Open Access | Peer-reviewed | Review Article
Department of Biochemistry, Molecular Biology laboratory, Government College, University, Faisalabad, 38000, Pakistan.
Shazia Anwer Bukhari
Department of Biochemistry, Molecular Biology laboratory, Government College, University, Faisalabad, 38000, Pakistan.
Department of Oncology, Allied Teaching Hospital Faisalabad, Faisalabad Medical University, Faisalabad, 38000, Pakistan.
Department of Biosciences and Technology, Khwaja Fareed University of Engineering and information technology, Rahim Yar Khan, Punjab, Pakistan.
Published: August 14, 2020 DOI: 10.5281/zenodo.3984965
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. 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.
Keywords: Hereditary Hearing Loss, sensorineural hearling loss, genetics of syndromic and non-syndromic Hearing Loss, methods for diseased locus/gene identification.
|Citation: Muhammad Noman et.al. (2020) A comprehensive review on inherited Sensorineural Hearing Loss and their syndromes, Journal of PeerScientist 3(2): e1000024.|
|Received: May 05, 2020; Accepted: August 08, 2020; Published: August 14, 2020.|
|Copyright:© 2020 Muhammad Noman et.al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
|Data Availability: All relevant data are within the paper and its Supporting Information files.|
|Funding:This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors, apart from the authors personal resources.|
|Competing interests: The authors have declared that no competing interests exist.|
|*E-mail: firstname.lastname@example.org | Phone: +92-333-7477407|
Deafness or hearing failures are seen as an extenuate form , 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 . Both genetics and environmental factors cause hearing failure , and the genetic factors contribute about 50% of all hearing loss (HL) patients . 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 . According to WHO prediction, hearing disability will affect ~900 million (or 1:10 peoples) by 2050 . 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 . The SSHL, hearing disability appeared with multiple physiological anomalies (diseases), and it is limited only to the inner ear .
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].
Figure 1: Schematic illustration of literature review.
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 [11-14]. 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 was 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 . 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) [19-21].
Figure 2: A. Outer ear the pinna and auditory canal separated from the middle ear by tympanic membrane. Ossicles (Malleus, Incus and Stapes) are positioned in middle ear and they connected to the Eustachian tube at the back of nose. The inner ear holds Cochlea and vestibular structures specific to generate nerve impulse and sustain balance of the body. B. Cochlea; the boney tube, filled with perilymph, in which membranous labyrinth floats filled with endolymphatic fluid. Perilymph separates the Scala media to Scala tympani. C. A cross-section of single piece Cochlea display comprehensive picture of the membranous labyrinth, and the Basilar membrane keeps the epithelial cells of hearing –the organ of Corti. The organ of Corti holds; inner hair cells (IHC’s), three outer hair cells (OHC’s), Hensen celles (HC’s), Deitters cells (DC’s), Pillar cells (PC’s) and the Inner Supporting cells (ISC’s) respectively. The auditory nerve linked to inner hair cell at their tip-link.
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) . 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 . 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 . 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 .
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) . 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 the inner ear, by bypassing the outer and middle ear and the calculated/obtained values are plotted on a graph paper [35-38], for sample of audiogram (figure 3).
Figure 3: The audiogram sample, defining various types of hearing loss constructed on the basis of types of ear defect. Horizontal axis represents frequencies in "Hz" while the vertical axis 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. The early 1990s, the identification and localization of genes causing deafness/HL is started, but till 1994 only a few gene loci have been mapped/identified on human genome; causing hearing loss/deafness either NSHL/SHL [27, 39]. Inherited HL consists 50–60% of all HL cases. The inherited form of HL is further classified to different categories [40-42]. Recent advances in genetics and genomics have led us to identification of over 300 SHLs and more than 100 chromosomal loci and more than 40 genes responsible for NSHL [30, 43-44]. Better understanding of impaired genes and their structure and function will open a new window for screening as well as the genetic approach to treatment of HL. In contrast, the identification of the single causative gene of linking in NSHL becomes very difficult in a single family, because it needs positional cloning; the linkage analysis and WES make it feasible.
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, 45-48]. 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 . 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 .
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 X-linked inheritance pattern found tremendously rare . 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 . 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 .
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 . Approximately 30% of all reported HL cases have several clinical anomalies with HL and termed as SHL . These are differentiated from other types of HL on the basis of associated symptoms in several vital organs . It is estimated that above 400 different syndromes of HL were reported and the majority of the cases had been identified with the pathogenic genes . This literature review focuses on the most common syndromes that highly diagnosed in various populations and their linked pathogenic genes (table 2). Major syndromes with HI are Alport, Stickler, Jervell & Lange-Nielsen, Waardenburg and Usher syndromes etc. Stickler and Waardenburg syndromes have dominant inheritance patterns, while the syndromes having autosomal recessive inheritance patterns are Usher and Jervell & Lange-Nielsen syndrome and the Alport syndrome is usually inherited with X-linked inheritance pattern [69,224].
Table 1: Pathogenic genes, locus and their positions on chromosomes, causing non-syndromic hearing loss in Humans:
Recessive syndromes of HL
Pandered first time was reported in 1986, and later after series by Faser in 1964 . It is diagnosed as goiter and thyroid dysfunction owing to the iodide organification defects with deafness. SLC26A4 encoded “Pendrin” an anion transporter protein, and in 1997 a pathogenic variant of this gene was first time identified and later in various studies different variants were also identified that coded [226-229]. In the majority of the affected individuals, goiter was developed during the second decade of life; caused due to the improper supply of iodide in the thyroid, even though affected persons are euthyroid . Defects in iodide transporter caused thyroid abnormalities and defects in chloride transporter caused HL and abnormal development of the cochlea. In the cochlea, abnormal fluid flux developed due to impaired chloride transporter, leading to HL and large vestibular aqueduct .
Usher Syndrome (USH)
Usher syndrome develops by functional loss of dual sensory systems; the visual and audio-vestibular 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 . 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 . 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 .
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 .
The relationship of abnormal development of gonads and deafness was studied in 1951 for the first time and later termed as Perrault syndrome . 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 . 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 . 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 [244-246]. 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]. Ontological, ophthalmological and dental abnormalities have also been seen in the diagnosed patients with TC syndrome .
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 .
Table 2: Syndromes, Mutated Genes, and their chromosomal location:
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, 254-259].
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 . Depending on the addition of medical anomalies with HL, It is further divided into four different types, as WS1, WS2, WS3 and WS4 . 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 .
Dominant syndromes of HL
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 . it occurs primarily in the 2nd period of life, with cataracts developing primarily in the fourth decade .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. Mutations in COL11A1, COL2A1 and COL11A2 are responsible for dominant inheritance pattern, while the mutations in COL9A1 and COL9A2 are responsible for recessive inheritance pattern [262, 267-270].
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 . It is genetically related to sensorineural HL, associated with syncopal episode and initiated with ventricular arrhythmias and unusual re-polarization, illustrated by extended “QT” pause on electrocardiogram . 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 . The incidence of RWS is approximately 1:2000 in all societies , whereas the JLNS develops in patients when bi-allelic heterozygous mutation in KCNQ1 or KCNE1 are originates [273-275].
JLNS is a very severe cardiac arrhythmia. It is genetic syndrome and its gene contains α and β subunits [276-278]. A high inflow of sodium ions causes cardiac action potential through the depolarization phase. Increased calcium ions in-flow and re-polarization lead to the development of the plateau-phase. This re-polarization is due to the component that quickly activating and a slowly activating factor IK. Mutation in KCNQ1 leads to loss of IK function which belongs to ventricular re-polarization 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 re-polarization 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 [282-285]. 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 [286-292].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 .
X-Linked syndromes of HL
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 . Persons with ND may grow blindness at birth, cataract, nystagmus and increased intraocular pressure . 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 . 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 [297-299]. 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 . Norrie is related to mucin-like proteins. Mucin has characteristic features owing to the existence of a knot-motif 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 affects the breakdown of sugar in the body with a frequency rate of 1:34000 and 1:162000 individuals [303-305]. It develops by genetic variations in iduronate-2-sulfatasegene, inherited as X-linked pattern and also known as Muco-poly-sacchari-dosis II [306-308]. It is predominantly present in males, and reported a prevalence rate of typically 1:100,000 individuals . 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 .
