Genetic screening for deafness

Pediatr Clin N Am 50 (2003) 315 – 329

Genetic screening for deafness Richard J.H. Smith, MD, FACS, FAAPa,*, Stephen Hone, MB, FRCSI(ORL)b a

Department of Otolaryngology, Molecular Otolaryngology Research Labs, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA b Pediatric Otolaryngology/HNS, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA

Our understanding of the genetics of hearing impairment has advanced rapidly over the past decade. Several genes that are essential for normal hearing have been cloned, and numerous others have been localized to specific chromosomal regions. As this basic science knowledge is translated from the laboratory bench to the patient’s bedside, it is changing the medical evaluation of hearing impairment. The focus of this article is to define these changes by explaining the role of genetics and genetic testing in the evaluation of deaf persons.

Epidemiology Developed countries have seen an increase in the relative incidence of hereditary childhood deafness because major causes of acquired prelingual deafness have been eliminated through improved neonatal care and universal immunization programs. For example, as a result of the vaccination program for congenital rubella, this major cause of acquired congenital deafness in the 1960s is now exceedingly uncommon; more recently, the vaccination program for Haemophilus influenzae type B has decreased the incidence of deafness from meningitis. Although current prevalence estimates of prelingual deafness vary, figures based on universal neonatal screening programs are probably the most accurate. In the United States, estimates from these programs place the rate of bilateral hearing loss greater than 35 dB at 1.4 to 3 per 1000 [1 –3]; European rates, obtained mainly from retrospective studies, are similar with ranges from 1.4 to 2.1

This article was supported, in part, by grants RO1-DC02842 and RO1-DC03544 from the National Institute for Deafness and Other Communication Disorders. * Corresponding author. E-mail address: [email protected] (R.J.H. Smith). 0031-3955/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved. doi:10.1016/S0031-3955(03)00026-9

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per 1000 [4 –6]. In more than half of these cases the deafness is inherited as the only trait (nonsyndromic) in a simple Mendelian recessive fashion (75% –80% of cases), with fractional autosomal dominant (
20%), X-linked (2% – 5%), and mitochondrial (
1%) contributions [5– 8]. Although systematic studies to determine the frequency and mode of inheritance in postlingual deafness are not available, many families segregating deafness have been described, and in nearly all the pattern of inheritance was autosomal dominant. These observations suggest that the majority of families with hereditary deafness fall into two categories: those segregating recessive prelingual deafness and those segregating dominant postlingual progressive deafness.

Recessive prelingual deafness In 1994, Guilford et al [9] mapped the first autosomal recessive nonsyndromic deafness (ARNSD) locus, DFNB1 (DFN, deafness; B, recessive; integer, loci in order of discovery) to chromosome 13q12. Three years later, the DFNB1 gene was identified as GJB2 [10]. Surprisingly, although 33 loci have now been localized and alleles variants of more than 15 genes have been related causally to ARNSD, mutations in GJB2 account for approximately half of hereditary deafness in most developed countries, including the United States, many European countries, Israel, and Australia. GJB2-related deafness also has been repeatedly described in several Asian, Latin American, and African countries, but it appears to be less frequent in these regions. Mutations in GJB2 cause deafness by altering the function of the encoded protein connexin 26 (Cx26) within the inner ear. Cx26 aggregates in groups of six around a central 2.3-nm pore to form a toruslike structure called a connexon. Connexons from neighboring cells covalently bond to form intercellular channels. Aggregations of these connexins are called plaques and are the constituents of gap junctions. Although the definitive function of Cx26 in the inner ear is not known, connexon channels allow for transmission of small ions such as potassium and calcium, and signaling molecules including cAMP and inositol triphosphate [11]. In the cochlea, Cx26 is expressed in the epithelial cell gap junction system and the connective tissue cell gap junction system. Presumably, these systems are involved in potassium circulation, allowing potassium that enters hair cells during sound mechanosensory transduction to be recycled to the stria vascularis [12]. Mutations in GJB2 affect the function of Cx26 and are believed to cause aberrancies in potassium recirculation, subsequently leading to cell death and deafness [13]. GJB2 and deafness Mutations causing GJB2-related deafness have been identified in 35% of sequential individuals referred for hearing loss or cochlear implantation in the United States [14]. The most common deafness-causing allele variants of GJB2 in

