A comprehensive review on inherited Sensorineural Hearing Loss and their syndromes

Hearing impairment is an immensely diagnosed genetic cause, 5% of the total world population effects with different kind of congenital hearing loss (HL). In third-world countries or countries where consanguineous marriages are more common the frequency rate of genetic disorders are at its zenith. Approximately, the incidence of hearing afflictions is ostensibly 7-8:1000 individuals whereas it is estimated that about 466 million peoples suffer with significant HL, and of theses deaf cases 34 million are children’s up to March, 2020. Several genes and colossal numbers of pathogenic variants cause hearing impairment, which aided in next-generation with recessive, dominant or X-linked inheritance traits. This review highlights on syndromic and non-syndromic HL (SHL and NSHL), and categorized as conductive, sensorineural and mixed HL, which having autosomal dominant and recessive, and X-linked or mitochondrial mode of inheritance. Many hundred genes involved in HL are reported, and their mutation spectrum becomes very wide. Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 14 August 2020 doi:10.20944/preprints202008.0308.v1 © 2020 by the author(s). Distributed under a Creative Commons CC BY license. Page 2 of 44 Mapping of pathogenic genes in consanguinity family is facilitated to understand the disease history. Review presents the bases of HL and also focused on various genetic factors that cause deafness like the basics of genetic inheritance, and classic and well-characterized inherited factors of it. It also overviews the application of linkage analysis, SNPs genotyping and whole exome sequencing methods, in mapping and identification of new locus, causative genes and their variants in families inherited with HL. Conclusively, this review supports researchers in understanding the location of chromosome, the causative genes and specific locus which causing deafness in humans.


Introduction
Deafness or hearing failures are seen as an extenuate form [1], in human it is one of the high prevailing neurosensory deficits that harshly negotiate the life value of individuals and can cause their social separation [2]. Both genetics and environmental factors cause hearing failure [3], and the genetic factors contributes about 50% of all hearing loss (HL) patients [4]. The worldwide estimated results report as of March, 2020 defines rounded 466 million peoples suffer with significant HL, and of theses deaf cases 34 million are children's (under 6 years old) (WHO MARCH 2020). Furthermore, before maturity 3/1000 children become deaf [5]. According to WHO prediction, hearing disability will affect ~900 million (or 1:10 peoples) by 2050 [6].
Basically, HL was categorized in two main groups non-syndromic sensorineural HL (NSHL) and syndromic sensorineural HL (SSHL). Genetic subsidizing factors to NSHL are remarkably diverse coverings, over autosomal (recessive and dominant), to X-linked (recessive and dominant), to mitochondrial patterns of inheritance [7]. The SSHL, hearing disability appeared with multiple physiological anomalies (diseases), and it is limited only to the inner ear [8].
Many hundreds or even thousands of genes are involved in hearing process and helps in proper functioning of inner ear, which is the most sensitive part of the ear in human body (figure 2B).
Several genes and their expressed protein families like (Myosin family, Gap-junction family and solute carrier proteins etc.) in inner ear function as, in control of adhesion of hair cell, in neurotransmitter release, intercellular transport, maintenance of ionic homeostasis and protection of cytoskeletons of hair cells, which supports to hear a sound [9,10].
During the period of last 10-12 years, the identification rate of causative genes associated with hearing loss becomes very high. Several hundred genes associated with hearing loss are reported, and their mutation spectrum becomes very wide, so that identification of disease-causing mutation is still more difficult. Linkage studies and auto zygosity methods used for mapping and identification of pathogenic genes in consanguineous families and with the advancement in technologies, Next-generation Sequencing, target-enrichment method and sanger sequencing makes it easy to identifying the novel gene and their variant in inherited heterogeneous disorders [11][12][13][14]. Whole Exome Sequencing (WES), used as stream-line approach now a days, for identifying the disease causing (causative) gene variants (mutation), which results specific phenotypic disorder [10,15]. This review presents an overview and description of the currently known genes related to hereditary HL. It reviews the basics of genetic inheritance, and also focusing on the classic and well-characterized, inherited factors that cause deafness. Brief overview of this review study shown in figure 1.