Ritscher-Schinzel/3c syndrome (RSS/3C)
RSS/3C (crania-cerebro-cardiac) is commonly recognized a heterogeneous developmental abnormality, clinically it is much rarely diagnosed and is characterized by congenital heart defects, craniofacial abnormalities, cerebellar brain malformation and intellectual disability . 80% of the RSS/3C patients have cardiac problems, which can comprise septal defects, tetralogy of Fallot, hypo-plastic left heart, double outlet right ventricle, pulmonic stenosis, aortic stenosis, and additional valvar anomalies. A lot of affected individuals confirm symptoms of Dandy-Walker malformation, posterior fossa cysts, ventricular dilatation and cerebellar vermis hypoplasia . In RSS/3C syndrome, facial dimorphism is defined as a prominent forehead, occiput, micrognathia, lowest ears, depressed nasal bridge and down-slanting palpebral fissures. In this syndrome, the phenotypic manifestation is varied as well as the cerebellar and cardiac manifestations do also not constantly exist. Therefore, through diagnosis, dysmorphic features of craniofacial pattern become crucial [312-313]. A study on the Canadian population reports homozygous sequence variants, in K1AA0196, that encodes strumpellin which is the subunit of WASH complex, as the type of RSS/3C syndrome [311-312]. Another study on Austrian family, founded a missense variant in CCDC22, that maps on sex chromosome Xp11.23, show X-linked inheritance pattern and features related to syndrome RSS/3C .
Walter Nance and Horan was reported as a rare X-linked hereditary disorder and famous as Nance-Horan syndrome (NHS) [314-315]. In 1990 a pathogenic variant was the first time mapped at cytogenetic location Xp21.1-Xp22.3 that was responsible for NHS [316-318]. Therefore, with a minute disparity of phenotype, several varied mutations were identified causing NHS [319-321]. 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 . A bulk of available literature was concentrating on genetic factors of NHS and congenital cataracts with partial illustrations of oral findings [222, 325-327]. 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 , 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 . Renal transplantation, in affected individuals with AS, shows graft and tolerant survival rates as compared to affect individuals of other renal diseases. Patients suffered in "ESKD" (end-stage kidney disease), owing to AS have analogous patients and grafts survival to those affected individuals with other reported causes of "ESKD". Early management and diagnosis indicate positive results in individuals of the affected group . 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; Next-generation 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 . Without any conflict, this method is so expansive, but it provides high yield results.
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. Fastidious alleles segregated with the disease often variate among the families, reflecting allelic heterogeneity or ancestral genetic recombination or event. Linkage analysis results are described as LOD score, results are reported, that representing the comparative likelihood that a disease locus and a genetic marker are linked genetically; instead of them are genetically unlinked. LOD minimum +3 score characteristically predicted verification of linkage and LOD score of -2 or less it indicates that region is not linked to the disease [334-335].
Linkage analysis is a method supportive in developing connections between the loci; i.e. two loci present on the identical chromosomes are expected to be linked if the observable fact of crossing-over does not separate them. During the process of recombination (crossing over) in meiosis the homologous chromosomes share their segments. Parental combinations are the original arrangement of alleles on the two chromosomes whereas the new combinations are originated after crossing over and denoted as recombinant. If two loci are actually slammed to each other on the same chromosome, then very few chances will happen they are separated through a recombination event. Haplotypes are the set of alleles for different markers or genes on the same chromosomes. 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].
In genetic studies, the single nucleotide polymorphism (SNP; a type of genetic variant) markers found sportive. Approximately, in humans about 10 Million SNPs exist, and it made the study of genome-wide scan association become easier; with the completion of HapMap Project and microarray techniques. The addition of microarray and HapMap technique limits the number of SNPs required for genotyping, approximately 0.25-1 million as compared to 10 million, that considers sufficient for gene mapping. For automated SNPs genotyping, Affymetrix and Illumine 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 .
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, whole-exome 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 , Roche 454 , 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.
Gene depiction and variant screening will unite the functional characteristics and permit to develop phenotype-genotype association. Mutations in genes or the interaction of several disordered genes caused HL and other genetic disabilities. Hearing impairment in adults is a major high prevailing disability, connected with severe psychosocial and communication issues, and face severe health care cost with financial problems at individual and societal level. Hearing impairment is divided into two broad categories; one is without clinical abnormality defines NSHL, while other with clinical abnormalities defines SHLs. This complete review exposes the latest developments in this field, and also focusing on different genetic players involved in it and various methods used in different studies to find these pathogenic genes and their variants. Various equipment’s and molecular approaches now available and under study to improve hearing in patients but these technologies have limited access due to serious implications like health policies, rules-regulations and high cost. Whereas, there is no proper treatment are still available for syndromic hearing impairment. In simple hearing loss doctors solved some level of hearing issues with cochlear implant and hearing aids, but in case of syndromic hearing impairment the patient still faces problems e.g. in Usher syndrome retinal complication still remains unresolved. Furthermore, delineation of pathogenic variants linked to hearing damage enables recommendations to hearing specialist for handling the patients that make sure the batter quality of life. Initial detection of HL ensures to early mediation and healthier patient results. Linkage analysis, SNP genotyping and Next generation sequencing method are most likely be used, and WES method is one of them highly used in most of the genetic studies to-date for quick and accurate findings of mutated genes. 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 counseling.
Acknowledgment: The authors acknowledge research facilities provided by Government College University, Faisalabad and Punjab University, Lahore, Pakistan. This literature review makes one part of Ph.D. thesis of Muhammad Noman.
- Denans, Nicolas, Sungmin Baek, and Tatjana Piotrowski. "Comparing Sensory Organs to Define the Path for Hair Cell Regeneration." Annual review of cell and developmental biology35 (2019): 567-589.
- Hoffman, Michael F., Alexandra L. Quittner, and Ivette Cejas. "Comparisons of social competence in young children with and without hearing loss: A dynamic systems framework." Journal of Deaf Studies and Deaf Education2 (2015): 115-124.
- Morell, Robert J., et al. "A new locus for late-onset, progressive, hereditary hearing loss DFNA20 maps to 17q25." Genomics1 (2000): 1-6.
- Liu, Wei-Hsiu, et al. "Mutation screening in non-syndromic hearing loss patients with cochlear implantation by massive parallel sequencing in Taiwan." PloS one1 (2019): e0211261.
- Dedhia, Kavita, Elise Graham, and Albert Park. "Hearing loss and failed newborn hearing screen." Clinics in perinatology4 (2018): 629.
- Davis, Adrian C., and Howard J. Hoffman. "Hearing loss: rising prevalence and impact." Bulletin of the World Health Organization10 (2019): 646.
- Khatami, Somayeh, et al. "Whole exome sequencing identifies both nuclear and mitochondrial variations in an Iranian family with non-syndromic hearing loss." Mitochondrion46 (2019): 321-325.
- Allen, Samantha B., and Julie Goldman. "Syndromic Sensorineural Hearing Loss (SSHL)." StatPearls [Internet]. StatPearls Publishing, 2019.
- Dror, Amiel A., and Karen B. Avraham. "Hearing impairment: a panoply of genes and functions." Neuron2 (2010): 293-308.
- Caspermeyer, Joseph. "All Ears: Genetic Bases of Mammalian Inner Ear Evolution." (2019): 2925-2926.
- Sloan-Heggen, Christina M., and Richard JH Smith. "Navigating genetic diagnostics in patients with hearing loss." Current opinion in pediatrics6 (2016): 705.
- Richard, Elodie M., et al. "Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss." Human mutation1 (2019): 53-72.
- Atik, Tahir, et al. "Comprehensive analysis of deafness genes in families with autosomal recessive nonsyndromic hearing loss." PLoS One11 (2015): e0142154.
- Shang, H., et al., "Targeted next-generation sequencing of a deafness gene panel (MiamiOtoGenes) analysis in families unsuitable for linkage analysis." BioMed research international, (2018). 2018.
- Konings, A., et al., "Candidate Gene Association Study for Noise‐induced Hearing Loss in Two Independent Noise‐exposed Populations." Annals of human genetics, 73.2 (2009): 215-224.
- Council, N.R., Hearing loss: Determining eligibility for social security benefits. 2004: National Academies Press.
- Dallos, P., "The active cochlea." Journal of Neuroscience, 12.12 (1992): 4575-4585.
- Maroonroge, S., D.C. Emanuel, and T.R. Letowski, "Basic anatomy of the hearing system." Helmet-Mounted Displays: Sensation, Perception and Cognition Issues. Fort Rucker, Alabama: US Army Aeromedical Research Laboratory, (2000): 279-306.
- Appler, J.M. and L.V. Goodrich, "Connecting the ear to the brain: Molecular mechanisms of auditory circuit assembly." Progress in neurobiology, 93.4 (2011): 488-508.
- Luers, J.C. and K.B. Hüttenbrink, "Surgical anatomy and pathology of the middle ear." Journal of anatomy, 228.2 (2016): 338-353.
