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Nonsyndromic Hearing Loss and Deafness, DFNB1

Summary

Disease characteristics.  DFNB1 is characterized by congenital, non-progressive mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.

Diagnosis/testing.  Diagnosis of DFNB1 depends upon molecular genetic testing to identify deafness-causing mutations in the GJB2 gene and/or GJB6 gene that alter the gap junction beta-2 protein (connexin 26) and the gap junction beta-6 protein (connexin 30), respectively. Molecular genetic testing of the GJB2 and GJB6 genes detects more than 99% of deafness-causing mutations in these genes and is available clinically.

Management.  Management of DFNB1 includes fitting with hearing aids and enrollment in appropriate educational programs. Cochlear implantation may be considered for individuals with profound deafness. Surveillance includes semi-annual examinations. If both deafness-causing mutations have been identified in an affected family member, molecular genetic testing can clarify the genetic status of a child at risk for DFNB1 so that appropriate early management is provided.

Genetic counseling.  DFNB1 is inherited in an autosomal recessive or possibly digenic manner. In each pregnancy, the parents of a proband have a 25% chance of having a deaf child, a 50% chance of having a hearing child who is a carrier, and a 25% chance of having a hearing child who is not a carrier. Once an at-risk sib is known to be hearing, the chance of his/her being a carrier is 2/3. When the mutation(s) causing DFNB1 are detected in one family member, carrier testing for at-risk family members and prenatal testing for at-risk pregnancies is possible.

Diagnosis

Clinical Diagnosis

DFNB1 is associated with the following:

• Congenital, generally non-progressive sensorineural hearing impairment that is moderate to profound by auditory brainstem response testing (ABR) or pure tone audiometry [Guilford et al 1994 , Maw et al 1995 , Scott et al 1995]

  Note: (1) Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 25 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90 dB), or profound (90 dB). The frequency of hearing loss is designated as low (<500Hz), middle (501-2000Hz), or high (>2000Hz) (See Hereditary Hearing Loss and Deafness Overview).

• No related systemic findings identified by medical history and physical examination

• A family history of nonsyndromic hearing loss consistent with autosomal recessive inheritance

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Genes.   GJB2, which encodes connexin 26, and GJB6, which encodes connexin 30, are the only two genes known to be associated with deafness at the DFNA1 locus.

• GJB2.  Approximately 98% of individuals with DFNB1 have two identifiable GJB2 mutations (i.e., they are homozygotes or compound heterozygotes). More than half of all persons of northern European ancestry with two identifiable GJB2 mutations are homozygous for the 35delG point mutation [Scott et al 1998].

• GJB6.  Approximately 2% of individuals with DFNB1 have one identifiable GJB2 mutation and one of two large deletions that include a portion of GJB6 (i.e., they are double heterozygotes)

Molecular genetic testing: Clinical uses

• Diagnostic testing
• Carrier testing
• Prenatal diagnosis

Molecular genetic testing: Clinical methods

GJB2 (encoding connexin 26)

• Sequence analysis.  Sequence analysis of the entire coding region detects both mutations in 98% of persons with DFNB1.

  Note: Mutation screening for DFNB1 is not complete unless screening for the splice site mutation (exon 1 of GJB2) and the large GJB6-containing deletions is included.

• Targeted mutation analysis.  Mutation analysis (looking for only a specific mutation) is generally not recommended as this type of analysis has an ethnic bias.

  • The 35delG mutation is most common in populations of northern European ancestry.
  • The 167delT mutation is most common in the Ashkenazi Jewish population.
  • The 235delC mutation is most common in the Japanese and Chinese populations.

GJB6 (encoding connexin 30)

• Targeted mutation analysis.  Two large deletions that include a portion of GJB6 ( GJB6-D13S1830 and GJB6-D13S1854) are known [Del Castillo et al 2003 , Del Castillo et al 2005]. GJB6-D13S1830 is the most common GJB6 mutation associated with DFNB1.

  • In one study, 67% of Spanish individuals with one identified GJB2 mutation had this deletion [Stevenson et al 2003 , Wu et al 2002].
  • In another study, GJB6-D13S1830 was found in 16% of individuals with one GJB2 mutation [Pandya et al 2003].