Ear anatomy and physiology
Auditory system of mammals is highly sensitive, integrated and the most complicated structure, which is planned to achieve both functions of interpreting the sound waves in an organized manner to nerve impulse and also to sustain the balance of the body. The vestibular systems of the human ear specific to sustain the balance of the body are composed of two parts: the membranous labyrinth and the bony labyrinth [16]. The function of the human ear is to collect sound waves from the sounding and interpret of these sound waves of different sound frequencies of range 20 to 20,000 Hz [17,18]. Ear can be defined as a microcomputer or an analytic microphone, that conducts sound waves towards the brain in type of nerve impulse, and it is divided into three structural partitions, which works like a unit; the outer ear; pinna, the auditory canal, and the tympanic membrane, middle ear; tympanic cavity, Ossicles bones (incus, malleus, and stapes), middle ear muscles and Eustachian tube, and the inner ear that perform two functions, transduction of sound waves into neurochemical signals which completed in cochlea, a main functioning organ of the ear and to maintains the optic fixation and support to sustain sanding body posture that takes place in the vestibular system during the process of movement (figure 2A) [19][20][21].

Organ of corti and hair cells
The power of identifying and separating the variable frequencies sounds of human cochlea mainly based on the portion of sensory epithelia named as organ of Corte; at the sensorineural end, the organ necessary for listening a sound (figure 2C) [22]. It contains placodal origin (membranous labyrinth) polarized epithelial cells (supporting and hair cells), the basil membrane (specialized basement membrane having layer of matrix), tectorial membrane and nerve endings [19,23,24].
In mammals, two types of hair cells are present, the inner hair cells (IHCs) and outer hair cells (OHCs). The "IHCs" actually the type of true sensory cell, transmits impulses through the auditory nerve, and OHCs are obliging in to increase the working capacity of the cochlea, quantitatively (increased sensitivity) and qualitatively (increased selectivity) [25,26]. The name "hair" cell was derived from the tuft of stereocilia that protrude from the apical domain of every cell [21,27,28].

Mechanism and types of hearing failure
Hearing failure may be partial or complete and it developed either in response of a damage, injury, physiological causes or congenital diseases which specify as conductive HL [29].Whereas when any injury or damage occurs in the inner ear, brain or vestibular nerve caused sensorineural hearing loss (SNHL), and mixed hearing damage caused both conductive and SNHL. The SNHL mostly occurred due to genetic variations in genes that regulate the intracellular transport, the adhesion of hair cells, ionic homeostasis, neurotransmitter release and structure of hair cells results to damage of the cochlea and the inner ear [30]. In the current century, with new inventions of genetic variants in congenital hearing loss, new treatment opportunity and genetic counseling have appeared and improved in accessibility [31].

Detection of hearing
Hearing level of suspects was evaluated through behavioral testing and pure tone audiometry.
Behavioral testing includes visual reinforcement audiometry (VRA) and behavioral observation audiometry (BOA) [32]. VRA is used for testing hearing level of child between age from six months to 2 ½ years and can provide reasonable complete information for audiogram while the BOA is used for evaluating the hearing level of infants from birth to six month age and this kind of testing is highly dependents on the skills of the testing persons, and is subject to error [33,34].
Pure tone audiometry means to identify the minimum frequency on which a person "hear" a pure tone, whereas the "bone conduction audiometry, depends on the sound waves reach the ear through a vibrator consists on the forehead mastoid bone, now the thresholds depend on the condition of  on the graph represents sound intensity in "dB", and this graph is defined as an audiogram. In audiogram, the right ear is denoted with the symbol "O" and the left ear is denoted with symbol "X".

Molecular genetics of HL
Hearing failure is the most common sensory impairment. It shows highly heterogeneous behavior.