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Table 1 Relative frequency of allele variants in persons with GJB2-related deafness Allele variant

Percentage

35delG 167delT V37I del342kBa 313del14 V84L R184P R143W 50 donor SSb

68.70% 6.87% 3.05% 1.91% 1.53% 1.15% 1.15% 1.15% 1.15%

a b

delGJB6-D13S1830. splice donor mutation, IVS1 + 1G > A.

the Midwest United States are the frameshift deletions 35delG and 167delT, the missense mutation V37I, and the large deletions del342kB (delGJB6-D13S1830) and 313del14 (Tables 1, 2). There are marked variations in the frequencies of these mutations, however, that are ethnic specific. For example, although the 35delG mutation is most common in persons of northern European descent, 167delT is most common among Ashkenazi Jews [15] and 235delC is most common among Asians [16]. Carrier rates for these mutations in hearing persons vary accordingly and have been reported to be 2.5% for the 35delG mutation in the Midwest United States, 4% for the 167delT in the Ashkenazi population, and 1% for the 235delG among Asians. The DFNB1 phenotype All individuals with GJB2-related deafness have sensorineural hearing loss. Usually, the deafness is profound (> 90 dB; 50% of cases) or severe (71 – 90 dB; 30% of cases), although moderately severe (56 –70 dB) or moderate (40 –55 dB) deafness also is common (20% of cases). A small fraction of persons (< 2%) have only a mild hearing loss (< 40 dB) [14,17 –20]. This degree of variability occurs even among individuals with the same mutations. The amount of residual hearing Table 2 Common genotypes in persons with GJB2-related deafness Genotype

Percentage

35delG-35delG 35delG-167delT 35delG-del342kBa 167delT-167delT V37I-V37I 35delG-269insT 35delG-313dell4 35delG-50 donor SSb

52.67% 7.63% 3.05% 2.29% 2.29% 1.53% 1.53% 1.53%

a b

delGJB6-D13S1830. splice donor mutation, IVS1 + 1G > A.

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in GJB2-related deafness is highly heritable, however; individuals from the same family tend to have similar levels of hearing, but can differ in the degree of residual hearing. Although it is presumed that the deafness in all individuals with GJB2-related deafness is congenital, two neonates homozygous for the 35delG mutation have been identified who passed neonatal screening tests and subsequently developed profound deafness [21]. Whether this type of rapid hearing loss is a frequent occurrence in the first year of life in individuals with GJB2related deafness is not known. The typical audiogram has a downsloping (two thirds of cases) or flat (one third of cases) pattern, although Mueller et al [19] found that 4 out of 31 persons with GJB2-related deafness had ‘‘U-shaped’’ audiograms. Estivill et al [22] also reported U-shaped audiograms among several profoundly deaf individuals, with hearing levels at 100 dB for the high and low frequencies in comparison with 120 dB for the midfrequencies. Selective low-frequency hearing loss has not been identified in Cx26 deafness. The degree of symmetry between ears is usually high, with differences between ears (< 20 dB) noted in less than one fourth of individuals [17,18]. A single case of unilateral mild hearing loss has been reported in one individual with atypical mutations [23]. Neither improvement nor fluctuation in hearing levels has been noted over the long term in GJB2-related deafness, and progression appears to be slow or nonexistent. Mueller et al [19] reported a 5-dB to 15-dB decrease in hearing in the better hearing ear in three individuals over at least 4 years and a less than 5-dB decrease in three individuals. Five out of ten individuals studied over at least 6 years by Cohn et al [17] had progression, ranging from 15 to 31dB. In contrast, none of the 12 individuals studied by Wilcox et al [24] showed progression, and only 2 out of 16 children studied over a 10-year period by Denoyelle et al [18] showed progression. The stability of Cx26 deafness is reliable enough to have clinical implications. Except for highly unusual cases, individuals with this type of deafness do not require more than annual audiologic follow-up to ensure the stability of their hearing. The lack of fluctuation also may aid in determining candidacy for cochlear implantation. Among individuals with high levels of residual hearing, brain stem auditory evoked responses are consistent with the degree of deafness. In contrast, distortion product otoacoustic emissions are suppressed out of proportion to the degree of deafness, and may be suppressed among normalhearing carriers of GJB2 deafness-causing allele variants [15,25]. Family history of deafness Because GJB2-related deafness is recessive, in most affected individuals there is no family history of deafness. Due to the high population carrier rate of GJB2 deafness-causing allele variants, an increased incidence of deafness among nonsibling relatives and pseudodominant inheritance patterns may be seen. The latter occurs when a deaf individual marries a carrier and has a deaf child. True dominant GJB2-related deafness (DFNA3) is rare, but has been identified in families with three unique mutations: R184Q, W44C, and C202F [26 –28].

