Genetics, Disability, and Deafness

Genes for Deafness and the Genetics Program at Gallaudet University

GENES FOR DEAFNESS AND THE GENETICS PROGRAM AT GALLAUDET UNIVERSITY Kathleen S. Arnos and Arti Pandya At least 1 in 1,000 newborn infants has severe to profound deafness, and genetic factors cause at least 50–60 percent of these cases (Marazita et al. 1993). Hereditary deafness is not a single entity; more than 400 forms are known to exist. Given that there are fewer than 40,000 genes in humans (International Human Genome Sequencing Consortium 2001), the fact that more than 1 percent of all genes are involved in determining the structure and functioning of the ear documents the complexity of this organ. Despite this striking heterogeneity of hereditary deafness, one form, known as GJB2, a gene that encodes the protein connexin 26, accounts for 20–30 percent of deafness in the United States (Cohn et al. 1999; Pandya et al. 2003). The many forms of genetic deafness can sometimes be distinguished from one another by audiologic characteristics, such as the type, degree, or progression of the hearing loss; the vestibular characteristics (the presence or absence of balance problems); the specific mode of inheritance ; or the presence or absence of other medical or physical characteristics . Two-thirds of hereditary deafness occurs as an isolated finding, 111 referred to as nonsyndromic deafness. Syndromic deafness, which accounts for the remaining one-third of genetic forms, refers to deafness that is associated with other medical or physical features (Gorlin et al. 1995). For example, some syndromic forms of deafness are associated with serious medical complications, such as alterations of the structure of the kidneys, irregular heart rhythm, and progressive loss of vision. Other syndromic forms of deafness are associated with mild variations, such as pigmentary changes causing two different colored eyes or changes in the hair color, or a thickening of the skin on the palms of the hands and soles of the feet. A few of the more common syndromic forms of deafness will be described later in this chapter. IDENTIFICATION AND CHARACTERIZATION OF GENES FOR DEAFNESS More than 110 genes for nonsyndromic and syndromic deafness have been identified in the past decade (Van Camp and Smith 2003). The methodologies used to accomplish this fall under the category of genetic mapping, which is the localization of a gene on a particular region of a chromosome. There are a variety of approaches to genetic mapping (Keats 2000; Avraham 2003), one of which is the study of the transmission of genetic markers through three to four generations of large families with the same form of hereditary deafness. Other techniques take advantage of mouse models of specific forms of deafness or inbred population isolates with several members who are deaf. Once a region is mapped, it is often possible to identify genes in the region and fully characterize them in terms of their biochemical components. It may then be possible to determine the protein product for which the gene codes and how the protein functions in the body (genes code for proteins , which perform a variety of critical functions in the body). This type of gene characterization can also lead to the ability to test for alterations or mutations of the gene. While genetic testing is costly and not now widely available, testing for a few, more common genes will soon become the standard of care for children who are identified as being deaf or hard of hearing (American College of Medical Genetics Expert Panel 2002). As genes involved in hearing and deafness are discovered, their characterization leads to important insights about the functioning of the intricate components of the inner ear (Tekin et al. 2002). Some of these 112 Kathleen S. Arnos and Arti Pandya genes code for proteins that form structural components of the hair cells and membranes of the cochlea. Others code for proteins that are responsible for the transport of ions, such as potassium and sodium, or other molecules, such as calcium, through the cells in the cochlea. The appropriate “balance” of these chemicals in different compartments of the cochlea and their transport from cell to cell are essential to the normal process of hearing. Still other recently discovered genes are important for regulating the development and functioning of the inner ear, including the “turning off” or “turning on” of genes at the appropriate developmental stage. Mutations in any of these genes can result in deafness, both syndromic and nonsyndromic forms. COMMON SYNDROMIC FORMS OF HEREDITARY DEAFNESS Usher...