handbook of genetic communicative disorders || genetic deafness

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    ROBERT J . R U B E N

    Departments of Otorhinolaryngology and Pediatrics Albert Einstein College of Medicine

    Yeshiva University New York, New York

    I. Introduction History of the Genetics of Hearing Impairment

    11. Nosology A. Anatomical B. Phenotype C. Mode of Inheritance D. Molecular Aberrations: Changes

    in Nuclear DNA and Mitochondrial DNA (mtDNA)

    III. Syndromic Hearing Impairment A. Alport Syndrome B. Branchio-Oto-Renal (BOR)


    C. Jervell and Lange-Nielsen Syndrome

    D. Mitochondrial Syndromes E. Norrie Disease F. Pendred Syndrome G. Stickler Syndrome H. Treacher Collins-Franceschetti

    Syndrome I. Usher Syndrome J. Waardenburg Syndrome K. Nonsyndromic Hearing

    Impairment L. Clinical Application M. Management


    The underlying processes that result in hearing loss and deafness are numerous and, in many instances, interact. The most common of these factors is the genetic make-up of the individual. It has been estimated that more than 50% of all hearing losses have a substantial genetic component. This is a low estimate, because for about 25% of those with hearing impairments the etiology is unknown, and many

    The Handbook of Genetic Communicative Disorders 8 9

    Copyright 2001 by Academic Press. All rights of reproduction in any form reserved.

  • 9 0 ROBERT J . RUBEN

    of these will eventually be proven to be genetically derived (see Chapter 1). Additionally, as various acquired causes of hearing loss are prevented, such as congenital rubella and Haemophilus influenzae meningitis, the percentage of persons with genetically determined deafness will increase proportionally (Parv-ing & Christensen, 1996). Some of the acquired deafness (e.g., from a standard non-ototoxic dose of aminoglycosides) has now been determined to come about because of genetic predispositions (Fischel-Ghodsian et al, 1993). Another in-stance of an extrinsic factor that causes a gene to be activated so as to result in hearing loss may be the relationship between otosclerosis and the measles virus (McKenna & Mills, 1989; Niedermeyer & Arnold, 1995). It is anticipated that there will be an increase in the percentage of hearing loss in which a genetic disposition plays a substantial role. Genetic hearing loss is associated with all the different forms of hearing loss whether classified by age, progression, and site of lesion(s) or interactions with extrinsic factors, for example, aminoglycosides (Fischel-Ghodsian r^ a/., 1993).

    The information concerning genetics and hearing expands almost daily, and this is expected to continue for the foreseeable future. Much of this new informa-tion will have direct utility for the care of patients. These rapid advances are made available in a timely manner through a number of Internet websites. There are two among many (Table 5.1) that both contain substantial information in very usable format and provide links to other pertinent sites.


    A famihal tendency for hearing loss has been recognized at least since the early seventeenth century. Bonet's book (1620), the first printed book concerning the education of the deaf, is based on the education of one child who had numerous hearing-impaired relatives (Plann, 1997). The first work to categorize systemati-cally familial and nonfamilial deafness is Wilde's Otology (1853). Wilde's data,

    TABLE 5 . 1 Pertinent Websites for Assessing Current Information Concerning the Genetics of Deafness





    Online Mendelian Inheritance in Man (OMIM)

    Hereditary Hearing Loss


    Information can be obtained by syn-drome, characteristics. Has numerous links to literature. Substantial detail and depth. Excellent search engine.

    Gives concise information of the state of the art of the known genes that re-sult in hearing loss


    developed before the recognition of Mendel's modes of inheritance, were not widely distributed. Love (1896) and others at the beginning of the twentieth century described and emphasized the role of inheritance as a significant etiology for hearing impairment.

    The recognition of familial bases of hearing loss has been used to harm affected individuals through attempts to prevent marriage, sterilize, and exterminate. This tragic aspect of the history of the genetics of hearing impairment begins with A. G. Bell's On a Deaf Variety of the Human Race (1880), in which he states that to eliminate deafness the deaf should not marry nor have children. This work, and others of Bell's veiled works (he used sheep breeding as a model for human eugenics) contributed to the early policies of the Nazi regime to sterilize and then exterminate deaf children. These crimes are well documented and published in Biesold's (1988, 1999) Klagende Hande {Crying Hands).