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GJB2-related deafness and temporal bone anatomy In general, GJB2-related deafness is not associated with bony abnormalities of the cochlea. Normal CT has been reported in 42 individuals with GJB2-related deafness examined by Cohn et al [17] and Denoyelle et al [18]. In contrast, Kenna et al [23] found bony overgrowth at the time of surgery and asymmetry of the right modiolus, each in one patient. Vestibular function All persons with GJB2-related deafness studied have had normal vestibular function and developmental motor milestones with the exception of two individuals—one person had vertigo and migraine accompanied by unilateral weakness and the second, a premature baby, had maturational vestibular weakness [17,18]. Comorbidity GJB2-related deafness is not associated with known medical abnormalities. Specific rare mutations in GJB2 are associated with deafness and skin abnormalities, including the Vohwinkle’s syndrome type of keratoderma (D66H), diffuse hyperkeratosis (R75W), and palmoplantar keratoderma (G59A and delE42) [29]. Tests of vision, intelligence, electrocardiography, and thyroid function, however, are normal [14,17,30,31]. Cochlear implantation In children with GJB2-related deafness, cognitive dysfunction is not reported and neural structures are preserved, two findings that predict excellent cochlear implantation candidacy. This prediction has been verified—children with GJB2related deafness exhibit the type of gains experienced by most children with congenital deafness after cochlear implantation, and, more importantly, they predictably demonstrate excellent results [30,31]. GJB2 mutation screening The genetic diagnosis of GJB2-related deafness is dependent on identifying mutations within the DNA of affected individuals. DNA may be extracted from any nucleated tissue, although peripheral whole blood (approximately 10 cm3) most commonly is used. Mutation screening of the extracted DNA can be completed using a variety of techniques. The most common mutation (ie, 35delG) may be identified through an allele-specific polymerase chain reaction assay or other techniques that identify specific DNA sequence variations. These mutationspecific techniques are known collectively as mutation identification strategies and suffer the weakness of failing to identify other allele variants. Additional general techniques for mutation screening include single-strand conformational polymorphism analysis, heteroduplex analysis, and denaturing high performance liquid chromatography (DHPLC) analysis. Bidirectional sequencing of DNA strands is the gold standard against which these other methods must be measured.

