**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.