- Milenkovic, I., et al., "Anatomy and physiology of the auditory pathway." Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft, (2020).
- Peter, M., et al., "Reactions in the organ of Corti to electrical stimulation: StED technology for detecting changes." HNO, 67.4 (2019): 251.
- Hudspeth, A.J., "How the ear's works work." Nature, 341.6241 (1989): 397-404.
- Boillat, M.-A., "The ear." Encyclopaedia of occupational health and safety, (1998): 11.1-11.7.
- Motallebzadeh, H., J.A. Soons, and S. Puria, "Cochlear amplification and tuning depend on the cellular arrangement within the organ of Corti." Proceedings of the National Academy of Sciences, 115.22 (2018): 5762-5767.
- Simoni, E., et al., "Regenerative medicine in hearing recovery." Cytotherapy, 19.8 (2017): 909-915.
- Carlile, S., "The auditory periphery of the ferret: postnatal development of acoustic properties." Hearing research, 51.2 (1991): 265-277.
- Tobin, M., et al., "Stiffness and tension gradients of the hair cell’s tip-link complex in the mammalian cochlea." Elife, 8 (2019): e43473.
- Horowitz, G., et al., "The impact of conductive hearing loss on balance." Clinical otolaryngology, 45.1 (2020): 106-110.
- Ren, Y., L.D. Landeg ger, and K.M. Stankovic, "Gene therapy for human sensorineural hearing loss." Frontiers in Cellular Neuroscience, 13 (2019): 323.
- Egilmez, O.K. and M.T. Kalcioglu, "Genetics of nonsyndromic congenital hearing loss." Scientifica, (2016). 2016.
- Saito, O., et al., "Audiological evaluation of infants using mother's voice." International Journal of Pediatric Otorhinolaryngology, 121 (2019): 81-87.
- Aval, M.H. and S. Jafarzadeh, "Effects of restricting maximum possible intensity on auditory steady-state responses." Auditory and Vestibular Research, 28.4 (2019): 217-220.
- Cole, E.B. and C. Flexer, Children with hearing loss: Developing listening and talking, birth to six. (2019).
- Korver, A.M., et al., "Congenital hearing loss." Nature reviews Disease primers, 3.1 (2017): 1-17.
- Leigh, I.W. and J.F. Andrews, Deaf People and Society: Psychological, Sociological and Educational Perspectives. (2016).
- Sabo, D.L., "The audiologic assessment of the young pediatric patient: the clinic." Trends in amplification, 4.2 (1999): 51-60.
- Shariff, M.E.A., "Analysis of hearing loss by pure tone audiometry in patients with chronic suppurative otitis media." National Journal of Physiology, Pharmacy and Pharmacology, 9.6 (2019): 515-518.
- Angeli, S., X. Lin, and X.Z. Liu, "Genetics of hearing and deafness." The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, 295.11 (2012): 1812-1829.
- Mahboubi, H., et al., "Genetics of hearing loss: where are we standing now?" European Archives of Oto-Rhino-Laryngology, 269.7 (2012): 1733-1745.
- Shearer, A.E., M.S. Hildebrand, and R.J. Smith, Hereditary hearing loss and deafness overview, in GeneReviews®[Internet], University of Washington, Seattle. (2017).
- Ben-Dov, T., et al., "Innovations in Research of Hereditary Deafness." Harefuah, 159.1 (2020): 117-122.
- Ouyang, X.M., et al., "The genetic bases for non-syndromic hearing loss among Chinese." Journal of human genetics, 54.3 (2009): 131-140.
- Gorlin, R.J., et al., Hereditary hearing loss and its syndromes. Oxford University Press, USA, 2 (1995).
- Bykhovskaya, Y., et al., "Candidate locus for a nuclear modifier gene for maternally inherited deafness." The American Journal of Human Genetics, 66.6 (2000): 1905-1910.
- Kalatzis, V. and C. Petit, "The fundamental and medical impacts of recent progress in research on hereditary hearing loss." Human molecular genetics, 7.10 (1998): 1589-1597.
- Riazuddin, S., et al., "Dominant modifier DFNM1 suppresses recessive deafness DFNB26." Nature genetics, 26.4 (2000): 431-434.
- Schultz, J.M., et al., "Modification of human hearing loss by plasma-membrane calcium pump PMCA2." New England Journal of Medicine, 352.15 (2005): 1557-1564.
- Morton, C.C. and W.E. Nance, "Newborn hearing screening—a silent revolution." New England Journal of Medicine, 354.20 (2006): 2151-2164.
- Smith, R.J. and M.-K.N. Jones, Nonsyndromic hearing loss and deafness, DFNB1, in GeneReviews®[Internet]. University of Washington, Seattle (2016).
- Rost, S., et al., "Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6." European Journal of Human Genetics, 22.2 (2014): 208-215.
- Ghosh, A. and R. Jackson, "Steroids in sudden sensorineural hearing loss." Emergency Medicine Journal, 22.10 (2005): 732-733.
- Van Camp, G., "Hereditary hearing loss homepage." http://webh01. ua. ac. be/hhh/, (2008).
- Kelsell, D.P., et al., "Connexin 26 mutations in hereditary non-syndromic sensorineural deafness." Nature, 387.6628 (1997): 80-83.
- Lynch, E.D., et al., "Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous." Science, 278.5341 (1997): 1315-1318.
- Guilford, P., et al., "A human gene responsible for neurosensory, non-syndromic recessive deafness is a candidate homologue of the mouse sh-1 gene." Human molecular genetics, 3.6 (1994): 989-993.
- Weil, D., et al., "The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene." Nature genetics, 16.2 (1997): 191-193.
- Kubisch, C., et al., "KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness." Cell, 96.3 (1999): 437-446.
- Friedman, T.B., et al., "A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17." Nature genetics, 9.1 (1995): 86-91.
- Wang, A., et al., "Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3." Science, 280.5368 (1998): 1447-1451.
- Xia, J.-h., et al., "Mutations in the gene encoding gap junction protein β-3 associated with autosomal dominant hearing impairment." Nature genetics, 20.4 (1998): 370-373.
- Baldwin, C.T., et al., "Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population." Human molecular genetics, 4.9 (1995): 1637-1642.
- Li, X.C., et al., "A mutation in PDS causes non-syndromic recessive deafness." Nature genetics, 18.3 (1998): 215-217.
- Gao, X., et al., "Mutation of IFNLR1, an interferon lambda receptor 1, is associated with autosomal-dominant non-syndromic hearing loss." Journal of medical genetics, 55.5 (2018): 298-306.
- Fukushima, K., et al., "Consanguineous nuclear families used to identify a new locus for recessive non-syndromic hearing loss on 14q." Human molecular genetics, 4.9 (1995): 1643-1648.
- Naz, S., et al., "Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus." The American Journal of Human Genetics, 71.3 (2002): 632-636.
- Grifa, A., et al., "Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus." Nature genetics, 23.1 (1999): 16-18.
- Jain, P.K., et al., "A human recessive neurosensory nonsyndromic hearing impairment locus is a potential homologue of the murine deafness (dn) locus." Human molecular genetics, 4.12 (1995): 2391-2394.
- Kurima, K., et al., "Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function." Nature genetics, 30.3 (2002): 277-284.
- Donaudy, F., et al., "Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4)." The American Journal of Human Genetics, 74.4 (2004): 770-776.
- Veske, A., et al., "Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan." Human molecular genetics, 5.1 (1996): 165-168.
- Yasunaga, S.i., et al., "A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness." Nature genetics, 21.4 (1999): 363-369.
- Scott, H.S., et al., "Insertion of β-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness." Nature genetics, 27.1 (2001): 59-63.
- Zheng, J., et al., "Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with α-tectorin and is mutated in autosomal dominant hearing loss (DFNA4)." Proceedings of the National Academy of Sciences, 108.10 (2011): 4218-4223.
- Van Laer, L., et al., "Nonsyndromic hearing impairment is associated with a mutation in DFNA5." Nature genetics, 20.2 (1998): 194-197.
- Bork, J.M., et al., "Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23." The American Journal of Human Genetics, 68.1 (2001): 26-37.
- Bespalova, I.N., et al., "Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss." Human molecular genetics, 10.22 (2001): 2501-2508.
- Mustapha, M., et al., "A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36." European Journal of Human Genetics. 6.3 (1998): 245-250.
- Fagerheim, T., et al., "Identification of a new locus for autosomal dominant non-syndromic hearing impairment (DFNA7) in a large Norwegian family." Human molecular genetics, 5.8 (1996): 1187-1191.
- Wesdorp, M., et al., "Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction." Human genetics, 137.5 (2018): 389-400.
