tyr528His) associated with late-onset hearing loss. Most of the individuals participating in this cohort initially had hearing loss which affected the high frequencies and subsequently progressed to involve middle and low frequencies [141].

5.3.4 Solute carrier family 7 member 8 (SLC7A8)

SLC7A8 functions as a sodium-independent transporter of L-type amino acids in many organs in vertebrates [142]. It is highly expressed in the inner ear [143, 144], and specifically localizes to the stria vascularis [143]. A study focused on the role of Slc7a8 in ARHL using mouse models demonstrated that in homozygous knockout mice (Slc7a8−/−) the loss of function leads to high-frequency hearing loss which progressively extends to low frequencies. While, interestingly, the young knockout mice heterozygous for Slc7a8 (Slc7a8+/−) did not show a hearing loss. However, with aging, these mice developed high-frequency hearing loss earlier than the wild-type mice [144]. Similarly, in a cohort of 66 ARHL patients from Italy, genome sequencing identified four heterozygous variants (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu) in SLC7A8 [144]. In vitro functional studies of these variants further confirmed a significant decrease in amino acid transport activity supporting SLC7A8 as a causative gene for ARHL.

5.4 Mitochondrial antioxidative enzymes

Mitochondrial DNA (mtDNA) variants have long been known to cause various human diseases, including non-syndromic hearing loss [145]. A significant increase in the contribution of mtDNA variants has been observed in aging human auditory system [146]. The postmortem analyses of human temporal bones have shown a 4977 bp deletion (also known as common deletion (CD)) in mtDNA as a frequent cause of ARHL [147, 148]. Additionally, a decrease in the expression of another mitochondrial enzyme cytochrome oxidase 3 (COX3) in spiral ganglion cells was also reported in ARHL patients [149].

Isocitrate dehydrogenase (IDH) is a key component of the aerobic metabolism in mitochondria, which facilitates the generation of NADPH and NADH thus regulating the cellular oxidative stress [150, 151]. It has been demonstrated in a mouse study that the expression of IDH2 normally decreases with age and when this gene was knocked out there was increased oxidative stress in the murine inner ear leading to the loss of hair cells and damage to spiral ganglion [152].

5.5 Hormonal factors

5.5.1 Insulin like growth factor 1 (IGF1)

Animal studies suggest that Igf1 promotes inner ear neuronal development by supporting neurogenesis, differentiation, and proliferation of neuronal progenitor cells [153, 154]. It has been ubiquitously detected in mouse inner ear, including the spiral ganglion, spiral ligament, stria vascularis, hair cells, and vestibular tissues [155, 156, 157]. Numerous variants in IGF1 have been associated with sensorineural hearing loss in humans and Larson’s syndrome; patients who also suffer from early-onset ARHL [158, 159, 160].

5.5.2 Estrogen related receptor γ (ESRRG)

Esrrg mRNA has been shown to be expressed at embryonic stages in the mouse cochlear and vestibular ganglion [161], which suggests a role in the inner ear function and development. Moreover, there is considerable evidence supporting an auditory protective effect of estrogen and estrogen-related receptors on the auditory system [162, 163]. In humans, several studies have shown that ARHL is more common and severe with early onset in men as compared to women [164, 165]. For instance, in an analysis of 6134 individuals from three separate European cohorts, an association was found between the minor allele of SNP rs2818964 and hearing status only in women. Additionally, Esrrg knockout mice revealed that at 12 weeks, average hearing thresholds in female mice were 15 dB worse than in males [166].

5.6 Genes involved in metabolic pathways

Studies on human subjects with ARHL have also identified specific polymorphisms in a few genes involved in the folate metabolism pathway. A recent report that genotyped an ARHL cohort from South India revealed several specific polymorphisms within genes encoding thymidylate synthase (TYMS) and 5,10-methylenetetrahydrofolate reductase (MTHFR). Some polymorphisms such as the MTHFR A1298C were noted to protect against the development of ARHL, while others such as MTHFR C677T were associated with an increased risk of ARHL in this population [167].

5.7 Other genes identified for ARHL

5.7.1 Glutamate receptor metabotropic 7 (GRM7)

GRM7 encodes a G-protein coupled receptor which plays an important role in the regulation of presynaptic neurotransmission in the mammalian brain. It is widely expressed in inner hair cells, outer hair cells, spiral ganglion, and vestibular hair cells. The expression of this gene increases with age [168]. GWAS on 3434 well-characterized individuals from different locations in Europe identified SNPs in GRM7 causing ARHL [168]. Two more studies on an American and Saami population cohort also corroborated the potential role of GRM7 in ARHL [169, 170].