Non-syndromic sensorineural Hearing Loss (NSHL)
Hereditary HL (HHL) is an immensely studied neurosensory disorder in worldwide. It is highly heterogeneous genetic disorder, and most often autosomal recessive and non-syndromic is approximately 80% of congenital HL [11,[45][46][47][48]. Most of the studies on NSHL predominantly focused on three main aspects; the kind of hearing defect, its degree of severity, and the configuration or inheritance pattern. Almost 60% cases of the congenital HL are on the account of genetic factors [49].
In humans hearing failure is a sensory disability that ambits from mild, moderate, severe and profound.
Approximately, the profound HL is comprised of 20-25%, while a higher ratio of individuals is damaged with moderate to severe HL [50].
Moreover, the NSHL are sorted in consonance with their inheritance patterns; as autosomal (dominant or recessive) or X-linked. Autosomal inheritance patterns of NSHL found ubiquitous, while the Xlinked inheritance pattern found tremendously rare [51]. In pre-lingual HL; inherited X-linked trait (1%-3%), autosomal recessive trait (70%-80%), while autosomal dominant trait (12%-24%), and mitochondrial (2%-3%) are observed [52]. In the NSHL, either an autosomal dominant or recessive inheritance pattern characterizes thrilling genetic heterogeneity, as more than hundreds specific deafness-causing genes and loci have been mapped and reported to date (table 1), among these causative-genes, most of them were reported from Pakistan according to hereditary hearing loss homepage [53].

Syndromic Hearing Loss (SHL)
Childhood congenital SHL is a major cause of birth defects in developed countries. There are many reasons are existed to study and identify the etiology of the HL [222]. Approximately 30% of all reported HL cases have several clinical anomalies with HL and termed as SHL [49]. These are differentiated from other types of HL on the basis of associated symptoms in several vital organs [223]. It is estimated that above 400 different syndromes of HL were reported and the majority of

Usher syndrome (USH)
Usher syndrome develops by functional loss of dual sensory systems; the visual and audiovestibular systems. Clinically it was classified into three subtypes (USHI, USH2 and USH3) and this classification is based on the existence or non-existence of vestibular dysfunction, the severity of HL and the time when night blindness developed [230]. It has been predicated, USH is 3-6 % of the total congenital deaf population, 50 % of the deaf-blind population and 8-33 % of affected individuals with "Retinitis pigmentosa (RP)". In various populations, the frequency of USH is between 3.5-6.2:100000, and the carrier frequency ranges 1:100 individuals [230]. USH become more prevalent in those states having small, isolated and beard population, including Pakistan, Israel, France, (Poitou-Charentes region), Finland and Accadian population of Louisiana, North Sweden and the United States [231].
Studies of clinical and molecular genetics USH have exposed extensive clinical and genetic heterogeneity. Genes of USH encode proteins of various classes/families, including motor proteins, scaffold proteins, proteins trans-membrane receptors and cell adhesion molecules [230,232]. It is hypothesized that USH causing proteins are from those protein groups that are functional inside the inner ear to regulate the hair bundle's morphogenesis [34,230]. Behavioral and Mental harms (psychotic symptoms and schizophrenia-like disorder) are also linked with USH. In Usher patients, neuro-imaging examination reports scatter involvement of central nervous system (CNS), signifying a probable function of CNS injury in the pathogenesis of psychiatric manifestations [233].

Perrault syndrome
The relationship of abnormal development of gonads and deafness was studied in 1951 for the first time and later termed as Perrault syndrome [234]. It is a rare disorder consisting of abnormal gonadal development such as ovarian abnormalities with SNHL in affected females [235,236], and only deafness in men [237]. So far, about 40 females globally were reported in different studies with this autosomal recessive disorder [235,238]. Intellectual abnormalities, cerebellar ataxia, motor and sensory peripheral neuropathies were reported in some females with this syndrome.
Beyond 10 pathogenic genes are to be identified that causes premature ovarian failure heterogeneously [239,240].