- Verhoeven, K., et al., "Mutations in the human α-tectorin gene cause autosomal dominant non-syndromic hearing impairment." Nature genetics, 19.1 (1998): 60-62.
- Charizopoulou, N., et al., "Gipc3 mutations associated with audiogenic seizures and sens orineural hearing loss in mouse and human." Nature communications, 2.1 (2011): 1-12.
- Rehman, A.U., et al., "Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p." Human genetics, 130.6 (2011): 759-765.
- Robertson, N.G., et al., "Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction." Nature genetics, 20.3 (1998): 299-303.
- Greinwald Jr, J.H., et al., "Localization of a novel gene for nonsyndromic hearing loss (DFNB17) to chromosome region 7q31." American journal of medical genetics, 78.2 (1998): 107-113.
- Wayne, S., et al., "Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus." Human molecular genetics, 10.3 (2001): 195-200.
- Ouyang, X., et al., "Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness." Human genetics, 111.1 (2002): 26-30.
- Ahmed, Z.M., et al., "Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC." Human genetics, 110.6 (2002): 527-531.
- Liu, X.-Z., et al., "Autosomal dominant non-syndromic deafness caused by a mutation in the myosin VIIA gene." Nature genetics, 17.3 (1997): 268-269.
- Schraders, M., et al., "Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment." The American Journal of Human Genetics, 91.5 (2012): 883-889.
- Moynihan, L., et al., "DFNB20: a novel locus for autosomal recessive, non-syndromal sensorineural hearing loss maps to chromosome 11q25–qter." European Journal of Human Genetics, 7.2 (1999): 243-246.
- McGuirt, W.T., et al., "Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13)." Nature genetics, 23.4 (1999): 413-419.
- Mustapha, M., et al., "An α-tectorin gene defect causes a newly identified autosomal recessive form of sensorineural pre-lingual non-syndromic deafness, DFNB21." Human molecular genetics, 8.3 (1999): 409-412.
- Young, T.-L., et al., "Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1." Human molecular genetics, 10.22 (2001): 2509-2514.
- Zwaenepoel, I., et al., "Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22." Proceedings of the National Academy of Sciences, 99.9 (2002): 6240-6245.
- Vahava, O., et al., "Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans." Science, 279.5358 (1998): 1950-1954.
- Ahmed, Z.M., et al., "PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23." Human molecular genetics, 12.24 (2003): 3215-3223.
- Fukushima, K., et al., "A gene for fluctuating, progressive autosomal dominant nonsyndromic hearing loss, DFNA16, maps to chromosome 2q23-24.3." The American Journal of Human Genetics, 65.1 (1999): 141-150.
- Khan, S.Y., et al., "Mutations of the RDX gene cause nonsyndromic hearing loss at the DFNB24 locus." Human mutation, 28.5 (2007): 417-423.
- Lalwani, A.K., et al., "Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9." The American Journal of Human Genetics, 67.5 (2000): 1121-1128.
- Schraders, M., et al., "Homozygosity mapping reveals mutations of GRXCR1 as a cause of autosomal-recessive nonsyndromic hearing impairment." The American Journal of Human Genetics, 86.2 (2010): 138-147.
- Bönsch, D., et al., "A novel locus for autosomal dominant, non-syndromic hearing impairment (DFNA18) maps to chromosome 3q22 immediately adjacent to the DM2 locus." European Journal of Human Genetics, 9.3 (2001): 165-170.
- Yousaf, R., et al., "Modifier variant of METTL13 suppresses human GAB1–associated profound deafness." The Journal of clinical investigation, 128.4 (2018): 1509-1522.
- Zhu, M., et al., "Mutations in the γ-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26)." The American Journal of Human Genetics, 73.5 (2003): 1082-1091.
- Van Wijk, E., et al., "A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26)." Journal of medical genetics, 40.12 (2003): 879-884.
- Pulleyn, L., et al., "A new locus for autosomal recessive non-syndromal sensorineural hearing impairment (DFNB27) on chromosome 2q23–q31." European Journal of Human Genetics, 8.12 (2000): 991-993.
- Kunst, H., et al., "Non‐syndromic autosomal dominant progressive non‐specific mid‐frequency sensorineural hearing impairment with childhood to late adolescence onset (DFNA21)." Clinical Otolaryngology & Allied Sciences , 25.1 (2000): 45-54.
- Shahin, H., et al., "Mutations in a novel isoform of TRIOBP that encodes a filamentous-actin binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss." The American Journal of Human Genetics, 78.1 (2006): 144-152.
- Riazuddin, S., et al., "Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness." The American Journal of Human Genetics, 78.1 (2006): 137-143.
- Melchionda, S., et al., "MYO6, the human homologue of the gene responsible for deafness in Snell’s waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss." The American Journal of Human Genetics, 69.3 (2001): 635-640.
- Wilcox, E.R., et al., "Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29." Cell, 104.1 (2001): 165-172.
- Mosrati, M.A., et al., "A novel dominant mutation in SIX1, affecting a highly conserved residue, result in only auditory defects in humans." European journal of medical genetics, 54.5 (2011): e484-e488.
- Walsh, T., et al., "From flies' eyes to our ears: mutations in a human class III myosin cause progressive nonsyndromic hearing loss DFNB30." Proceedings of the National Academy of Sciences, 99.11 (2002): 7518-7523.
- Häfner, F.M., et al., "A novel locus (DFNA24) for prelingual nonprogressive autosomal dominant nonsyndromic hearing loss maps to 4q35-qter in a large Swiss German kindred." The American Journal of Human Genetics, 66.4 (2000): 1437-1442.
- Mburu, P., et al., "Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31." Nature genetics, 34.4 (2003): 421-428.
- Ruel, J., et al., "Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice." The American Journal of Human Genetics, 83.2 (2008): 278-292.
- Delmaghani, S., et al., "Mutations in CDC14A, encoding a protein phosphatase involved in hair cell ciliogenesis, cause autosomal-recessive severe to profound deafness." The American Journal of Human Genetics, 98.6 (2016): 1266-1270.
- Kemperman, M.H., et al., "A Dutch family with hearing loss linked to the DFNA20/26 locus: longitudinal analysis of hearing impairment." Archives of Otolaryngology–Head & Neck Surgery, 130.3 (2004): 281-288.
- Medlej-Hashim, M., et al., "Non-syndromic recessive deafness in Jordan: mapping of a new locus to chromosome 9q34. 3 and prevalence of DFNB1 mutations." European Journal of Human Genetics, 10.6 (2002): 391-394.
- Nakano, Y., et al., "Defects in the alternative splicing-dependent regulation of REST cause deafness." Cell, 174.3 (2018): 536-548. e21.
- Collin, R.W., et al., "Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35." The American Journal of Human Genetics, 82.1 (2008): 125-138.
- Peters, L.M., et al., "Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28." Human molecular genetics, 11.23 (2002): 2877-2885.
- Naz, S., et al., "Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction." Journal of medical genetics, 41.8 (2004): 591-595.
- Mangino, M., et al., "Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26." European Journal of Human Genetics, 9.9 (2001): 667-671.
- Ahmed, Z.M., et al., "Mutations of MYO6 are associated with recessive deafness, DFNB37." The American Journal of Human Genetics, 72.5 (2003): 1315-1322.
- Snoeckx, R., et al., "A novel locus for autosomal dominant non-syndromic hearing loss, DFNA31, maps to chromosome 6p21. 3." Journal of medical genetics, 41.1 (2004): 11-13.
- Ansar, M., et al., "Localization of a novel autosomal recessive non-syndromic hearing impairment locus (DFNB38) to 6q26-q27 in a consanguineous kindred from Pakistan." Human heredity, 55.1 (2003): 71-74.
- Bönsch, D., et al., "A new gene locus for an autosomal-dominant non-syndromic hearing impairment (DFNA 33) is situated on chromosome 13q34-qter." HNO, 57.4 (2009): 371-376.
- Schultz, J.M., et al., "Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39." The American Journal of Human Genetics, 85.1 (2009): 25-39.
- Nakanishi, H., et al., "NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy." Proceedings of the National Academy of Sciences, 114.37 (2017): e7766-e7775.
- Delmaghani, S., et al., "DFNB40, a recessive form of sensorineural hearing loss, maps to chromosome 22q11. 21–12.1." European journal of human genetics, 11.10 (2003): 816-818.
- Borck, G., et al., "Loss-of-function mutations of ILDR 1 cause autosomal-recessive hearing impairment DFNB42." The American Journal of Human Genetics, 88.2 (2011): 127-137.
- Santos-Cortez, R.L.P., et al., "Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish." Human molecular genetics, 23.12 (2014): 3289-3298.