    Although there were some pertinent publications during the first half of the twentieth century, it was not until 1976, with the publication of two books, Fraser's (1976) and the posthumous publication of Konigsmark's work (Konigsmark & Gorlin, 1976), that there was widespread appreciation of the genetics underlying deafness. These works preceded the current enhanced ability to localize genes on chromosomes and to determine the aberrations in the protein sequences. A sym-posium held in 1990 under the auspices of the New York Academy of Sciences (Ruben et al, 1991) brought together the current information concerning the molecular basis of the genetics of deafness. Since the 1990 meeting, information on the genetics of deafness has vastly increased. During the period 1990 to 2000, the National Library of Medicine (as determined by computer search) has indexed more than 1500 articles that relate to genetics and deafness and/or hearing loss. This growth of information is expected to continue. The present era should be one of defining the molecular abnormalities resulting in deafness and lesser hearing losses, determining how these aberrations affect the hearing mechanisms, and constructing successful interventions to prevent, cure, or ameliorate the effects of the gene action.



    There are numerous ways by which the various genetically based hearing disorders can be classified. The anatomical site(s) of gene action can be used to organize the information in a useful manner. Knowledge of whether the outer ear, external ear canal, middle ear, cochlea, vestibular apparatus, statoacoustic nerve, and/or the central nervous system are affected is useful to the clinician in the care of the specific genetic disorder. One gene may affect a number of sites, and an abnormality at one locus can result in a variety of different anatomical defects.

  • 9 2 "^'" ROBERT J . RUBEN


    The apparent characteristics of the gene action, the phenotype, are another useful means of classification. There are at least two general phenotypic modes of classification: syndromic and nonsyndromic. The first is defined in terms of whether there are other abnormalities associated with the deafness, such as are found in the various Waardenburg or Usher syndromes. If the deafness is deter-mined to be of genetic etiology and there is no other detectable expression of the gene actions, then these are classified as nonsyndromic.

    The second, nonsyndromic phenotypic classification concerns various features of the hearing loss. A time dimension can be applied to classify whether the loss was congenital, early onset, middle life, or presbycusis, thus mapping the presence of progression of the loss. The characteristics of the pure tone audiogram are also used to classify the abnormality. The audiometric profiles can be high tone, low tone, U-shaped audiograms, and others.


    The genetically determined hearing losses can be categorized as to whether they are dominant (DFNA#), recessive (DFNB#), X-linked (DFN#), or mitochon-drial. (The suffixed numeral refers to the order of identification. Thus, DFNAl is the first dominant gene to be assigned a locus and DFNB5 is the fifth recessive gene to be.) There are both phenotypic and molecularly defined genetic hearing losses that appear to have more than one mode of inheritance. The difference between a recessive inheritancecarrying two identical abnormal genes or two different abnormal genes (compound heterozygous)and a dominant mode of inheritancecarrying only one abnormal genemay appear as a difference in the amount of the hearing impairment (Zlotogora, 1997).


    There are several types of abnormalities in the structure of an individual's DNA that result in a symptomatic form of hearing impairment. These consist of dele-tions or insertions of a portion of the DNA; substitution of one or more nucleic acids in a segment of DNA; a translocation, in which a piece of the DNA is exchanged for another piece of the DNA; and inversions, in which the orientation of a segment of DNA is flipped; or duplication of a stretch of DNA (see Gerber, 1998). Additionally, there may abnormalities in chromosome number.

    Mitochondria, the energy-producing organelles, contain their own genetic ma-terial. Changes in mtDNA occur in a number of syndromic and nonsyndromic hearing impairments. The mitochondrial disorders are transmitted from the mother to the child.



    There are numerous forms of syndromic deafness and hearing impairments. The 10 for which the gene is known