A Short Overview on Hearing Loss and Related Auditory Defects

*Hina Khan, Hafiza Idrees, Zunaira Munir and Memoona Ramzan*

## **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.

### **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

#### *A Short Overview on Hearing Loss and Related Auditory Defects DOI: http://dx.doi.org/10.5772/intechopen.105222*

incidence of 10 in 100,000 individuals [20–22]. 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].