- Xiao, S., et al., "Dentinogenesis imperfecta 1 with or without progressive hearing loss is associated with distinct mutations in DSPP." Nature genetics, 27.2 (2001): 201-204.
- Bhatti, A., et al., "Mapping of a new autosomal recessive non-syndromic hearing impairment locus (DFNB45) to chromosome 1q43-q44." Clinical genetics, 73.4 (2008):
- Yan, D., et al., "Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise." Proceedings of the National Academy of Sciences, 110.6 (2013): 2228-2233.
- Mir, A., et al., "Mapping of a novel autosomal recessive nonsyndromic deafness locus (DFNB46) to chromosome 18p11. 32‐ 31." American Journal of Medical Genetics Part A, 133.1 (2005): 23-26.
- Xia, J., et al., "A novel locus for autosomal dominant nonsyndromic hearing loss identified at 5q31. 1-32 in a Chinese pedigree." Journal of human genetics, 47.12 (2002): 0635-0640.
- Hassan, M.J., et al., "A novel autosomal recessive non-syndromic hearing impairment locus (DFNB47) maps to chromosome 2p25. 1-p24. 3." Human genetics, 118.5 (2006): 605-610.
- Flex, E., et al., "Mapping of a new autosomal dominant non-syndromic hearing loss locus (DFNA43) to chromosome 2p12." Journal of medical genetics, 40.4 (2003): 278-281.
- Ahmad, J., et al., "DFNB48, a new nonsyndromic recessive deafness locus, maps to chromosome 15q23-q25. 1." Human genetics, 116.5 (2005): 407-412.
- Modamio-Høybjør, S., et al., "A Mutation in CCDC50, a Gene Encoding an Effector of Epidermal Growth Factor–Mediated Cell Signaling, Causes Progressive Hearing Loss." The American Journal of Human Genetics, 80.6 (2007): 1076-1089.
- Riazuddin, S., et al., "Tricellulin is a tight-junction protein necessary for hearing." The American Journal of Human Genetics, 79.6 (2006): 1040-1051.
- Girotto, G., et al., "Linkage study and exome sequencing identify a BDP1 mutation associated with hereditary hearing loss." PLoS One, 8.12 (2013): e80323.
- D'Adamo, P., et al., "A new locus (DFNA47) for autosomal dominant non-syndromic inherited hearing loss maps to 9p21-22 in a large Italian family." European journal of human genetics, 11.2 (2003): 121-124.
- Shaikh, R.S., et al., "A new locus for nonsyndromic deafness DFNB51 maps to chromosome 11p13-p12." American journal of medical genetics. Part A, 138.4 (2005):
- Chen, W., et al., "Mutation of COL11A2 causes autosomal recessive non-syndromic hearing loss at the DFNB53 locus." Journal of medical genetics, 42.10 (2005): e61-e61.
- Mencia, A., et al., "Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss." Nature genetics, 41.5 (2009): 609-613.
- Irshad, S., et al., "Localization of a novel autosomal recessive non‐syndromic hearing impairment locus DFNB55 to chromosome 4q12‐ 2." Clinical genetics, 68.3 (2005): 262-267.
- Walsh, T., et al., "Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51." The American Journal of Human Genetics, 87.1 (2010): 101-109.
- Delmaghani, S., et al., "Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy." Nature genetics, 38.7 (2006): 770-778.
- Ben Said, M., et al., "A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60." Human genetics, 135.5 (2016).
- Yan, D., et al., "A novel locus for autosomal dominant non-syndromic deafness, DFNA53, maps to chromosome 14q11. 2-q12." Journal of medical genetics, 43.2 (2006): 170-174.
- Liu, X.Z., et al., "Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss." Human molecular genetics, 12.10 (2003): 1155-1162.
- Gürtler, N., et al., "DFNA54, a third locus for low-frequency hearing loss." Journal of molecular medicine, 82.11 (2004): 775-780.
- Ali, G., et al., "The mapping of DFNB62, a new locus for autosomal recessive non‐syndromic hearing impairment, to chromosome 12p13. 2‐ 23." Clinical genetics, 69.5 (2006): 429-433.
- Zhao, Y., et al., "Exome sequencing and linkage analysis identified tenascin-C (TNC) as a novel causative gene in nonsyndromic hearing loss." PloS one, 8.7 (2013): e69549.
- Du, X., et al., "A catechol-O-methyltransferase that is essential for auditory function in mice and humans." Proceedings of the National Academy of Sciences, 105.38 (2008): 14609-14614.
- Ahmed, Z.M., et al., "Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans." Nature genetics, 40.11 (2008): 1335.
- Bönsch, D., et al., "A new locus for an autosomal dominant, non-syndromic hearing impairment (DFNA57) located on chromosome 19p13. 2 and overlapping with DFNB15." Hno, 56.2 (2008): 177-182.
- Tariq, H., D. Thomson, and D. Kahn, "10-year review of Africa's first student surgical society-UCT Surgical Society." South African Journal of Surgery, 55.2 (2017): 6-8.
- Lezirovitz, K., et al., "A novel autosomal dominant deafness locus (DFNA58) maps to 2p12‐p21." Clinical genetics, 75.5 (2009): 490-493.
- Grati, M.h., et al., "A missense mutation in DCDC2 causes human recessive deafness DFNB66, likely by interfering with sensory hair cell and supporting cell cilia length regulation." Human molecular genetics, 24.9 (2015): 2482-2491.
- Chatterjee, A., et al., "A novel locus DFNA59 for autosomal dominant nonsyndromic hearing loss maps at chromosome 11p14. 2–q12. 3." Human genetics, 124.6 (2009): 669-675.
- Tlili, A., et al., "A novel autosomal recessive non-syndromic deafness locus, DFNB66, maps to chromosome 6p21. 2-22.3 in a large Tunisian consanguineous family." Human Heredity, 60.3 (2005): 123-128.
- Kalay, E., et al., "Mutations in the lipoma HMGIC fusion partner‐like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss." Human mutation, 27.7 (2006): 633-639.
- Cheng, J., et al., "Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64." The American Journal of Human Genetics, 89.1 (2011): 56-66.
- Santos-Cortez, R.L.P., et al., "Autosomal-recessive hearing impairment due to rare missense variants within S1PR2." The American Journal of Human Genetics, 98.2 (2016): 331-338.
- Azaiez, H., et al., "TBC 1 D 24 Mutation Causes Autosomal‐Dominant Nonsyndromic Hearing Loss." Human mutation, 35.7 (2014): 819-823.
- Chishti, M.S., et al., "Novel autosomal recessive non-syndromic hearing impairment locus (DFNB71) maps to chromosome 8p22–21.3." Journal of human genetics, 54.3 (2009): 141-144.
- Nyegaard, M., et al., "A novel locus harbouring a functional CD164 nonsense mutation identified in a large danish family with nonsyndromic hearing impairment." PLoS genetics, 11.7 (2015): e1005386.
- Riazuddin, S., et al., "Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome." The American Journal of Human Genetics, 85.2 (2009): 273-280.
- Thoenes, M., et al., "OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67)." Orphanet journal of rare diseases, 10.1 (2015): 15.
- Waryah, A., et al., "DFNB74, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 12q14. 2‐q15." Clinical genetics, 76.3 (2009): 270-275.
- Ahmed, Z.M., et al., "Functional null mutations of MSRB3 encoding methionine sulfoxide reductase are associated with human deafness DFNB74." The American Journal of Human Genetics, 88.1 (2011): 19-29.
- Azaiez, H., et al., "HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice." PLoS Genet, 11.3 (2015): e1005137.
- Horn, H.F., et al., "The LINC complex is essential for hearing." The Journal of clinical investigation, 123.2 (2013).
- Gao, J., et al., "Whole exome sequencing identified MCM2 as a novel causative gene for autosomal dominant nonsyndromic deafness in a Chinese family." PLoS One, 10.7 (2015):
- Grillet, N., et al., "Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans." The American Journal of Human Genetics, 85.3 (2009): 328-337.
- Seco, C.Z., et al., "Allelic mutations of KITLG, encoding KIT ligand, cause asymmetric and unilateral hearing loss and Waardenburg syndrome type 2." The American Journal of Human Genetics, 97.5 (2015): 647-660.
- Rehman, A.U., et al., "Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79." The American Journal of Human Genetics, 86.3 (2010): 378-388.
- Mosrati, M.A., et al., "Genome-wide analysis reveals a novel autosomal-recessive hearing loss locus DFNB80 on chromosome 2p16. 1-p21." Journal of human genetics, 58.2 (2013): 98-101.
- Chen, D.-Y., et al., "A dominant variant in DMXL2 is linked to nonsyndromic hearing loss." Genetics in Medicine, 19.5 (2017): 553-558.
