NIDCD Working Group Considerations for Developing and Implementing Genetic Diagnostic Tests for Hereditary Hearing Impairment and Other Communication Disorders
December 8, 1998
Since the early 1990's, scientists have localized over fifty genes that segregate in families with a history of deafness. Ten of the relevant genes for non-syndromic deafness have been identified, six within the last year. Mutations in these genes are important contributors to hearing impairment in some population groups. For example, mutations in the GJB2 gene that encodes the gap junction protein, Connexin 26, are reported to be the most common cause of autosomal recessive non-syndromic deafness in several parts of the world; however, the clinical phenotype may be variable. The degree of hearing loss in persons with Connexin 26-related deafness varies from moderate to profound, and it appears that there may be a variable time of initial expression as well as a variable rate of progression. Deafness-causing mutations in GJB2 are relatively common in some populations with a carrier frequency of more than 1 in 40 (2.5%). Other mutations have been identified that are more common in specific subgroups of the population.
With the identification of genes that contribute to hearing function, genetic testing becomes technically possible. This possibility does not necessarily imply that genetic testing should be performed. Prior to clinical implementation of genetic testing, several issues must be addressed to assess the utility of such tests. There are many unresolved issues regarding the prevalence and penetrance of mutations in various populations, the clinical significance of these mutations, and the short and long-term impact of such testing and information on individuals and their families. Further, there is no information on the knowledge and attitudes about this type of testing or the level in interest in such testing, particularly among families in which hearing impairment has occurred. Finally, it is recognized that there are unique challenges pertaining to genetic testing for deafness and hearing impairment because these conditions are not universally considered to be disabling or undesirable.
The Working Group considered the role of genetic testing as it pertains to the research community engaged in the study of the genetics of hearing, and separately as it pertains to the clinical research and clinical practice communities of otolaryngology, audiology, and speech pathology. Issues needing attention by these communities before such testing should be considered are summarized below. Of significant concern to the Working Group was that the rapidly advancing information on GJB2 mutations could be interpreted to suggest that genetic testing should be performed on all infants who fail routine newborn hearing screening. Because many of the clinical, ethical, and social issues have not been adequately addressed, the Working Group believes that routine genetic screening for GJB2 mutations is premature except as part of an appropriately designed clinical trial. Examples of issues that must be addressed prior to implementation of genetic testing for hearing impairment follow:
- Clinical Genetic Studies
a. The development of studies to determine the prevalence and penetrance of various mutations in normal hearing populations, as well as in populations with hearing impairment or deafness.
b. The development of longitudinal and comprehensive studies of individuals with deafness/hearing impairment to address genotype/phenotype correlations. This includes the natural history of hearing loss in individuals with various mutations in various populations. Necessary phenotypic information includes degree of hearing loss as well as age of onset and rate of progression of hearing loss.
c. The development of clinical trials to study the value of these genetic tests as a complement to existing clinical screening procedures, diagnostic procedures and management practices. Questions include understanding the value of using genetic testing to screen for hearing impairment, determining the impact of genetic testing for hearing impairment, as well as understanding the short and long term effects of genetic testing for hearing impairment.
- Study Design Issues
a. Development of adequate informed consent procedures about the use of DNA specimens for genetic testing and further genetic research related to hearing impairment.
b. Establish criteria by which decisions will be made about whether research results should be made available to participants in the research. Initial studies of genotype/phenotype correlations may not yet have clinical relevance to individuals.
- Studies that provide results to test subjects should address the following testing and counseling issues:
a. Laboratories are required to have Clinical Laboratory Improvement Act (CLIA) approval when results are provided to clinicians and/or to individuals.
b. The determination of the impact of genetic testing and the utilization of information on attitudes and behavior for various cultural groups as well as for individuals.
c. The evaluation of methods to provide education and counseling to facilitate comprehension and subsequent informed decision making about reproductive issues and treatment strategies. In particular, it may be advantageous to develop programs that utilize professionals already involved with the various communities.
To accomplish these goals, the Working Group recommends:
- The organization of a consortium of investigators studying genes in communication disorders, including GJB2 mutations, to permit the rapid pooling of information.
- Support for laboratories, protocols and carefully designed studies to address the issues of concern raised above.
- The inclusion of individuals with hearing impairment and individuals who are deaf as well as related organizations representing the spectrum of involved communities of deaf or hearing impaired people in the formulation and establishment of guidelines and future recommendations regarding genetic testing. These recommendations should be directed to genetic research, clinical research, and clinical practice communities involved in the genetic testing for hereditary hearing impairment.