Note: Nonsense or missense mutations of GJB6 that would be detected by sequence analysis have not been associated with DFNB1.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in DFNB1 Test Method Mutations Detected Mutation Detection Rate Test Availability Two mutations One mutation Sequence analysis GJB2 sequence alterations 98% ~2%  1 Clinical Targeted mutation analysis GJB6 deletions  2 NA  3 ~2%  1 Clinical

1. Percentages vary depending on ethnicity. Numbers in table reflect screening of a US population primarily of northern European ancestry. 2.  GJB6-D13S1830 and GJB6-D13S1854 3. NA = not applicable

Interpretation of rest results

• For issues to consider in interpretation of sequence analysis results, click here .
• The diagnosis of DFNB1 is established if an individual or affected sibling has recognized deafness-causing mutations in GJB2 or in GJB2 and GJB6.
• If only one GJB2 mutation is detected and a large deletion that includes a portion of GJB6 is not present, the affected individual is either: (1) deaf and coincidentally a carrier of a GJB2 mutation; or (2) deaf with DFNB1 secondary to a novel non- GJB2 non-complementary mutation in the DFNB1 interval.

  Note: It is difficult to determine the percentage of deaf persons with one GJB2 mutation who fall into these two categories. In a screen of deaf 35delG heterozygotes, analysis of single-nucleotide polymorphisms (SNPs) in the GJB2-GJB6 region strongly supports the existence of novel mutations in the DFNB1 interval in some of these persons [Azaiez et al 2004 , Del Castillo et al 2005].

Testing Strategy

For individuals with nonsyndromic hearing loss:

• The first step in diagnosis is sequence analysis of GJB2 exon 2. If two deafness-causing mutations are identified, the diagnosis of DFNB1 is established.
• If one deafness-causing mutation is identified, targeted mutation analysis for the two deletions, GJB6-D13S1830 and GJB6-D13S1854 is warranted.
• If no deafness-causing mutations of GJB2 are identified, targeted mutation analysis for GJB6-D13S1830 and GJB6-D13S1854 is not warranted. The frequency of these two deletions in all populations is not high enough to result in a large number of deaf persons homozygous for these mutations. They represent fewer than 0.5% of all individual with prelingual deafness and without mutations in GJB2 [Del Castillo et al 2003 , Del Castillo et al 2005].

Genetically Related (Allelic) Disorders

Other phenotypes have been associated with mutations in GJB2 and GJB6:

GJB2

• DFNA3 , an autosomal dominant disorder of progressive, moderate-to-severe sensorineural impairment

• Palmoplantar keratoderma, characterized by diffuse hyperkeratosis of the hands and feet [Richard et al 1998 , Heathcote et al 2000]

• Keratitis-ichthyosis-deafness (KID) syndrome, an ectodermal dysplasia in which affected individuals have vascularizing keratitis, progressive erythrokeratoderma, and profound sensorineural hearing loss, as well as scarring alopecia and predisposition to squamous cell carcinoma [Richard et al 2002 , van Geel et al 2002 , van Steensel et al 2002]. KID is caused by heterozygous mutation in GJB2.

• Hystrix-like ichthyosis-deafness (HID) syndrome, an autosomal-dominantly inherited keratinizing disorder characterized by sensorineural hearing loss and hyperkeratosis of the skin. Shortly after birth, erythroderma develops, with spiky and cobblestone-like hyperkeratosis of the entire skin surface appearing by one year of age. Severe palmoplantar keratoderma and scarring alopecia occurs in some. HID syndrome is considered to differ from KID syndrome in: (1) the extent and time of occurrence of skin symptoms; (2) the severity of keratitis; and (3) electron microscopic features. Both KID and HID syndromes are caused by the same mutation in GJB2 [van Geel et al 2002].

• Vohwinkel syndrome, an autosomal dominant condition classified as a "mutilating" diffuse keratoderma because circumferential hyperkeratosis of the digits can lead to autoamputation. Mild-to-moderate sensorineural hearing loss is often associated with the disease [Maestrini et al 1999].

  Note: The M34T mutation described in a family with palmoplantar keratoderma and autosomal dominant sensorineural deafness [Kelsell et al 1997] is not a cause of dominant hearing loss [Cucci et al 2000]. This same DNA variant has been identified in normal hearing persons [Scott et al 1995 , Denoyelle et al 1998 , Kelley et al 1998], and a screen of 128 grandparents or heads of individual families not known to be related and included in CEPH (Centre d'Etude du Polymorphisme Humain) identified three individuals (2.3%) with the mutation [unpublished data]. The possible pathogenicity of the M34T remains controversial [Snoeckx et al 2005].

