DFNB15 is in parentheses because it is equally likely to be on chromosomes 3 and 19, and USH1F is in parentheses because its cytogenetic location on chromosome 10 is unknown. Documentation of awareness that inheritance is important in hearing impairment can be traced back to the sixteenth century.
According to Goldstein , the earliest known author to have recognized that some forms of deafness may be hereditary was Johannes Schenck — who noted a family in which several children were born deaf. Stephens includes a pedigree drawing of a sixteenth century family of the Spanish aristrocracy in which members in three generations were documented as deaf.
In the papal physician Paolus Zacchias — recommended that the deaf abstain from marriage because of evidence that their children will also be deaf Cranefield and Federn , indicating his conviction that heredity is important in deafness. Reardon ascribes to Sir William Wilde — the awareness that deafness shows different patterns of inheritance, that consanguinity is a relevant factor, and that there is an excess of males among the congenitally deaf.
Genetic hearing loss and deafness
These findings were confirmed by Hartmann who carried out extensive studies in schools for the deaf in Germany. More recently, Konigsmark , Konigsmark and Gorlin , and Fraser provided comprehensive reviews of hereditary hearing impairment, and emphasized the pronounced heterogeneity. The phenotypic and genetic heterogeneity is underscored by Gorlin et al.
Several studies attempted to estimate the number of loci for deafness in various populations Stevenson and Cheeseman ; Chung et al.
Clinically, hearing impairment may be associated with other disorders syndromic or it may be the only symptom nonsyndromic. However, both syndromic and nonsyndromic phenotypes can result from mutations in the same gene e. Also, more extensive examination of nonsyndromic patients may reveal subclinical defects in other organs or tissues. Syndromic hearing impairment tends to be less genetically heterogeneous than nonsyndromic, but more than one locus has been identified for several syndromes.
The identification of these genes may provide additional examples of different mutations in the same gene causing both syndromic and nonsyndromic hearing impairment. Other syndromes for which more than one gene has been identified include Waardenburg, Stickler, Alport, and Jervell and Lange-Nielsen.
Ears - The Inheritance of hearing loss and deafness
Collagen is also defective in Alport syndrome, which is associated with mutations in genes encoding type IV collagen. However, mutations in the genes that encode two other subunits of type IV collagen are known to cause autosomal-recessive Alport syndrome. Each of these type IV collagens is found in the basilar membrane, parts of the spiral ligament, and stria vascularis, but how defects in these collagens result in sensorineural hearing loss has not yet been elucidated.
Mutations in these genes also cause Ward-Romano syndrome, an autosomal-dominant disorder in which affected individuals have a prolonged Q—T interval but they are not hearing impaired Wang et al. A major reason for the increase in the percentage caused by genetic factors is the reduction in environmental causes such as rubella. However, an underlying genetic predisposition is likely to be relevant in the majority of cases in which environmental factors are known to have played a role.
Sill et al. The data strongly suggested a genetic etiology in a large percentage of the participants, but a precise estimate could not be determined. Age-dependent penetrances need to be incorporated into the genetic analysis of later-onset hearing loss. Additionally, the likely possibility of phenocopies must be taken into account in the analysis of family data, regardless of age of onset. One member with hearing loss showed recombination with markers on chromosome 5. The pattern of hearing loss in this individual was different from that in other affected members, and mutational analysis of the POU4F3 gene demonstrated that this individual does not have the mutation associated with hearing loss in other members of the family.
Severe-to-profound hearing impairment with onset before 12 months of age is a characteristic of the affected members of most of the families for which genes causing recessive hearing impairment have been localized. This locus DFNB8 was mapped to the long arm of chromosome In general, loci for hearing impairment in unrelated families have been mapped to different chromosomal regions. Additionally, the same GJB2 mutation 30delG is found in a large percentage of these individuals Denoyelle et al. However, a different mutation delT probably accounts for the majority of cases of nonsyndromic recessive deafness in the Ashkenazi Jewish population Morell et al.
Most loci for autosomal-dominant hearing impairment have been mapped in single large pedigrees. The onset of the hearing loss in families with a dominant mode of inheritance is generally after the development of speech, and the frequencies affected tend to be consistent among members of the same family. An exception is the hearing loss in members of the DFNA3 family in which the onset is before 4 yr of age and is severe-to-profound across all frequencies Chaib et al.
Sometimes ancestry may allow prediction of the location of the disease gene. For example, all families of Acadian ancestry with Usher syndrome type I map to a narrow region on the short arm of chromosome The majority of the affected individuals are homozygous for the same haplotype over a 6-cM interval, suggesting a single mutation Keats et al. This haplotype has not been found on Acadian chromosomes that do not have the disease allele.
Thus, for profoundly hearing impaired infants of Acadian ancestry, marker typing can differentiate between nonsyndromic hearing impairment and Usher syndrome type IC. The development of high-resolution genetic and physical maps, together with the construction of genomic and cDNA libraries, and the availability of sequence databases for many species, have provided the tools for finding genes for hearing impairment. A human fetal cochlear cDNA library Robertson et al. By studying sets of related hearing impaired individuals who are likely to have the same defective gene, DNA pooling strategies Sheffield et al.