- Grati, M.h., et al., "MYO3A causes human dominant deafness and interacts with protocadherin 15‐CD2 isoform." Human mutation, 37.5 (2016): 481-487.
- Yariz, K.O., et al., "Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss." The American Journal of Human Genetics, 91.5 (2012): 872-882.
- Shahin, H., et al., "Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families." European Journal of Human Genetics, 18.4 (2010): 407-413.
- Booth, K.T., et al., "Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non-syndromic hearing impairment." Journal of medical genetics, 55.8 (2018): 555-560.
- Rehman, A.U., et al., "Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86." The American Journal of Human Genetics, 94.1 (2014): 144-152.
- Wang, L., et al., "A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss." Human genetics, 137.6-7 (2018): 437-446.
- Jaworek, T.J., et al., "An alteration in ELMOD3, an Arl2 GTPase-activating protein, is associated with hearing impairment in humans." PLoS Genet, 9.9 (2013): e1003774.
- Xia, W., et al., "Novel TRRAP mutation causes autosomal dominant non‐syndromic hearing loss." Clinical genetics, 96.4 (2019): 300-308.
- Basit, S., et al., "DFNB89, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 16q21-q23. 2." Human genetics, 129.4 (2011): 379-385.
- Morgan, A., et al., "Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss." Human mutation, 40.12 (2019): 2286-2295.
- Ali, G., et al., "Novel autosomal recessive nonsyndromic hearing impairment locus DFNB90 maps to 7p22. 1-p15. 3." Human heredity, 71.2 (2011): 106-112.
- Lu, X., et al., "Whole exome sequencing identifies SCD5 as a novel causative gene for autosomal dominant nonsyndromic deafness." European Journal of Medical Genetics, (2020): 103855.
- Sırmacı, A., et al., "A truncating mutation in SERPINB6 is associated with autosomal-recessive nonsyndromic sensorineural hearing loss." The American Journal of Human Genetics, 86.5 (2010): 797-804.
- Mutai, H., et al., "Variants encoding a restricted carboxy-terminal domain of SLC12A2 cause hereditary hearing loss in humans." PLoS genetics, 16.4 (2020): e1008643.
- Tabatabaiefar, M.A., et al., "DFNB93, a novel locus for autosomal recessive moderate-to-severe hearing impairment." Clinical genetics, 79.6 (2011): 594-598.
- Simon, M., et al., "Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome." PLoS Genet, 11.3 (2015): e1005097.
- Ansar, M., et al., "A new autosomal recessive nonsyndromic hearing impairment locus DFNB96 on chromosome 1p36. 31–p36. 13." Journal of human genetics, 56.12 (2011): 866-868.
- Mujtaba, G., et al., "A mutation of MET, encoding hepatocyte growth factor receptor, is associated with human DFNB97 hearing loss." Journal of medical genetics, 52.8 (2015): 548-552.
- Liu, X., et al., "Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2." The American Journal of Human Genetics, 86.1 (2010): 65-71.
- Delmaghani, S., et al., "Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness." Human molecular genetics, 21.17 (2012): 3835-3844.
- De Kok, Y., et al., "Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4." Science, 267.5198 (1995): 685-688.
- Li, J., et al., "Whole‐Exome Sequencing Identifies a Variant in TMEM 132 E Causing Autosomal‐Recessive Nonsyndromic Hearing Loss DFNB 99." Human mutation, 36.1 (2015): 98-105.
- Schraders, M., et al., "Next-generation sequencing identifies mutations of SMPX, which encodes the small muscle protein, X-linked, as a cause of progressive hearing impairment." The American Journal of Human Genetics, 88.5 (2011): 628-634.
- Huebner, A.K., et al., "Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss." The American Journal of Human Genetics, 88.5 (2011): 621-627.
- Yousaf, R., et al., "Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse." PLoS genetics, 14.3 (2018): e1007297.
- Del Castillo, I., et al., "A novel locus for non-syndromic sensorineural deafness (DFN6) maps to chromosome Xp22." Human molecular genetics, 5.9 (1996): 1383-1387.
- Imtiaz, A., D.C. Kohrman, and S. Naz, "A frames hift mutation in GRXCR 2 causes recessively inherited hearing loss." Human mutation, 35.5 (2014): 618-624.
- Zong, L., et al., "Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder." Journal of medical genetics, 52.8 (2015): 523-531.
- Behlouli, A., et al., "EPS8, encoding an actin-binding protein of cochlear hair cell stereocilia, is a new causal gene for autosomal recessive profound deafness." Orphanet journal of rare diseases, 9.1 (2014): 1-6.
- Seco, C.Z., et al., "Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5." European Journal of Human Genetics, 23.2 (2015): 189-194.
- Wang, Q., et al., "Y-linked inheritance of non-syndromic hearing impairment in a large Chinese family." Journal of medical genetics, 41.6 (2004): e80-e80.
- Diaz-Horta, O., et al., "FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing." Proceedings of the National Academy of Sciences, 111.27 (2014): 9864-9868.
- Buniello, A., et al., "Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing." EMBO molecular medicine, 8.3 (2016): 191-207.
- Rohacek, A.M., et al., "ESRP1 mutations cause hearing loss due to defects in alternative splicing that disrupt cochlear development." Developmental cell, 43.3 (2017): 318-331.
- Wesdorp, M., et al., "MPZL2, encoding the epithelial junctional protein myelin protein zero-like 2, is essential for hearing in man and mouse." The American Journal of Human Genetics, 103.1 (2018): 74-88.
- Li, C., et al., "Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss." Proceedings of the National Academy of Sciences, 116.4 (2019): 1347-1352.
- Ingham, N.J., et al., "Mouse screen reveals multiple new genes underlying mouse and human hearing loss." PLoS biology, 17.4 (2019): e3000194.
- Sineni, C.J., et al., "A truncating CLDN9 variant is associated with autosomal recessive nonsyndromic hearing loss." Human genetics, 138.10 (2019): 1071-1075.
- Parker, M. and M. Bitner-Glindzicz, "Genetic investigations in childhood deafness." Archives of disease in childhood, 100.3 (2015): 271-278.
- Burke, W., T. Lenarz, and H. Maier, "Hereditary hearing loss: Part 2: Syndromic forms of hearing loss." HNO, 62.10 (2014): 759.
- Koffler, T., K. Ushakov, and K.B. Avraham, "Genetics of hearing loss: syndromic." Otolaryngologic Clinics of North America, 48.6 (2015): 1041-1061.
- Fraser, G., "Association of congenital deafness with goitre (Pendred's syndrome)." Annals of human genetics, (1965).
- Coyle, B., et al., "Molecular analysis of the PDS gene in Pendred syndrome (sensorineural hearing loss and goitre)." Human Molecular Genetics, 7.7 (1998): 1105-1112.
- Everett, L.A., et al., "Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS)." Nature genetics, 17.4 (1997): 411-422.
- Wémeau, J.-L. and Kopp, "Pendred syndrome." Best Practice & Research Clinical Endocrinology & Metabolism, 31.2 (2017): 213-224.
- Ejaz, S., "Pendred Syndrome." (2019).
- Yan, D. and X.Z. Liu, "Genetics and pathological mechanisms of Usher syndrome." Journal of human genetics, 55.6 (2010): 327-335.
- Géléoc, G.G. and A. El-Amraoui, "Disease mechanisms and gene therapy for Usher syndrome." Hearing research, (2020): 107932.
- Mathur, and J. Yang, "Usher syndrome: hearing loss, retinal degeneration and associated abnormalities." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1852.3 (2015): 406-420.
- Domanico, D., et al., "Psychosis, mood and behavioral disorders in Usher syndrome: review of the literature." Medical Hypothesis, Discovery and Innovation in Ophthalmology, 4.2 (2015): 50.
- Pierce, S.B., et al., "Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome." Proceedings of the National Academy of Sciences, 108.16 (2011): 6543-6548.
- Geethalakshmi, S. and V. Narendrakumar, "Perrault syndrome–a rare case report." Journal of Clinical and Diagnostic Research: JCDR, 9.3 (2015): OD01.
- Al-Jaroudi, D., S. Enabi, and M.S. AlThagafi, "Perrault syndrome with amenorrhea, infertility, Tarlov cyst, and degenerative disc." Gynecological Endocrinology, 35.12 (2019): 1037-1039.
- Newman, W.G., et al., Perrault syndrome, in GeneReviews®[Internet]. University of Washington, Seattle (2018).
- Demain, L.A., et al., "Expanding the genotypic spectrum of Perrault syndrome." Clinical genetics, 91.2 (2017): 302-312.