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If only a single deafness-causing allele variant of GJB2 is identified, additional screening must be completed. In some cases, ambiguous data are generated, making it impossible to establish a definitive genetic diagnosis. SLC26A4 and deafness In 1896, Vaughan Pendred [32], a British physician, described an Irish family in which two out of 10 children were congenitally deaf and had goiters. This condition, now known as Pendred syndrome (PS), is estimated to account for 1% to 8% of congenital deafness. The PS phenotype The hearing loss in PS is typically bilateral, prelingual, more severe in the high frequencies, and associated with specific cochlear malformations. HvidbergHansen et al [33] provided the first description of the temporal bone histopathology in their study of a single patient who had dilation of the endolymphatic duct and sac, enlargement of the vestibular aqueduct, and cochlear dysplasia. In a premorbid assessment of 17 affected persons using axial pyramidal tomography, Johnsen et al [34] found Mondini dysplasia (the presence of both an abnormal cochlea and a dilated vestibular aqueduct) in all cases. This anomaly is not an invariable finding, however, as documented in a study by Andersen [35], in which Mondini dysplasia was found in only 8 out of 13 affected persons. With the improved resolution of CT and MRI, Phelps et al [36] found bilateral dilated vestibular aqueducts (DVAs) in 31 out of 40 affected persons, and Mondini dysplasia in 8 persons. Based on these data, a temporal bone assessment should be included in the diagnostic evaluation of PS. The goitrous changes of the thyroid usually do not present until puberty. Morgans et al [37] have shown that the thyroid abnormality is due to abnormal iodide processing demonstrable with the perchlorate discharge test. In this test, individuals are given radiolabeled iodine. Potassium perchlorate, a competitive inhibitor of iodide transport into the thyroid, also is administered. In normal individuals, the amount of iodide in the thyroid remains stable, reflecting the rapid oxidation of iodide to iodine and its incorporation into thyroglobulin. In persons with PS, however, incorporation is delayed and as iodide leaks back into the bloodstream, the amount of radiolabeled iodine in the thyroid decreases by more than 10%. To determine the course of thyroid disease, Friis et al [38] studied 17 affected persons and found that 8 remained euthyroid. Of the 9 who became hypothyroid, 4 previously had undergone thyroidectomy. Reardon et al [39] studied 43 affected persons with goitrous changes and showed that 24 were euthyroid and 19 were hypothyroid. Thus, in the majority of cases, persons with PS remain euthyroid. Phenotypic heterogeneity has made it difficult to reach a consensus on the best screening strategy to diagnose PS. For example, in a two-sibling family described by Johnsen et al [34], one sibling demonstrated the classic features of PS—severe-to-profound sensorineural hearing loss (SNHL), goiter, and a pos-

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itive perchlorate discharge test—but the other sibling had only mild sensorineural deafness and no goiter. Reardon et al [39] found goiter in 83% of people with a positive perchlorate discharge test, but found that thyroid manifestations and the degree of hearing loss could vary between individuals in a family. Furthermore, the perchlorate discharge test is not consistently positive, as illustrated by a study [40] in which only three out of six individuals with confirmed PS had greater than 10% iodide washout. In addition, Reardon et al [39] reported a 2.9% falsenegative rate for this test. Therefore, there is no single sign or clinical test that can unambiguously identify PS. The genetics of PS In 1996, PS was mapped to a 9-cm region on the long arm of chromosome 7 (7q21 –34) [41]. Other groups [42 – 45] confirmed this linkage result and, with fine mapping, the candidate interval was reduced to 0.8 cm. In 1997, 100 years after the disease was first recognized, Everett et al [46] cloned the causative gene and named it PDS. To date, 62 mutations have been found in a total of 116 families [47]. Most of these mutations have been reported in single families; however, 15 mutations have been reported in more than one family and four (L236P, IVS8 + 1G > A, T416P, and H723R) accounted for approximately 60% of the total PS genetic load [48]. A form of nonsyndromic deafness, DFNB4 (characterized by sensorineural deafness and DVA) localizes to the same genomic region and is allelic to PS. As is implied by the nomenclature, persons with DFNB4 do not have thyroid anomalies. In 1998, Li et al [49] demonstrated two mutations in PDS in a consanguineous Indian family with DFNB4. Usami et al [50] also demonstrated seven mutations in six families with DFNB4. Functional studies by Scott et al [51] suggest that the observed phenotype may correlate with the degree of residual function of the encoded protein pendrin. Mutations that result in no residual transport function appear to be associated with the PS phenotype; minimal transport ability prevents thyroid dysfunction, but sensorineural deafness and temporal bone anomalies still occur and affected persons have DFNB4. Based on similarities to other solute carrier proteins, PDS has been renamed SLC26A4. This gene is now known to be the major genetic cause of PS and DFNB4. PS patient care In 2001, Campbell et al [48] studied genotype –phenotype correlations in relation to temporal bone abnormalities. The group found mutations in SLC26A4 in 82% of multiplex families with DVA or Mondini dysplasia, but in only 30% of simplex families—results suggesting that mutations in SLC26A4 are the major genetic cause of DVA or Mondini dysplasia. Reardon et al [39] have advocated for genetic testing to establish a diagnosis of PS, because variability in onset and severity of goiter is an unreliable clinical indicator of disease. The perchlorate test also is unreliable, as illustrated in two consanguineous Tunisian families with a genetic diagnosis of PS in which 11 out of 23 affected individuals with goiter and mutations in SLC26A4 had negative perchlorate washouts [52]. These results,

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coupled with the data reported by Campbell et al [48] in which patients were ascertained based on temporal bone findings, make mutation screening of SLC26A4 the most reasonable diagnostic test in individuals with sensorineural deafness and cochlear malformations (DVA or Mondini). Although a positive result currently does not impact habilitation, it does permit a definitive diagnosis and makes accurate genetic counseling possible.