5.7.2 Grainyhead drosophila homolog of 2 (GRHL2)

GRHL2 is known to have an essential role in the development and morphogenesis of epithelia of several organs in flies, mice, frogs, and zebrafish [171]. Variants in GRHL2 have been known to cause non-syndromic autosomal dominant hearing loss [172, 173]. Additionally, a study comprised of 2418 cases from seven different European countries emphasized the association of SNPs enriched in intron 1 of GRHL2 with ARHL [174].

5.7.3 Neuropillin-1 (Nrp1)

NRP1 is an essential component of Neurolippin-1/Semaphorin 3A signaling pathway. This pathway is responsible for the proper development of vascular and neuronal structures in inner ear as well as hair cell organization [175, 176]. A GWAS study on mice showed progressive hearing loss with age and abnormalities in inner ear microvasculature [177]. Although these investigations suggest that Nrp1 can be associated with ARHL in mice, no such studies have been performed in humans.

5.7.4 Cadherin related family member 23 (Cdh23Ahl)

Cdh23Ahl is characterized as a hypomorphic allele for a calcium-dependent cell adhesion protein, otocadherin. It helps in the organization of stereocilia bundle and vestibular hair cells and is required for maintaining this organization in later stages of life [178]. Based on the association of Cdh23Ahl with ARHL in mice, GWAS on a large cohort of Han Chinese population was performed to investigate the role of CDH23 in ARHL in humans. This study demonstrated that SNPs in CDH23 do not cause ARHL in humans [179]. However, another study on the methylation patterns in CDH23 showed a positive correlation between an increase in methylation of the gene and ARHL [180].

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6. Tinnitus

Tinnitus is derived from a Latin verb tinnire (to ring), and it describes the conscious perception of hissing, sizzling, or ringing sound in the absence of a corresponding external stimulus. Tinnitus can sometimes be random voices, music, or a mixture of sounds [181]. It can be constant or intermittent, or may be perceived in one (mostly left) or both ears, or centrally within the head. The reason for the left-sided predisposition of tinnitus is yet unknown.

Most of the studies to investigate the prevalence of tinnitus have been carried out in USA or Europe which gave a rough estimate of 10–15% of individuals suffering from tinnitus in these populations. National Study of Hearing in England was one of the largest (n = 48,313) and most reliable studies conducted to determine the prevalence of tinnitus among adult population. The results showed a prevalence of 10–15% among adults. Similarly, results from studies in Egypt [182, 183], Japan [184, 185, 186], and Nigeria [187, 188], also indicated that the rate of prevalence of tinnitus in these countries is analogous to the results from the Europe [189] and the USA [190, 191, 192].

6.1 Risk factors and genetic pathology of tinnitus

There are many risk factors known to be associated with tinnitus. To name one of the most common is hearing loss. All the patients with hearing loss may not develop tinnitus, however, individuals with tinnitus have a predictive diagnosis for hearing loss depending on the responses to pure tone thresholds [181]. Other possible risk factors include noise exposure, head trauma, obesity, alcohol consumption, and ototoxic drugs, such as salicylates, quinines and platinum-based drugs can also trigger tinnitus. It can also be found associated with severe otological diseases like Meinnere’s disease, acoustic neuroma, and otosclerosis [193].

There are many publications stating the risk factors for tinnitus, but none of them describes the complete mechanism or molecular biology of this disorder. It is speculated that tinnitus is also caused by cochlear or auditory nerve damage. Despite its close relatedness to hearing loss patients suffering from tinnitus do not have the auditory nerve or cochlear degeneration as a common cause. This indicates the involvement of other systems in the brain with or without the involvement of the auditory system.

Determination of heritability of tinnitus remained an important task and it is still an arguable debate in the field. A large study held in Norway shows a significant familial aggregation of tinnitus among the participating population (aged >75 years) [194]. There are few more studies that emphasize the involvement of genetic factors in tinnitus with slight variation in their data [195]. The variation in the results may have appeared due to small sample size or the difference in population characteristics. With the utilization of new scientific technologies, it can be expected that researchers will provide a better and more appropriate conclusion to this debate.

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7. Conclusion

Hearing loss is one of the most common sensory defects that affects about 5% of the world population. Genetics is a major contributor to deafness causing about 50% of all cases. Although elucidation of the genetics of hearing loss has advanced rapidly in the past 20 years, still lacking is a complete understanding of all the networks and pathways required for normal audition. In future, continued studies will reveal further insights into function of the auditory system and treatment due to its malfunction.

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Written By

Hina Khan, Hafiza Idrees, Zunaira Munir and Memoona Ramzan

Submitted: 27 April 2022 Reviewed: 09 May 2022 Published: 15 June 2022