With some mutations of GJB2, the epidermal disease and hearing loss cosegregate, while with other mutations, the severity of the disease phenotype varies, suggesting that other factors modify gene expression [Kelsell et al 2001].

GJB6

• Hidrotic ectodermal dysplasia type 2 (Clouston syndrome), autosomal dominant ectodermal dysplasia, alopecia, palmoplantar hyperkeratosis [Smith et al 2002]

Clinical Description

Natural History

DFNB1 is characterized by congenital (present at birth), non-progressive sensorineural hearing impairment. Intrafamilial variability in the degree of deafness occurs. If an affected person has severe-to-profound deafness, an affected sibling with the same GJB2 deafness-causing allele variants has a 91% chance of having severe-to-profound deafness and a 9% chance of having mild-to-moderate deafness. However, if an affected person has mild-to-moderate deafness, an affected sibling with the same GJB2 deafness-causing allele variants has a 66% chance of having mild-to-moderate deafness and a 34% chance of having severe-to-profound deafness.

In a large cross-sectional analysis of GJB2 genotype and audiometric data from 1531 persons with autosomal recessive, mild-to-profound, nonsyndromic deafness (median age 8 years; 90% within 0-26 years of age) from 16 countries, linear regression analysis of hearing thresholds on age in the entire study and in subsets defined by genotype did not show significant progression in any [Snoeckx et al 2005]. This finding is in concordance with prior studies [Denoyelle et al 1999 , Orzan et al 1999 , Loffler et al 2001]; however, progression of hearing loss cannot be excluded definitively given the cross-sectional nature of the regression analysis. Although Snoeckx et al (2005) did find a slight degree of asymmetry, the difference in pure tone age at 0.5, 1.0, and 2.0 kHz between ears was less than 15 dB in 90% of persons.

Vestibular function is normal; affected infants and young children do not experience balance problems and learn to sit and walk at age-appropriate times.

Except for the hearing impairment, affected individuals are healthy and enjoy a normal life span.

Genotype-Phenotype Correlations

Numerous studies have shown that it is possible to predict phenotype based on genotype. The largest study to date involved a cross-sectional analysis of GJB2 genotype and audiometric data from 1531 persons from 16 different countries with autosomal recessive, mild-to-profound, nonsyndromic deafness [Snoeckx et al 2005]. Of the 83 different mutations identified, 47 were classified as non-truncating and 36 as truncating. By classifying mutations this way, the authors defined three genotype classes:

• Biallelic truncating (T/T) mutations.  1183 of the 1531 persons studied (77.3%) segregated two truncating mutations that represented 64 different genotypes (36% of all genotypes found). The degree of hearing impairment in this cohort was: profound in 59-64% of persons; severe in 25-28%; moderate in 10-12%; and mild in 0-3%.

• Biallelic non-truncating (NT/NT) mutations.  95 of the 1531 persons studied (6.2%) segregated two non-truncating mutations that represented 42 different genotypes (24% of all genotypes found). The degree of hearing impairment was mild in 53% of persons and severe-to-profound in 20%.

• Compound heterozygous truncating/non-truncating (T/NT) mutations.  253 of the 1531 persons studied (16.5%) segregated one truncating and one non-truncating mutation that represented 71 different genotypes (40% of all genotypes found). The degree of hearing impairment was profound in 24-30% of persons and severe in 10-17%.

Scatter diagrams were constructed to show the binaural mean pure tone age at 0.5, 1 and 2 kHz (PTA0.5,1,2 kHz) for each person within each genotype class, using persons homozygous for the 35delG allele as a reference group.

• T/T: Only two genotypes differed significantly from the 35delG/35delG homozygote reference group:

  • 35delG/del(GJB6-D13S1830) had significantly more hearing impairment (median PTA0.5,1,2 kHz = 108 dB; p < 0.0001)
  • 35delG/IVS1+1GA had significantly less hearing impairment (median PTA0.5,1,2 kHz = 64 dB; p < 0.0001).