- Pierce, S.B., et al., "Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome." The American Journal of Human Genetics, 92.4 (2013): 614-620.
- Duan, X., et al., "Clinical and genetic analysis of a patient with Perrault syndrome and additional neurological features." Zhonghua yi xue yi chuan xue za zhi= Zhonghua yixue yichuanxue zazhi= Chinese journal of medical genetics, 36.6 (2019): 577-580.
- Thomson, A., "Notice of several cases of malformation of the external ear, together with experiments on the state of hearing in such persons." Monthly Journal of Medical Science, 1.6 (1846): 420.
- Toynbee, J., "Description of a congenital malformation in the ears of a child." Monthly Journal of Medical science, 1.10 (1847): 738.
- Scully, C., J. Langdon, and J. Evans, "Marathon of eponyms: 20 Treacher Collins syndrome." Oral diseases, 17.6 (2011): 619-620.
- Sakai, D., et al., "Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation." Nature communications, 7.1 (2016): 1-13.
- Sarella, L.K., Kumar, and K. Kumari, "Treacher-Collins syndrome." International Journal of Medical Science Research and Practice, 1.3 (2014): 105-107.
- Aljerian, A. and M.S. Gilardino, "Treacher collins syndrome." Clinics in Plastic Surgery, 46.2 (2019): 197-205.
- Sheffer, R. and J. Zlotogora, "Autosomal dominant inheritance of Klein–Waardenburg syndrome." American journal of medical genetics, 42.3 (1992): 320-322.
- Srinath, S., "Treacher Collins Syndrome." Journal of Pharmaceutical Sciences and Research, 6.6 (2014): 247.
- Vesna, A., "Treacher Collins Syndrome." International Biological and Biomedical Journal, 3.4 (2017): 157-161.
- Ruf, R.G., et al., "SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1–SIX1–DNA complexes." Proceedings of the National Academy of Sciences, 101.21 (2004): 8090-8095.
- Ruf, R., et al., "A gene locus for branchio-otic syndrome maps to chromosome 14q21. 3-q24. 3." Journal of medical genetics, 40.7 (2003): 515-519.
- Hone, S.W. and R.J. Smith. Genetics of hearing impairment. in Seminars in Neonatology. (2001).
- Kumar, S., et al., "Genomewide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications." The American Journal of Human Genetics, 66.5 (2000): 1715-1720.
- Cremers, C. and M. Fikkers-Van Noord, "The earpits-deafness syndrome. Clinical and genetic aspects." International journal of pediatric otorhinolaryngology, 2.4 (1980): 309-322.
- Fitch, N. and H. Srolovitz, "Severe renal dysgenesis produced by a dominant gene." American Journal of Diseases of Children, 130.12 (1976): 1356-1357.
- Heimler, A., et al., "Branchio‐oto‐renal syndrome: Reduced penetrance and variable expressivity in four generations of a large kindred." American journal of medical genetics, 25.1 (1986): 15-27.
- Pennie, B. and H. Marres, "Shoulder abnormalities in association with branchio-oto-renal dysplasia in a patient who also has familial joint laxity." International journal of pediatric otorhinolaryngology, 23.3 (1992): 269-273.
- Preisch, J.W., D. Bixler, and F.D. Ellis, "Gustatory lacrimation in association with the branchio‐oto‐renal syndrome." Clinical genetics, 27.5 (1985): 506-509.
- Weber, K.M. and B.G. Kousseff, "‘New’manifestations of BOR syndrome." Clinical genetics, 56.4 (1999): 306-312.
- Thirunavukarasu, R., et al., "A study of brainstem evoked response audiometry in high-risk infants and children under 10 years of age." Indian Journal of Otology, 21.2 (2015): 134.
- Sánchez-Martín, M., et al., "SLUG (SNAI2) deletions in patients with Waardenburg disease." Human molecular genetics, 11.25 (2002): 3231-3236.
- Robin, N.H., R.T. Moran, and L. Ala-Kokko, Stickler syndrome, in GeneReviews®[Internet]. University of Washington, Seattle (2017).
- Coussa, R.G., J. Sears, and E.I. Traboulsi, "Stickler syndrome: exploring prophylaxis for retinal detachment." Current opinion in ophthalmology, 30.5 (2019): 306-313.
- Vilaplana, F., et al., "Stickler syndrome. Epidemiology of retinal detachment." Archivos de la Sociedad Española de Oftalmología (English Edition), 90.6 (2015): 264-268.
- Snead, M., et al., "Stickler syndrome: correlation between vitreoretinal phenotypes and linkage to COL 2A1." Eye</ em>, 8.6 (1994): 609-614.
- Wang, D.-D., et al., "Mutation Spectrum of Stickler Syndrome Type I and Genotype-phenotype Analysis in East Asian Population: a systematic review." BMC Medical Genetics, 21.1 (2020): 1-7.
- Alzahrani, F., et al., "LOXL3, encoding lysyl oxidase-like 3, is mutated in a family with autosomal recessive Stickler syndrome." Human genetics, 134.4 (2015): 451-453.
- Baker, S., et al., "A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome." American Journal of Medical Genetics Part A, 155.7 (2011): 1668-1672.
- Faletra, F., et al., "Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene." American Journal of Medical Genetics Part A, 164.1 (2014): 42-47.
- Sun, W., et al., "A novel deep intronic COL2A1 mutation in a family with early‐onset high myopia/ocular‐only Stickler syndrome." Ophthalmic and Physiological Optics, 40.3 (2020): 281-288.
- Jervell, A. and F. Lange-Nielsen, "Congenital deaf-mutism, functional heart disease with prolongation of the QT interval, and sudden death." American heart journal, 54.1 (1957): 59-68.
- Tyson, J., et al., "IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome." Human molecular genetics, 6.12 (1997): 2179-2185.
- Jackson, H., et al., "LQTS in Northern BC: homozygosity for KCNQ1 V205M presents with a more severe cardiac phenotype but with minimal impact on auditory function." Clinical Genetics, 86.1 (2014): 85-90.
- Mizusawa, Y., M. Horie, and A.A. Wilde, "Genetic and clinical advances in congenital long QT syndrome." Circulation Journal, (2014): CJ-14-0905.
- Vyas, B., et al., "KCNQ1 mutations associated with Jervell and Lange–Nielsen syndrome and autosomal recessive Romano–Ward syndrome in India—expanding the spectrum of long QT syndrome type 1." American Journal of Medical Genetics Part A, 170.6 (2016): 1510-1519.
- Jespersen, T., M. Grunnet, and S.- Olesen, "The KCNQ1 potassium channel: from gene to physiological function." Physiology, 20.6 (2005): 408-416.
- Schulze-Bahr, E., et al., "KCNE1 mutations cause jervell and Lange-Nielsen syndrome." Nature genetics, 17.3 (1997): 267.
- Zhang, M., et al., "Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue." Proceedings of the National Academy of Sciences, 111.50 (2014): e5383-e5392.
- Maltret, A., et al., "Type 2 short QT syndrome and vestibular dysfunction: Mirror of the Jervell and Lange-Nielsen syndrome?" International journal of cardiology, 171.2 (2014): 291-293.
- Neyroud, N., et al., "A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome." Nature genetics, 15.2 (1997): 186-189.
- Chen, Y.-H., et al., "KCNQ1 gain-of-function mutation in familial atrial fibrillation." Science, 299.5604 (2003): 251-254.
- Hughes, S.S., et al., "Family history and clefting as major criteria for CHARGE syndrome." American Journal of Medical Genetics Part A, 164.1 (2014): 48-53.
- Issekutz, K.A., et al., "An epidemiological analysis of CHARGE syndrome: preliminary results from a Canadian study." American Journal of Medical Genetics Part A, 133.3 (2005): 309-317.
- Blake, K.D., et al., "CHARGE association: an update and review for the primary pediatrician." Clinical pediatrics, 37.3 (1998): 159-173.
- Martin, G.C., et al., "Functional Vision Analysis in Patients With CHARGE Syndrome." Journal of Pediatric Ophthalmology and Strabismus, 57.2 (2020): 120-128.
- Aramaki, M., et al., "Phenotypic spectrum of CHARGE syndrome with CHD7 mutations." The Journal of pediatrics, 148.3 (2006): 410-414.
- Butcher, D.T., et al., "CHARGE and Kabuki syndromes: gene-specific DNA methylation signatures identify epigenetic mechanisms linking these clinically overlapping conditions." The American Journal of Human Genetics, 100.5 (2017): 773-788.
- Hale, C.L., et al., "Atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria." American Journal of Medical Genetics Part A, 170.2 (2016): 344-354.