Dominant progressive deafness At this time, genetic testing of small families segregating autosomal dominant nonsyndromic deafness (ADNSD) is difficult for two reasons. First, there are more than 40 loci currently known to be associated with ADNSD with no single locus making a substantial relative contribution to the total ADNSD genetic load. This fact means that genetic testing requires mutation screening of numerous genes, a labor-intensive process. Any identified nucleotide changes then must be studied to determine whether they affect protein function—in most cases, a definitive diagnosis will be impossible to make. The second limitation reflects the general inability to correlate genotype with audiologic phenotype. This limitation means that it is not possible to identify a particular gene for mutation screening based on the audiogram. There is, however, one notable exception. DFNA6/14 DFNA6 and DFNA14 were originally mapped to nonoverlapping, adjacent regions on chromosome 4p16; however, a subsequent study indicated that these loci are allelic. The DFNA6/14 hearing loss is caused by allele variants of WFS1, a gene predicted to encode an 890 amino acid transmembrane protein with nine helical transmembrane segments. The DFNA6/14 phenotype Persons with DFNA6/14 have a moderate, bilateral, symmetrical hearing loss below 4000 Hz. In the high frequencies, their hearing is often normal [53,54]. This type of low-frequency hearing loss also is a characteristic of DFNA1; with DFNA1, however, there is rapid progression and ultimately a profound loss across all frequencies. DFNA6/14, in contrast, shows no or only mild progression, although in some families, age-related hearing loss in the high frequencies eventually results in a flat audiogram with a moderate hearing loss [55]. In evaluating families segregating presumed ADNSD it is very useful to construct a pedigree and an audioprofile. The latter is a composite audiogram that shows on a single graph the audiograms of several family members averaged decade by decade. If the audioprofile shows preservation of low-frequency hearing in a family segregating ADNSD, mutation screening of WFS is warranted. In approximately 85% of families meeting these criteria, WFS1 mutations will be found (Fig. 1) [56].

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Fig. 1. Audioprofile of DFNA6/14 deafness. This composite audiogram shows the decade-by-decade change in average auditory function that is typical for DFNA6/14 deafness. Hearing in the low frequencies is preserved. In families showing this type of profile, mutation screening of WFS is warranted. (Courtesy of Patrick L.M. Huygen, PhD.)

Hearing loss and WFS1 Mutations in WFS1 are associated with Wolfram syndrome (WS) and DFNA6/14. WS shows an autosomal-recessive inheritance pattern and also is known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). The minimal diagnostic criteria are diabetes mellitus and optic atrophy [57], although additional symptoms include sensorineural deafness, ataxia, peripheral neuropathy, urinary tract atony, and psychiatric illness [58,59]. Remarkably, the hearing impairment in WS patients affects the high frequencies [60,61]. According to the Human Gene Mutation Database, 65% of WS mutations are inactivating, suggesting that loss of function of WFS1 is the cause of the DIDMOAD phenotype [62]. In contrast, no inactivating mutations have been found in DFNA6/14, indicating that specific mutations that do not disrupt the complete protein are responsible for the low-frequency hearing loss phenotype [56]. The majority of frameshift and nonsense mutations that have been identified in WS patients are localized to predicted transmembrane domains [63]. With the exception of the K193Q mutation, which is located in the first extracellular domain, all mutations identified in families segregating DFNA6/14 are located in the fifth intracellular domain [56]. This finding suggests that mutations in this domain affect a limited number of functions and that this domain plays an important role in the function of the inner ear.