• T/NT: Nine genotypes differed significantly from the 35delG/35delG homozygote reference group:

  • One genotype, 35delG/R143W, showed significantly more hearing impairment
  • Eight genotypes had significantly less hearing impairment. The three genotypes with the least hearing impairment were 35delG/V37I (median PTA_{0.5,1,2 kH}z = 40 dB, p < 0.0001), 35delG/M34T (median PTA_{0.5,1,2 kHz} = 34 dB, p < 0.0001) and del(GJB6-D13S1830)/M34T (median PTA0.5,1,2 kHz = 25 dB, p < 0.0001). The finding in the T/NT genotype class regarding the threshold distribution in persons with 35delG/L90P suggested a bimodal distribution, as seven 35delG/L90P compound heterozygotes had a PTA_{0.5,1,2 kHz} > 95 dB and 34 had a PTA0.5,1,2 kHz < 65 dB, with the PTA0.5,1,2 kHz of only one person falling between these two values (65-95 dB).

• NT/NT: Three genotypes differed significantly from the 35delG/35delG homozygote reference group in having less hearing impairment: M34T/M34T (median PTA_{0.5,1,2 kHz} = 30 dB, p < 0.0001), V37I/V37I (median PTA_0.5,1,2 kHz = 27 dB, p < 0.0001) and M34T/V37I (median PTA_{0.5,1,2 kHz} = 23 dB, p < 0.001).

Nomenclature

DFNB followed by a suffix integer is used to designate loci for autosomal recessive nonsyndromic deafness.

Mutations in GJB2 and deletions involving GJB6 are both associated with deafness at the DFNB1 locus.

Prevalence

DFNB1 accounts for approximately 50% of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss in the United States, France, Britain, and New Zealand/Australia [Denoyelle et al 1997 , Green et al 1999]. Its approximate prevalence in the general population is 14/100,000, based on the following calculation: the incidence of congenital hereditary hearing impairment is 1:2000 neonates, of which 70% have nonsyndromic hearing loss. Seventy-five to eighty percent of cases of nonsyndromic hearing loss are autosomal recessive, and of these, 50% result from GJB2 mutations. Thus, 5/10,000 x 0.7 x 0.8 x 0.5 = 14/100,000.

Given the extreme heterogeneity of autosomal recessive nonsyndromic hearing impairment, it is not surprising that epidemiologic studies in other populations have shown that the frequency of GJB2 mutations as a cause of hearing impairment is high variable. For example, among families segregating autosomal recessive nonsyndromic hearing impairment, GJB2 mutations are causally related to congenital hereditary hearing impairment in ~25% of Palestinian families [Shahin et al 2002], at least 16% of Chinese families [Liu et al 2002], approximately 22% of the Kurdish population of Iran [Mahdieh at al 2004], and about 24% of Altaians from Siberia [Posukh et al 2005].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

See Hereditary Hearing Loss and Deafness Overview .

Autosomal recessive syndromes with hearing loss and:

• Retinitis pigmentosa.  Three types of Usher syndrome are recognized; all are inherited in an autosomal recessive manner [Smith et al 1994].

  Usher syndrome type I is characterized by a congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. Unless fitted with a cochlear implant, persons with Usher syndrome type 1 do not typically develop speech. Retinitis pigmentosa (RP), a progressive, bilateral, symmetrical degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity. The diagnosis of Usher syndrome type I is established on clinical grounds using electrophysiologic and subjective tests of hearing and retinal function. Causative genes at seven loci [ USH1A, MYO7A (USH1B), USH1C (USH1C), CDH23 (USH1D), USH1E, PCDHB15 (USH1F), and SANS (USH1G)] have been identified.

  Usher syndrome type II is characterized by congenital, bilateral sensorineural hearing loss predominantly in the higher frequencies that ranges from mild to severe and adolescent-to-adult onset of retinitis pigmentosa. Vestibular function is normal. One of the most important clinical distinctions between Usher syndrome type I and Usher syndrome type II is that children with Usher syndrome type I are usually delayed in walking until 18 months to two years of age because of vestibular involvement, whereas children with Usher syndrome type II usually begin walking at about one year of age. Mutations in genes at four different loci cause Usher syndrome type II. Two of these four genes, USH2A (usherin, USH2A) and VLGR1 (USH2C) have been identified, and molecular genetic testing is available.

  Usher syndrome type III is characterized by postlingual progressive sensorineural hearing loss, late-onset RP, and variable impairment of vestibular function. Mutations in USH3 are causative. Older persons with Usher syndrome type III may have profound hearing loss and vestibular disturbance resembling Usher syndrome type I.