Treacher Collins (TC) syndrome
In 1846, first time Thomson and later on in 1847 Toynbee reported this syndrome [241,242].
Berry discussed an abnormality in colobomata of the lower eye-lid [243]. It is a rare syndrome.
There are two types with respects to severity: minimal severity includes oblique pulperal fissures and major severity includes craniofacial development such as hypertelorism, micrognathia, maxillary-hypoplasia, high arched plate, conductive HL, external malformation and narrow nostrils [244][245][246]. The occurrence rate of this syndrome is between 1:25000 and 1:50000 [244,245]. TCOF1, POLR1D and POLR1C have been identified to cause this syndrome. Transmission of these genes takes place through the autosomal dominant or autosomal recessive pattern of inheritance [245,[247][248][249]. Ontological, ophthalmological and dental abnormalities have also been seen in the diagnosed patients with TC syndrome [249].

Branchio-Oto-Renal (BOR) syndrome
Branchio-Oto-Renal syndrome, a developmental disorder inherited with an autosomal recessive pattern, and is distinguished by the occurrence of renal and gill vault defects combined with HL.
In the early two-phase of life, the malformations of the urinary tract are the major cause of chronic renal failure [250,251]. Commonly, the dispersion ratio of the BOR syndrome in the general population is 1:40,000 individuals, whereas in deaf children's its ratio is about 2% of the total deaf population. The early onset of the HL varies from childhood to adulthood [250,252]. The clinical expression of BOR has a wide range of inter-and intra-family variability, and become assumed the occurrence rate of BOR syndrome is reduced [253]. The syndrome BOR and their main features that diagnosed in 93% of the affected subjects, is HL either it is neurosensory, conductive or mixed. In addition to ear defects, branchial arch and kidney problems have been described in various kinds of BOR syndrome in other organic systems. Among these dysfunctions, the association of the lacrimal duct system is more common [251,[254][255][256][257][258][259].

Waardenburg syndrome (WS)
Waardenburg is pigmentary disorders with sensorineural HL, a rare genetic disorder with the prevalence rate of 1:40,000 individuals, and is inherited with a recessive mode of inheritance. This congenital disorder is developed due to the abnormalities in the embryonic neural crest. The majority of the deaf population is congenital HL and is also develops in late-onset due to encephalitis, meningitis and complications faced during prematurity [260]. Depending on the addition of medical anomalies with HL, It is further divided into four different types, as WS1, WS2, WS3 and WS4 [261]. The WS1 is associated with dystopia canthorum, while the WS2 developed without dystopia, and these are the main subtypes of WS. The WS1 is developed by the failures of neural crest, but the WS2 is developed due to the failure of specific melanocyte [261].

Stickler syndrome
Gunnar Stickler in 1965 first time reported Stickler syndrome with predicted frequency of 1:10,000 births. It develops in addition of connective tissue anomalies with HL, including retinal detachment, cataract, ocular anomalies of myopia, early arthritis, spondyloepiphyseal dysplasia, underdeveloped cleft-plate and HL of either conductive or sensorineural [262,263]. The cause of retinal detachment with HL was highly diagnosed sign of Stickler syndrome [262]. it occurs primarily in the 2 nd period of life, with cataracts developing primarily in the fourth decade [264].This syndrome is further classified into type-1 and type-2 Stickler syndrome, and on the basis of vitreo-retinal phenotype, type-1 diagnosed with congenital vitreous irregularity and developed as mutations in COL2A1, whereas type-2 is diagnosed with congenital vitreo-retinal irregularity [265,266]. It is inherited either autosomal recessive or dominant inheritance pattern.