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Genetic testing Its perceived value Although genetic testing can be offered to deaf and hard-of-hearing persons and their families, it is useful to ask whether this service is perceived as valuable. This question is not trivial, because deafness differs from most conditions for which genetic testing is available. Testing for genetically determined cancer, for example, may permit an at-risk individual to make lifestyle changes or pursue screening protocols to prevent disease or limit its impact. Many persons, however, consider deafness neither a disease nor a handicap. For example, members of the deaf community embrace their deafness as an integral part of their identity, shared history, and social customs [64]. They historically have espoused a negative attitude toward the medical community, which they perceive as a threat to their culture [65]. This negative attitude extends to genetics and genetic research on deafness, as documented by a recent survey of members of the deaf community who showed a predominantly negative attitude toward the use of genetic testing for deafness [66]. Most deaf individuals believe that genetic testing does more harm than good and remain concerned about the implications and ramifications of future discoveries in genetics. Although these data are helpful in understanding the perspectives of this community, they cannot be generalized to individuals who do not consider themselves ‘‘culturally’’ deaf. Most hearing parents who unexpectedly have a deaf child perceive deafness as a disability and turn to medical specialists for assistance. These parents do not know how to relate to their child, and do not know how their child will be able to relate to the ‘‘hearing’’ world. Their initial reaction to a diagnosis of deafness is similar to the reaction expressed by parents who have a child with multiple congenital malformations. There is a sense of shock, denial, disbelief, grief, pain, helplessness, guilt, and depression—feelings that reflect the sense of loss associated with the hopes and dreams that parents may have had for their child’s future. Often, parents blame themselves for their child’s perceived ‘‘handicap’’ and desperately search for an explanation for the condition. Not infrequently, parents conclude that the cause was due to their own ignorance, neglect, or misfortune during or after the pregnancy. By providing these parents with a specific etiology of deafness, more accurate information can be provided, which can alleviate incorrect or inaccurate beliefs [67]. Genetic counseling Because 90% to 95% of deaf children are born to normal hearing parents, understanding the attitudes of this group (ie, normal-hearing parents of deaf children) is necessary for optimal counseling strategies [68]. In a study that addressed these issues, Brunger et al [69] surveyed 96 normal-hearing parents of deaf children and found that the vast majority (96%) approve of genetic testing for deafness and believe that it should be offered prenatally (87%). Although

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answers to several questions, however, clearly verified that normal-hearing parents of deaf children have an overall positive attitude toward genetic testing for deafness, their understanding of genetics is poor. Most normal-hearing parents of deaf children (>90%) have inaccurate beliefs about their own and their child’s recurrence chances. Remarkably, there was no difference between parents who had had genetic testing for their children and those who had not had such testing. In fact, some parents (32%, or 6 out of 19) who received negative GJB2 test results believed that their child did not have ‘‘the gene’’ that causes deafness. These individuals did not understand that deafness is heterogeneous and mistakenly thought that their recurrence chance for having another deaf child was 0%. Clearly the majority of parents either did not receive genetic counseling or received counseling that was inadequate. Such inaccuracies provide a clear example of why formal pretest and posttest genetic counseling is important. If normal-hearing parents of deaf children are provided appropriate and accurate information, they can make informed decisions about genetic testing for deafness. Formal counseling also ensures that those who receive genetic test results have a clear understanding of their meaning, including how recurrence chances are changed. These benefits have been verified in families who received counseling for other genetic conditions [70].

Summary Genetic testing for deafness has become a reality. It has changed the paradigm for evaluating deaf and hard-of-hearing persons and will be used by physicians for diagnostic purposes and as a basis for treatment and management options. Although mutation screening is currently available for only a limited number of genes, in these specific instances, diagnosis, carrier detection, and reproductive risk counseling can be provided. In the coming years there will be an expansion of the role of genetic testing and counseling will not be limited to reproductive issues. Treatment and management decisions will be made based on specific genetic diagnoses. Although genetic testing may be a confusing service for the practicing otolaryngologist, it is an important part of medical care. New discoveries and technologies will expand and increase the complexity of genetic testing options and it will become the responsibility of otolaryngologists to familiarize themselves with current discoveries and accepted protocols for genetic testing.

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