Heredity has long been recognized as a major cause of hearing loss. Approximately one in 1,000 newborns has hearing loss and over half of these cases are due to genetic causes. Genetic factors are also responsible for some hearing loss that is not present at birth, but begins later in life. Genetics may even play a role in progressive hearing loss associated with aging.
In the past 15 years, researchers have made remarkable progress identifying more than 60 genes that cause hearing loss. Studying these genes has greatly advanced our knowledge of the molecular processes underlying the development and function of the auditory system and will improve our understanding of how alterations in these processes lead to hearing impairment. When it is known which gene is responsible for an individual's hearing loss, it may be possible to treat the hearing loss more effectively and to provide the individual and their family with appropriate counseling.
There are two types of genetic deafness, syndromic and nonsyndromic. About 30 percent of the genetic cases of deafness are syndromic, meaning the hearing loss is accompanied by other medical problems such as kidney problems (Alport syndrome), heart problems (Jervell and Lange-Nielsen syndrome), thyroid enlargement (Pendred syndrome) or blindness (Usher syndrome). Hundreds of syndromes that include hearing loss have been described and most forms are rare. Many genes that cause syndromic forms of deafness have been identified and these genes tend to be involved in the proper development of multiple organ systems, which is why hearing loss may occur in conjunction with other medical problems.
Most genetic deafness is nonsyndromic, meaning that the only obvious medical problem is hearing loss. Over 40 genes causing nonsyndromic deafness have been identified and these genes are involved in the correct functioning of the inner ear. Approximately 80 percent of nonsyndromic genetic deafness is due to recessive gene mutations. Recessive deafness occurs when both copies of a gene, one inherited from the mother and one from the father, have a mutation. Because recessive forms of hearing loss are the most common, the majority of children with hearing loss are born to parents who are not deaf. These hearing parents would have only one copy of the mutated gene and are commonly referred to as "carriers." Mutations in GJB2, the gene encoding the protein connexin 26, are the most common cause of recessive deafness. It is estimated that up to 40 percent of all cases of nonsyndromic genetic deafness are caused by mutations in this single gene.
Dominant gene mutations account for about 15 percent of nonsyndromic genetic deafness. In dominant deafness, a mutation in a single copy of a gene causes hearing loss. In general, most individuals with dominant deafness have progressive hearing loss that begins later in life, while those with recessive deafness have hearing loss at birth or shortly thereafter. The remaining approximately five percent of cases of nonsyndromic genetic deafness are caused by X-linked mutations and mitochondrial mutations (see "Genetics 101," p. 21).
Understanding the Ear
Genetic research has significantly enhanced our understanding of the fundamental processes necessary for normal hearing. While the critical role of the hair cells of the inner ear has long been recognized, most of the structural components of the hair-like projections that give the cells their name have been discovered through genetic studies. Precise structural organization of the hair cell is essential to proper hearing. Each hair cell consists of rows of hair-like projections, called stereocilia, and the height of the stereocilia increases in each row forming a step-like pattern. The hair cells are also arranged in rows and are oriented with their stereocilia all facing the same direction. Genetic investigations have revealed that mutations in numerous deafness genes, such as MYO7A, disrupt the delicate organization of the stereocilia. Further, the products of these genes were found to be components of the stereocilia and are critical for proper stereocilia formation and structural integrity.
The process of turning a sound wave into a nerve impulse that can be interpreted by the brain depends on the availability of potassium and other ions in the inner ear fluid that bathes the hair cells. When sound is detected, potassium enters the hair cells causing them to stimulate the nerve cells. This potassium must then be recycled from the hair cells back to the inner ear fluid in order to maintain the potassium levels. The discovery that mutations in several potassium and ion transport genes, including GJB2, cause deafness illustrates the significance of this mechanism for proper hearing.
In addition to revealing the importance of hair cells and potassium recycling for hearing, genetic research has also given us insight into the critical role of cells in other areas of the cochlea in the hearing process. Furthermore, there are deafness genes whose functions are currently unknown, so we still have much to learn about our hearing machinery.
Applied Knowledge
Genetic research may also have direct benefits for individuals with hearing loss. Following the identification of genes involved in deafness and the subsequent development of diagnostic genetic testing, it may be possible to determine the exact gene mutation responsible for an individual's hearing loss. This information can be useful for clinical care decisions. For example, consider a situation where a baby fails the newborn hearing screen and genetic testing reveals two recessive mutations in the MYO7A gene. In some cases, mutations in this gene cause isolated deafness; however, many individuals with two recessive mutations in this gene also develop progressive blindness. Therefore, the child's vision should be closely monitored as a part of good clinical care. Knowledge of the genetic cause of an individual's hearing loss may also be useful in evaluating the best option for treatment – for example, whether a cochlear implant or other hearing device is most appropriate. Additionally, this knowledge may facilitate accurate genetic counseling and risk assessment for families.
Genetic tests can be very useful in determining the risk of deafness in the future children of hearing individuals with family histories of deafness. For example, consider the scenario in which a woman and her husband are planning on having a child and the woman has a nephew who is profoundly deaf due to two recessive mutations in the GJB2 gene. Her normal hearing brother (the father of the deaf child) carries one copy of the mutated gene. She would like to know the probability of her future child having hearing loss. A genetic test would tell her if, like her brother, she inherited a mutated copy of GJB2. If she does not carry the mutated gene, the chance of her child having hearing loss is very low. If she does carry the mutated gene, then her child's chance of having hearing loss may still be very low or it may be estimated at 25 percent if her husband is also found to be a carrier of a mutation in the same gene.
Although research into genetic causes of deafness has progressed remarkably in the last decade, there are many deafness genes that have not yet been discovered and we need to more fully understand the deafness genes that have already been identified. As our knowledge increases and technology advances, research on the role of genetics in hearing loss will surely continue at a rapid pace, further enhancing testing and diagnostic options and improving personalized treatments for hearing loss.