• Thyroid enlargement.  Pendred syndrome is diagnosed in individuals with (1) hearing impairment that is usually congenital and often severe to profound, although mild-to-moderate progressive hearing impairment also occurs; (2) bilateral dilation of the vestibular aqueduct (DVA, also called enlarged vestibular aqueduct or EVA) with or without cochlear hypoplasia (DVA and cochlear hypoplasia is known as Mondini malformation or dysplasia); and (3) either an abnormal perchlorate discharge test or goiter. Thyroid abnormality is variable; goitrous changes are typically not present at birth, but do develop in early puberty (40%) or adulthood (60%). In addition, vestibular function is usually abnormal. Sequence analysis of the SLC26A4 gene identifies disease-causing mutations in about 50% of affected individuals from multiplex families and 20% of individuals from simplex families. Inheritance is autosomal recessive.

• Cardiac conduction defects.  Jervell and Lange-Nielsen syndrome (JLNS) includes congenital profound bilateral sensorineural hearing loss and long QTc, usually greater than 500 msec [Splawski et al 1997]. The latter is associated with tachyarrhythmias, which may culminate in syncope or sudden death. Over half of untreated children with JLNS die prior to age 15 years. Treatment involves use of beta adrenergic blockers, cardiac pacemakers, and implantable defibrillators as well as avoidance of drugs that cause further prolongation of the QT interval and of activities known to precipitate syncopal events. The diagnosis should be considered in any child with congenital sensorineural deafness with negative DFNB1 testing especially if that child has a history of syncope or seizure or a family history of sudden death before age 40 years. Homozygous for disease-causing mutations in either the KCNQ1 gene or the KCNE1 gene is confirmatory. Inheritance is autosomal recessive.

Autosomal recessive nonsyndromic hearing loss without an identifiable GJB2 mutation and with progression of hearing loss:

• With a dilated vestibular aqueduct on thin-cut computed tomography (CT) of the temporal bones suggests DFNB4 [Li et al 1998]
  OR
• With a Mondini malformation on thin-cut CT of the temporal bones suggests Pendred syndrome . A perchlorate test and molecular genetic testing of SLC26A4 should be considered [Everett et al 1997].

Other causes of congenital severe-to-profound hearing loss should be considered in children who represent single cases in their family:

• CMV (cytomegalovirus), the most common cause of congenital, non-hereditary hearing loss)
• Prematurity, low birth weight, low Apgar scores, infection, and any illness requiring care in a neonatal intensive care unit

Management

Evaluations at Initial Diagnosis to Establish the Extent of Involvement

• Complete assessment of auditory acuity using age-appropriate tests like ABR testing, auditory steady-state response (ASSR) testing and pure tone audiometry
• Ophthalmologic evaluation for refractive errors. Note: It is not possible to exclude RP, a retinal manifestation of the three types of Usher syndrome, before close to the end of the first decade of life.

Treatment of Manifestations

• Fitting with appropriate hearing aids
• Enrollment in an appropriate educational program for the hearing impaired
• Consideration for cochlear implantation, a promising habilitation option for persons with profound deafness
• Recognition that unlike many clinical conditions, the management and treatment of severe-to-profound congenital deafness largely impacts the social welfare and educational systems rather than the medical care system [Smith et al 2005]

Surveillance

• Semiannual examination by a physician familiar with hereditary hearing impairment
• Repeat audiometry to confirm stability of hearing loss

Testing of Relatives at Risk

Clarifying the genetic status of a child at 25% risk for DFNB1 should be considered shortly after birth so that appropriate and early support and management can be provided to the child and family.

DNA-based testing can only be considered if both deafness-causing mutations have been identified in an affected family member.

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

DFNB1 is inherited in an autosomal recessive or digenic manner.

Risk to Family Members — Autosomal Recessive Inheritance

Autosomal recessive DFNB1 occurs in individuals who are:

• Homozygotes or compound heterozygotes for GJB2 mutations
• Homozygotes or compound heterozygotes for GJB6 deletions that include a portion of GJB6.

Parents of a proband

• The parents are obligate heterozygotes and, therefore, carry a single copy of a deafness-causing mutation.
• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib has a 25% chance of being deaf, a 50% chance of being a hearing carrier, and a 25% chance of being hearing and not a carrier.
• Once an at-risk sib is known to be hearing, the chance of his/her being a carrier is 2/3.
• Heterozygotes are asymptomatic.

Offspring of a proband.   All of the offspring are obligate carriers.

Other family members of a proband.   Each sib of an obligate heterozygote has a 50% chance of being a carrier.

