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A New Age in the Genetics of Deafness

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A New Age in the Genetics of Deafness , September/October 1999. Vol. 1 . No. 6 invited review/cme article A new age in the genetics of deafness Heidi L. Rehtu, MMSC' ot~dCytltllia C. Morton, PAD' Over the last several years, an understanding of the genetics SYNDROMIC AND NONSYNDROMIC DEAFNESS of hearing and deafness has grown exponentially. This progress , The prevalence of severe to profound bilateral congenital has been fueled by fast-paced developments in gene mapping hearing loss is estimated at 1 in 1000 births? When milder I and discovery, leading to the recent cloning and characteriza- forms of permanent hearing impairment at birth are included, tion of many genes critical in the biology of hearing. Among this estimate increases four-fold. Congenital deafness refers to the most significant advances, especially from a clinical per- deafness present at birth, though the cause of such hearing spective, is the discovery that up to 50% of nonsyndromic re- impairment may be genetic (hereditary) or environmental (ac- cessive deafness is caused by mutations in the GIB2 gene, which quired). Various studies estimate that approximately one-half encodes the connexin 26 protein (Cx26).I.' The clinical use of of the cases of congenital deafness are due to genetic factor^,^ screening for mutations in Cx26 and other genes involved in and these factors can be further subdivided by mode of inher- hearing impairment is still a new concept and not widely avail- itance. Approximately 77% of cases of hereditary deafness are able. However, the eventual availability of an array of genetic autosomal recessive, 22% are autosomal dominant, and 1% are tests is likely to have a major impact on the medical decisions X-linked.-l In addition, a small fraction of hereditary deafness made by hearing-impaired patients, their families, and their (< 1%) represents those families with mitochondria1 inheri- physicians. It is likely that information from these tests will tance in which the trait is passed through the maternal lineage. I simplify the diagnoses, prognoses, and treatment decisions of- ' Aside from mode of inheritance, there are a number of other fered by the physician. Furthermore, the use of genetic testing descriptions used to classify types of deafness. These include will assist individuals in understanding the molecular basis and age of onset (prelingual vs. postlingual), severity (mild, mod- heritability of their hearing loss. erate, severe, or profound, unilateral vs. bilateral), presence of This review presents an overview of current topics relating other anomalies (nonsyndromic vs. syndromic),etiology (ge- to the genetics of deafness including the different forms of netic vs. acquired), type of pathology (sensorineural, conduc- , deafness and their prevalence. The basic process of hearing and tive, or mixed), and stability of the hearing loss (temporary vs. the functions of the various genes that have been cloned for permanent, stable, progressive, or fluctuating). An important I nonsyndromic deafness will be described. In addition, nonge- distinction exists between sensorineural deafness and conduc- netic causes of deafness will be reviewed, because they are im- tive deafness. Conductive hearing loss typically results from portant in the differential diagnosis when considering a genetic problems associated with the esternal or middle ear, whereas basis for a patient's deafness. The implications of universal sensorineural loss indicates dysfunction of the cochlea or au- newborn hearing screening and its recent implementation in ditory nerve. Although the type of pathology varies widely many states will also be addressed. Furthermore, important among the syndromic forms of deafness, with minor excep- factors involved in the clinical diagnosis of the etiology of deaf- tion, nonsyndromic deafness is typically. - sensorineural. An ad- ness, as well as factors relating to intervention and manage- ditional consideration is whether the hearing loss is prelingual ment of children with hearing impairment, will be discussed. or postlingual. Even though hearing loss can develop at any Finally, this review will consider genetic counseling for deaf- age, this distinction is important because prelingual deafness ness and some of the issues important to the Deaf community. often leads to difficulties with speech and language develop- Although the topics presented here have not seen their last ment. assessment, this review will explore the basics upon which new Although the incidence of prelingual hearing loss is rela- knowledge can be gradually added. tively high as compared with other childhood disorders, an even larger percentage of the population is affected by postlin- gual hearing impairment, with the majority