Cardio-auditory (Jervell and Lange-Neilsen) syndrome (JLNS)
In 1957, cardio-auditory syndrome designated as Jervell and Neilsen syndrome was studied in the Norwegian family [271]. It is genetically related to sensorineural HL, associated with syncopal episode and initiated with ventricular arrhythmias and unusual repolarization, illustrated by extended "QT" pause on electrocardiogram [272]. Long QT syndrome categorized into different classes on the basis of two clinical phenotype and inheritance patterns, like syndrome Romano-Ward, inherited as autosomal dominant, while syndrome JLNS inherited as autosomal recessive inheritance pattern [273]. The incidence of RWS is approximately 1:2000 in all societies [274], whereas the JLNS develops in patients when bi-allelic heterozygous mutation in KCNQ1 or KCNE1 are originates [273][274][275]. JLNS is a very severe cardiac arrhythmia. It is genetic syndrome and its gene containsα and βsubunits [276][277][278]. A high inflow of sodium ions causes cardiac action potential through the depolarization phase. Increased calcium ions in-flow and repolarization lead to the development of the plateau-phase. This repolarization is due to the component that quickly activating and a slowly activating factor IK. Mutation in KCNQ1 lead to loss of IK function which belongs to ventricular repolarization prolongation and result in ventricular arrhythmias (LQT syndrome) and also congenital bilateral deafness in its result (JLNS) [271,279,280]. There is another life hazardous ventricular arrhythmia termed as type-2 Short QT syndrome (SQTS) considered due to ventricular repolarization shortening [280,281].

Charge syndrome (CS)
CS diagnosed ear abnormalities including deafness and vestibular disorder with anomalies of heart defects, growth retardation, atresia of the choanae, coloboma of the eye, genital or urinary abnormalities, and is inherited with the autosomal dominant pattern with occurrence rate of 1:8500 -15000 live births [282][283][284][285]. Genetically variation in 7(CHD7) genes considered the major cause of CS, which encodes a chromo-domain helicase DNA binding protein. According to clinical diagnostic research following the above criteria, among the people registered in different studies 70%-90% individuals are reported as the victim of CS [286][287][288][289][290][291][292].With respect to molecular biology, the abnormalities yet not completely understood. Recent research has proved that CHD7 plays a vital role in the development of multi-potent migratory cells inside the neural crest. From neural tubes, these migratory cells migrate towards the several parts of the embryo and differentiated into much different type of tissues like craniofacial and heart structure. A few CHD7 genes have been studied that was responsible for the development of neural crest [291,293]. Lalani et al reported that a gene SEMA3E having the same molecular process is responsible for charge syndrome [287].

Norrie syndrome (NS)
Norrie Disease (ND), is a rare X-linked disorder inherited with recessive inheritance pattern, and it developed mainly in the form of early onset of child vision loss with HL [294]. Persons with ND may grow blindness at birth, cataract, nystagmus and increased intraocular pressure [295].
Affected males could transfer the mutated gene to their daughters. Carrier females inherit the pathogenic variant to her offspring in any pregnancy. Females who transmit the pathogenic variant will be a carrier or will be unaffected. On the other hand, carrier male will be affected [296]. In 1992, a mutation in the NDP gene (Pseudoglioma) was identified that is responsible for ND and later in 2020 a missense variant of this gene was identified [297][298][299]. Norrie gene expression encoded a protein; and this secretory protein containing a knot-motif of cysteine with 133 amino acids. In the growth vascular system of the retina, Norrie protein plays a vital role [300]. Norrie is related to mucin-like proteins. Mucin has characteristic features owing to the existence of a knotmotif of cysteine, and it's a structural and functional motif found in many growth factors. Other than the biochemical factors, molecular aspects also involved in the NS, like in eye signal transduction pathway "Wnt-receptor-β-catenin" is involved in the failure of hyaloid vessels, and in addition it also functional in the growth of retina, and in this pathway it works as a ligand [296,301,302].