- Jongmans, M., et al., "CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene." Journal of medical genetics, 43.4 (2006): 306-314.
- Lalani, S.R., et al., "SNP genotyping to screen for a common deletion in CHARGE syndrome." BMC medical genetics, 6.1 (2005): 1-7.
- Lalani, S.R., et al., "Toward a genetic etiology of CHARGE syndrome: I. A systematic scan for submicroscopic deletions." Amer ican Journal of Medical Genetics Part A, 118.3 (2003): 260-266.
- Vissers, L.E., et al., "Mutations in a new member of the chromodomain gene family cause CHARGE syndrome." Nature genetics, 36.9 (2004): 955-957.
- Schulz, Y., et al., "CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance." Human genetics, 133.8 (2014): 997-1009.
- Andarva, M., et al., "A novel c. 240_241insGG mutation in NDP gene in a family with Norrie disease." Clinical and Experimental Optometry, 101.2 (2018): 255-259.
- Yang, X., et al., "Genetic analysis and prenatal diagnosis for a pedigree affected with X-linked Norrie disease." Zhonghua yi xue yi chuan xue za zhi= Zhonghua yixue yichuanxue zazhi= Chinese journal of medical genetics, 36.5 (2019): 462-464.
- Abeshi, A., et al., "Genetic testing for Norrie disease." The EuroBiotech Journal, 1.s1 (2017): 77-79.
- Berger, W., et al., "Isolation of a candidate gene for Norrie disease by positional cloning." Nature genetics, 1.3 (1992): 199-203.
- Chen, Z., et al., "Isolation and characterization of a candidate gene for Norrie disease." Nature genetics, 1.3 (1992): 204-208.
- Yang, F., et al., "Norrie disease caused by a c. 361C> T missense variant of the NDP gene in a pedigree." Zhonghua yi xue yi Chuan xue za zhi= Zhonghua Yixue Yichuanxue Zazhi= Chinese Journal of Medical Genetics, 37.1 (2020): 25-27.
- Meitinger, T., et al., "Molecular modelling of the Norrie disease protein predicts a cystine knot growth factor tertiary structure." Nature genetics, 5.4 (1993): 376-380.
- Wu, W.-C., et al., "Retinal phenotype–genotype correlation of pediatric patients expressing mutations in the Norrie disease gene." Archives of Ophthalmology, 125.2 (2007): 225-230.
- Wang, Z., et al., "Wnt Signaling in vascular eye diseases." Progress in Retinal and Eye Research, 70 (2019): 110-133.
- Lowry, R., et al., "An update on the frequency of mucopolysaccharide syndromes in British Columbia." Human genetics, 85.3 (1990): 389.
- Peters, C. and W. Krivit, "Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome); an ethical commentary." Bone marrow transplantation, 25.10 (2000): 1097-1099.
- Joseph, R., E.B. DiCesare, and A. Miller, "Hunter syndrome: is it time to make it part of newborn screening?" Advances in Neonatal Care, 18.6 (2018): 480-487.
- Gort, L., A. Chabas, and M. Coll, "Hunter disease in the Spanish population: molecular analysis in 31 families." Journal of inherited metabolic disease, 21.6 (1998): 655-661.
- Chen, Z., et al. The Metabolic and Molecular. in Bases of Inherited Disease; McGraw-Hill, Inc., Health Professions Division.Citeseer (2001).
- Gomes, C., et al., "A New Mutation in IDS Gene Causing Hunter Syndrome: A Case Report." Frontiers in genetics, 10 (2020): 1383.
- Baehner, F., et al., "Cumulative incidence rates of the mucopolysaccharidoses in Germany." Journal of Inherited Metabolic Disease: Official Journal of the Society for the Study of Inborn Errors of Metabolism, 28.6 (2005): 1011-1017.
- Tomatsu, S., et al., Mucopolysaccharidoses Update (2 Volume Set). Nova Science Publishers (2018).
- Kolanczyk, M., et al., "Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome." European Journal of Human Genetics, 23.5 (2015): 633-638.
- Leonardi, M.L., et al., "Ritscher‐Schinzel cranio‐cerebello‐cardiac (3C) syndrome: Report of four new cases and review." American journal of medical genetics, 102.3 (2001): 237-242.
- Elliott, A.M., et al., "A novel mutation in KIAA0196: identification of a gene involved in Ritscher–Schinzel/3C syndrome in a First Nations cohort." Journal of medical genetics, 50.12 (2013): 819-822.
- HORAN, M.B. and F. Billson, "X‐linked cataract and hutchinsonian teeth." Journal of Paediatrics and Child Health, 10.2 (1974): 98-102.
- Nance, W., et al., "Congenital X-linked cataract, dental anomalies and brachymetacarpalia." Birth defects original article series, 10.4 (1974): 285-291.
- Burdon, K., et al., "Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation." The American Journal of Human Genetics, 73.5 (2003): 1120-1130.
- De Souza, N., et al., "Oral manifestations of Nance–Horan syndrome: A report of a rare case." Contemporary Clinical Dentistry, 10.1 (2019): 174.
- Stambolian, D., et al., "Nance-Horan syndrome: localization within the region Xp21. 1-Xp22. 3 by linkage analysis." American journal of human genetics, 47.1 (1990): 13.
- Coccia, M., et al., "X-linked cataract and Nance-Horan syndrome are allelic disorders." Human molecular genetics, 18.14 (2009): 2643-2655.
- Khan, A.O., et al., "Phenotype-genotype correlation in potential female carriers of X-linked developmental cataract (Nance-Horan syndrome)." Ophthalmic genetics, 33.2 (2012): 89-95.
- Hernández, V., et al., "Great clinical variability of Nance Horan syndrome due to deleterious NHS mutations in two unrelated Spanish families." Ophthalmic Genetics, 40.6 (2019): 553-557.
- Li, A., et al., "Identification of a novel NHS mutation in a Chinese family with Nance-Horan syndrome." Current eye research, 40.4 (2015): 434-438.
- Tug, E., et al., "A Turkish family with Nance-Horan Syndrome due to a novel mutation." Gene, 525.1 (2013): 141-145.
- Liao, H.-M., et al., "Identification of a microdeletion at Xp22. 13 in a Taiwanese family presenting with Nance-Horan syndrome." Journal of human genetics, 56.1 (2011): 8-11.
- Florijn, R.J., et al., "New mutations in the NHS gene in Nance–Horan Syndrome families from the Netherlands." European journal of human genetics, 14.9 (2006): 986-990.
- Huang, K.M., et al., "Identification of three novel NHS mutations in families with Nance-Horan syndrome." Molecular vision, 13 (2007): 470.
- Reches, A., et al., "Prenatal detection of congenital bilateral cataract leading to the diagnosis of Nance‐Horan syndrome in the extended family." Prenatal Diagnosis: Published in Affiliation with the International Society for Prenatal Diagnosis, 27.7 (2007): 662-664.
- Gjørup, H., et al., "Nance–Horan syndrome—The oral perspective on a rare disease." American Journal of Medical Genetics Part A, 173.1 (2017): 88-98.
- Alport, A.C., "Hereditary familial congenital haemorrhagic nephritis." British medical journal, 1.3454 (1927): 504.
- Kelly, Y., et al., "Outcomes of kidney transplantation in Alport syndrome compared with other forms of renal disease." Renal failure, 39.1 (2017): 290-293.
- Eriksen, K.O. and Ø.K. Jørstad, "Multiple Vitelliform Lesions as a Retinal Manifestation of Alport Syndrome." Case Reports in Ophthalmology, 11.1 (2020): 79-84.
- Nicklason, E., et al., "Corneal endothelial cell abnormalities in X-linked Alport syndrome." Ophthalmic Genetics, 41.1 (2020): 13-19.
- Konings, A., L. Van Laer, and G. Van Camp, "Genetic studies on noise-induced hearing loss: a review." Ear and hearing, 30.2 (2009): 151-159.
- Cantor, R.M., Analysis of Genetic Linkage, in Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics, (2019): 227-236.
- ZAHOOR, M.Y., Molecular Characterization Of Congenital Mental Retardation In Pakistan., University of the Punjab, Lahore (2011).
- Hirschhorn, J.N., et al., "A comprehensive review of genetic association studies." Genetics in medicine, 4.2 (2002): 45-61.
- Ondov, B.D., et al., "Efficient mapping of Applied Biosystems SOLiD sequence data to a reference genome for functional genomic applications." Bioinformatics, 24.23 (2008): 2776-2777.
- Quail, M.A., H. Swerdlow, and D.J. Turner, "Improved protocols for the illumina genome analyzer sequencing system." Current protocols in human genetics, 62.1 (2009): 18.2.1-18.2.27.