ofthese cases being age-related hearing loss (presbycusis). In fact, it is estimated that hearing impairment affects one-half of the population in the United States by age This emphasizes the finding that hearing loss is a major public health concern affecting a large segment of the general population. Despite the observation that the majority of deaf and hear- ing-impaired individuals have no other symptoms, approxi- , Genetics ry5ICdicine 295 Rehm et a1 mately 30°A) of patients with prelingual deafness also have ad- In general, autosomal recessive forms of deafness are prelin- ditional medical anomalies.' More than 400 such syndromic gual and autosomal dominant ones tend to result in progres- forms ofdeafness have been characterized, with the most com- sive, postlingual deafness. This likely reflects the fact that most plete collection of these disorders found in Gorlin and col- recessive disorders represent a complete loss of a gene's func- leagues' Hcr.cllitclry Hc17rirlg LOSS1111~1 Its S~II~~~OIIIL~S.Many of tion, whereas dominant disorders may mechanistically repre- these syndron~esare quite rare. and the responsible genes are sent an interaction between the activity of the normal gene unknown, yet the genes for the most common syndromes and product and the activity of the mutant product. a few for the rarer forms have been cloned in recent years. The responsible gene has been identified at 15 of these non- Those syndron~eswith higher prevalence are listed in Table 1 syndromic loci, marking great achievement in the last 3 years. with their accompanying phenotype (not including deafness) Much of this success can be attributed to the vast contributions and responsible protein. of the Human Genome Project in establishing high-density The other 70% of hearing impairment cases fall into the genetic maps and other tools for genetic analysis. However, category of nonsyndromic deafness. In these cases, the only there are still many genes to be identified. For a full surnmaryof clinical finding is hearing loss with the exception that some these loci, please refer to the frequently updated Hereditary patients may have accompanying vestibular symptoms. Al- Hearing Loss Homepage, which contains many tables summa- though deafness and vestibular dysfunction do not always oc- rizing the details of these nonsyndromic loci, as well as a wealth cur together, the existence of many disorders involving both ofother information related to research on the genetics ofdeaf- the auditory and vestibular systems reflects their close ana- nes5 This web site represents an excellent resource for the tomic proximity and similar developmental origin and struc- research community and for others interested in hereditary ture. deafness. One of the difficulties in studying nonsyndromic deafness As each gene is cloned, a small piece of the puzzle is assem- and discovering the underlying genetic causes has been the bled in an ongoing attempt to understand cochlear function immense genetic heterogeneity that exists among nonsyn- and how dysfunction can lead to deafness. Although the com- dromic forms of deafness. Although subtle pathologic differ- plexity of the hearing organ has long been appreciated, its in- ences may allow clinical differentiation between certain sub- tricacies are underscored by the great variety of functions pro- types of nonsyndromic deafness, there still exist a plethora of posed for the deafness genes that have already been cloned. The genes whose dysfunction can result in highly similar pheno- functions of these genes and how they may contribute to the types. In fact, mapping efforts have located more than 66 inde- hearing process are described below. pendent loci for nonsyndromic deafness.' Each locus is labeled "DFN" followed by "A" for dominant inheritance, "B" for re- cessive, or no additional letter for X-linked. A unique number Anatomy and Function of the Cochlea is then added to the locus designation to indicate the sequential The hearing organ is an anatomically beautiful structure, order in which the loci were mapped. consisting of many different cell types and unique elements Table 1 Common forms of syndromic deafness Syndrome Malor Features (bes~desdeatness) Proteln Alport syndrome Nephr~t~s,ocular abnorrnal~tlea Collagen type IV a5 (XL) X-llnked (XL) Collagen type IV a3 (AR) Autosomal recesa~veIAR) Collagen type IV a4 (AR) Branchlo-oto-renal syndrome Branchla1 remnants; renal anomalies EYAI lervell and Lange-Nielsen syndrome (JLNS1-2) Cardlac conduction defects Neurofibrornatosis type 2 Acoustic neuromas Merlin Pendred syndrome Thyro~dgoiter Pendrin Stickler syndrome (STL1-3) Orofacial deform'lties; ocular abnornialities; arthrlt~s Collagen type I1 a1 (STL1) Collagen type XI a2 (STL2) Collagen type XI a1 (STL3) Usher syndrome (USHIA-F, USH2A-(1. USH3) Retinitis pigmentosa
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