Hunter syndrome (HS)
HS is a metabolic storage disorder that effect the breakdown of sugar in the body with a frequency rate of 1:34000 and 1:162000 individuals [303][304][305]. It develops by genetic variations in iduronate-2-sulfatasegene, inherited as X-linked pattern and also known as Muco-poly-sacchari-dosis II [306][307][308]. It is predominantly present in males, and reported a prevalence rate of typically 1:100,000 individuals [309]. The patient show symptoms like, thick skin, develop macrocephaly, coarse facies, abnormalities in cardiac valves, hepatosplenomegaly, joint construction, deafness, airway compromise, cranial nerve and degeneration of central nervous system [310].
This syndrome is distinguished from other syndromes due to the presence of congenital cataracts, dental abnormalities, anteverted pinnae, broad nose and short fingers with HL [44, 322,323].
Furthermore, in literature mental retardation and illustrations of autism in NHS are also reported, but these results are more conflicting [324]. A bulk of available literature was concentrating on genetic factors of NHS and congenital cataracts with partial illustrations of oral findings [222,[325][326][327]. In patients of NHS, the description in the morphology of molar, use of the term "bud molar" is recommended. The relative mixture of congenital cataracts, bud-shaped molars, and screwdriver-shaped incisors are the key medical symptoms of NHS [44,328].

Alport syndrome (AS)
AS is a rare X-linked renal failure (glomerulo-nephritis) syndrome initially reported in 1927 [329], and is characterized by HL with renal failure, lamellated glomerular basement membrane, and hematuria. In the case of nephritis, AS with ultra-structural faults in BGM (glomerular basement membranes) of affected individuals, altered and affected the protein structure [330]. Renal  [330]. It also diagnosed with anomalies of several ocular phenotypes, including Corneal and retinal manifestations [331,332].

Methods used in mapping/identification of causative-genes
Mapping/identification of the pathogenic gene, in large size consanguineous families, is facilitated by linkage analysis and auto-zygosity. Variable inheritance patterns, inherited with deafness/HL genes, have been identified in countries like Pakistan, Iran, Tusinia, India, Palestine and Turkey.
Several hundred genes have been reported which have a strong association with HL, and the mutation spectrum of these reported genes becomes very wide so that the identification of pathogenic mutations is still difficult. The development of advanced techniques like; Nextgeneration Sequencing and target-enrichment method, makes it easy to identify the novel gene and mutations, especially in disorders having a heterogeneous mode of inheritance. During the period of the last 10-12 years, the identification rate of causative genes associated with HL becomes very high. WES used as a first-line approach nowadays, for identifying the pathogenic gene variants that discharge a specific phenotypic disorder [333]. Without any conflict, this method is so expansive, but it provides high yield results.

Linkage analysis
Linkage analysis method is successfully used for verifying the genetic location of the pathogenic gene in the lack of any other abnormality (e.g., co-inherited disorders, no cytogenetic abnormality, known protein product or good candidate gene). Precise duplicates of the genomic region encouraging the pathogenic genes are co-inherited with the disease within a family; these consequences confirmed the lack of recombination among the pathogenic variants and the adjacent genetic markers, owing to their close proximity. In a family, subjects who share a disease will typically share alleles at the marker close to the pathogenic gene. The phrase linkage refers to the loci, not to definite alleles at these loci. Linkage analysis is a technique, which is most likely to be used to find the location, in genetic material, for the pathogenic gene [334,335].

SNP Genotyping
In genetic studies, the single nucleotide polymorphism (SNP; a type of genetic variant) markers are two commercially available platforms are available. The basic principles of these two apparatus are the same, but it differs from each other in a few aspects [336].

Next-generation sequencing
The exome holds, exons of all the genome, and is represented as the coding regions of the genes.
In a complete human genome, the exons are the only 1%. However, more than 70-80% of the pathogenic mutations are identified in this coding region of the genome. For this reason, wholeexome sequencing is an extra-ordinary accurate method to study the different inheritance patterns such as autosomal dominant, recessive and sex-linked traits in HHL. Designed for whole exome sequencing, three basic platforms are available, namely Applied Biosystems SOLiD [337], Roche 454 [338], and Illumina Genome Analyzer [337,338]. The design and chemistry of every platform are specific but the working principle of each platform is the same.

Conclusion
Gene depiction and variant screening will untie the functional characteristics and permit to develop This study suggested that functional characterization of these variants will help to better understand the pathophysiology of disease and will improve the procedures of genetic testing and genetic counselling.