In most cases, this approach has led to a single location for the defective gene. However, DFNB15 is equally likely to be in two locations, one on chromosome 3 and the other on chromosome 19, based on the analysis of three affected and three unaffected offspring of first cousins Chen et al. The maximum lod score for both locations is 2. This study demonstrates the necessity of performing a complete genome search, especially in small, consanguineous families.
The usual strategy for localizing a hearing impairment locus in a family is to begin by genotyping markers in the vicinity of all of the mapped loci. Using this approach, several of the loci for dominant and recessive forms of hearing impairment have been mapped to the same regions Fig. Although X-linked and mitochondrial forms of nonsyndromic hearing impairment are much less common than autosomal forms, advances in genome research have facilitated the identification of defective X-linked and mitochondrial genes in these forms of hearing impairment. As might be expected, the first nonsyndromic hearing impairment locus mapped was in families showing X-linked inheritance Brunner et al.
This mixed conductive and sensorineural hearing impairment is associated with perilymphatic gushers if stapedectomy is done. Three other nonsyndromic hearing-impairment genes have been localized on the X-chromosome Fig. Hearing impairment is often one of the components of the phenotype in mitochondrial myopathies that are caused by specific mitochondrial DNA mtDNA mutations Fischel-Ghodsian In some families hearing impairment may be the only anomaly.
This same mutation is associated with aminoglycoside-induced hearing loss Prezant et al. Another form of hearing loss that may be associated with mtDNA mutations is presbycusis. Fischel-Ghodsian et al. Comparative genomics has made many valuable contributions to disease gene identification Meisler , and hearing impairment is no exception Brown and Steel A major advantage of using the mouse for finding disease genes is the relative ease of obtaining large numbers of informative progeny.
A relevant example is the human USH1B locus and the mouse deafness mutant shaker-1 sh1 , which were hypothesized to be caused by mutations in orthologous genes because they had been mapped to a conserved linkage group on human chromosome 11q13 and mouse chromosome 7.
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This hypothesis was proven to be correct when Gibson et al. Similarly, the mouse mutant shaker-2 sh2 and the deafness in kindred DFNB3 are both caused by mutations in another unconventional myosin MYO15 and complementary work in mice and humans led to this finding Probst et al. Both of the genes for Waardenburg syndrome were identified because of previous studies in mice. The POU4F3 gene became a candidate for the dominant hearing impairment in the DFNA15 family when it was mapped to a region of the long arm of chromosome 5 that shares homology with the region on mouse chromosome 18 containing the Pou4f3 also known as Brn3c and Brn Targeted deletion of both alleles of Pou4f3 had been shown to cause deafness in mice Erkman et al.
Although the critical region on chromosome 5 was too large 25 cM to begin a physical mapping approach to finding the gene, the hunch that POU4F3 may be the defective gene proved to be true Vahava et al.
Genetic Hearing Loss - My Baby’s Hearing
The sv gene encodes an unconventional myosin heavy chain, myosin VI myo6 Avraham et al. Both of these mouse mutants are deaf and show the typical head-tossing behavior of mice with inner ear defects, and it seems likely that hearing impaired patients with defects in these genes will be found eventually.
Another likely ortholog of a human gene for hearing impairment is the deafness dn gene on mouse chromosome 19 Keats et al. Studying endogamous populations, consanguineous matings, and large pedigrees minimizes heterogeneity but does not necessarily eliminate it.
In some cases auditory testing may detect phenotype differences among members of the same kindred. Such findings may be the result of etiological differences and provide critical information for genetic studies. Figure 2 shows a flow diagram of the auditory pathway linking the external ear to the cochlea to the brainstem. The auditory tests that can be done to determine the location of the hearing deficit in patients are provided in Table 1.
For example, the pure tone audiogram plots the lowest intensity at which a patient responds against the frequency of a pure tone that is placed into the ear for up to several seconds. Both air and bone are used for conduction of the sound, and if both audiograms are abnormal the hearing loss is sensorineural. However, if the bone conduction audiogram is normal or substantially better than the air conduction audiogram, then the loss is conductive and caused by a problem in the middle ear which is for the most part bypassed with bone-conducted sound.
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Abnormal tympanometry a mechanical test of middle ear impedance as well as elevation or elimination of middle-ear muscle reflex responses provide confirmation of a conductive loss. A more precise categorization of sensorineural hearing loss can be made by testing otoacoustic emissions, which are sounds coming from the motion of the outer hair cells. They allow cochlear function to be assessed independently of neural function, and recent studies Morell et al.
In some patients, otoacoustic emissions may be normal but the auditory brainstem response ABR which monitors synchrony of the auditory cochlear nerve may be abnormal or absent, providing differentiation between a sensory and a neural loss Starr et al. Thus, extensive auditory testing provides critical information for determining the location of the hearing deficit and consequently detecting phenocopies in family data.
Sophisticated analyses of ABR and otoacoustic emission data may eventually allow prediction of the gene defect that is causing the hearing impairment.
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Most forms of hearing impairment involve abnormal development of the outer and inner hair cells sensory cells in the cochlea Fig. The outer hair cells are structurally well-organized and are motile.
The inner hair cells do not move, but both types of cells have an upper surface of w-shaped stereocilia that consist of an actin core and a myosin outer cover, and are joined to one another by tip links. In response to sound vibrations, the stereocilia bend and pull on the tip links, and this movement opens ionic channels that allow transduction of mechanical to electrical energy within the hair cells.