Risk to Family Members — Digenic Inheritance

Persons who are heterozygous for a GJB2 deafness-causing allele variant and either GJB6-D13S1830 or GJB6-D13S1854 may have digenic DFNB1 (i.e., they are double Heterozygotes), although the impact of the two deletions on cis GJB2 transcription has not been studied. It is possible that the two deletions affect upstream regulatory regions of GJB2, much like large deletions upstream of POU3F4 affect transcription of this gene and cause deafness at the DFN3 locus.

Parents of a proband

• The parents are obligate heterozygotes; one parent carries a GJB2 deafness-causing mutation and the other parent carries either GJB6-D13S1830 or GJB6-D13S1854.
• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib has a 25% chance of being deaf, a 25% chance of being a hearing carrier of the GJB2 deafness-causing allele variant, a 25% chance of being a hearing carrier of either GJB6-D13S1830 deletion or GJB6-D13S1854, and a 25% chance of being hearing and a carrier of neither mutation.
• Once an at-risk sib is known to be hearing, the chance of his/her being a carrier is 2/3.
• Heterozygotes are asymptomatic.

Offspring of a proband.  All offspring are carriers of either the GJB2 mutation or the large upstream deletion that includes a portion of GJB6.

Other family members of a proband.  Each sib of an obligate heterozygote has a 50% chance of being a carrier.

Carrier Detection

Carrier testing is available on a clinical basis once the mutations have been identified in the proband.

Related Genetic Counseling Issues

The following points are noteworthy:

• Communication with individuals who are deaf requires the services of a skilled interpreter.
• Deaf persons may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." In fact, having a child with deafness may be preferred over having a child with normal hearing.
• Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. As in all genetic counseling, it is important for the counselor to identify, acknowledge, and respect the individual's/family's questions, concerns, and fears.
• The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "affected," "abnormal," and "disease-causing" should be avoided.

Family planning.  The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking.   DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of deaf individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained from amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. Both deafness-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Many deaf individuals are interested in obtaining information about the underlying etiology of their hearing loss rather than information about reproductive risks. It is therefore important to ascertain and address the questions and concerns of the family/individual. "In contrast to the medical model which considers deafness to be a pathologic condition, many deaf people do not consider themselves to be handicapped but define themselves as being part of a distinct cultural group with its own language, customs, and beliefs. Strategies for effective genetic counseling to deaf people include the recognition that perception of risk is very subjective and that some deaf individuals may prefer to have deaf children." [Arnos et al 1991].

Requests for prenatal testing for conditions such as DFNB1 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the deafness-causing mutations have been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

GJB2

Normal allelic variants: Most connexin genes have a common architecture, with the entire coding region contained in a single large exon separated from the 5'-untranslated region by an intron of variable size. The coding sequence of GJB2 (exon 2) is 681 base pairs (including the stop codon) and is translated into a 226-amino acid protein.

The M34T variant was described first as an autosomal dominant mutation [Kelsell et al 1997], consistent with the study by White et al (1998) in which it was reported to have a dominant-negative effect over wild-type CX26 in Xenopus oocytes. This result, however, was later attributed to an artifact in the expression levels of mutant and wild-type RNA not controlled in the exogenous system [Skerrett et al 2004]. The M34T allele also has been considered a pathologic autosomal recessive mutation [Houseman et al 2001 , Kenneson et al 2002 , Wilcox et al 2000 , Wu et al 2002] and a benign allele [Feldmann et al 2004 , Griffith et al 2000].

Assuming the M34T variant is a benign polymorphism, deaf persons with the 35delG/M34T genotype are carriers of only one GJB2 mutation (35delG) and their hearing loss must be caused by other unidentified mutations at the DFNB1 locus or by other genes. Because of the large phenotypic variability seen with genetic hearing impairment, a similar degree of variability in hearing loss would be expected in these persons. However a recent study that included 38 persons with the 35delG/M34T genotype showed that all had mild-to-moderate hearing loss with a median PTA_{0.5,1,2 kHz} of 34 dB [Snoeckx et al 2005]. The 16 persons homozygous for M34T had an even lower median PTA_{0.5,1,2 kHz} value (30 dB) [Snoeckx et al 2005].

The V37I variant has also been reported as not pathogenic [Hwa et al 2003 , Kelley et al 1998 , Kudo et al 2000 , Wattanasirichaigoon et al 2004]; however, Snoeckx et al (2005) have documented an association of this allelic variant with mild hearing loss in nine of ten genotypic combinations. This result is consistent with other studies of the allele [Abe et al 2000 , Kenna et al 2001 , Lin et al, 2001 , Marlin et al 2001 , Wilcox et al 2000].

Pathologic allelic variants: Numerous different deafness-causing mutations of GJB2 that result in autosomal recessive nonsyndromic hearing loss are listed on the Connexin-deafness Home page . The most common mutation in persons of northern European descent is the 35delG variant. This mutation has also been reported in persons of Arab, Bedouin, Indian and Pakistani ethnicity. Based on tightly linked single-nucleotide polymorphisms (SNPs), a founder mutation arising in southern Europe approximately 10,000 years ago has been predicted [Van Laer et al 2001]. Consistent with this prediction is a northwest-to-southeast 35delG deafness gradient through the Persian Gulf countries [Najmabadi et al 2005] and a south-to-north 35delG deafness gradient in Europe [Gasparini et al 2000 , Lucotte & Mercier 2001 , Rothrock et al 2003].

The spectrum of pathologic GJB2 allelic variants diverges substantially among populations as reflected by specific ethnic biases for common mutations. As mentioned above, the 35delG allele is common among Caucasians with a carrier rate of 2-4% [Estivill et al 1998 , Green et al 1999], whereas 235delC is most common in the Japanese population (carrier rate: 1-2%) [Abe et al 2000 , Kudo et al 2000], 167delT in the Ashkenazi Jewish population (carrier rate: 7.5%) [Morell et al 1998], and V37I in Thailand (carrier rate: 11.6%) [Hwa et al 2003]. (For more information, see Genomic Databases table above.)

Normal gene product: Connexin 26 is a beta-2 gap junction protein. Connexins aggregate in groups of six around a central 2.3-nm pore to form a connexon. Connexons from adjoining cells covalently bond forming a channel between cells. Large aggregations of connexons called plaques are the constituents of gap junctions. Gap junctions permit direct intercellular exchange of ions and molecules through their central aqueous pores. Postulated roles include the rapid propagation of electrical signals and synchronization of activity in excitable tissues and the exchange of metabolites and signal molecules in non-excitable tissues [Zhang & Nicholson 1994].

A connexin protein contains two extracellular (E1-E2), four transmembrane (M1-M4), and three cytoplasmic domains. Each extracellular domain has three cysteine residues with at least one disulfide bond joining the E1 and E2 loops [Goodenough et al 1996]. The presumed importance of these six cysteines can be inferred from connexin 32 experiments in which any Cys mutation completely blocks the development of gap-junction conductances between Xenopus oocyte pairs. The third transmembrane domain (M3) is amphipatic and lines the putative wall of the intercellular connexon channel [Bruzzone et al 1996]. If the connexons contributed by each cell are composed of the same connexin, the channel is homotypic; if each connexon is formed by a different connexin, it is heterotypic. With the exception of connexin 26, all connexins are phosphoproteins [Goodenough et al 1996]. Connexin 26 forms functional combinations with itself, connexin 32, connexin 46, and connexin 50 [Bruzzone et al 1996].

Abnormal gene product: Gap junction channels are permeable to ions and small metabolites with relative molecular masses up to approximately 1.2 kd [Harris & Bevans 2001]. Differences in ionic selectivity and gating mechanisms among gap junctions reflect the existence of over 20 different connexin isoforms in humans. Only a few GJB2 abnormal allelic variants have been tested in recombinant expression systems, with most showing loss of function as a result of altered sorting (G12V, S19T, 35delG, L90P), inability to induce formation of homotypic gap junction channels (V37I, W77R, S113R, delE120, M163V, R184P and 235delC), or interference with translation (R184P) [Snoeckx et al 2005].

GJB6

Normal allelic variants: The majority of gap junction genes have two exons; a few have only one exon, and one, GJB6, has three exons, of which only the third is coding. The translated protein is 261 amino acids long.

Pathologic allelic variants: Pathologic allelic variants of GBJ6 are associated with DFNB1, DFNA3, and hidrotic ectodermal dysplasia (Clouston syndrome). The DFNB1-associated mutations are large deletions that involve most of GJB6 and a large portion of the upstream region. Whether these deletions affect transcription of GJB2 or represent an example of digenic inheritance at the DFNB1 locus has not been determined. (For more information, see Genomic Databases table above.)

Normal gene product: Connexin 30 is a beta-6 gap junction protein. It shares an architecture that is common to all connexins (see above).

Abnormal gene product: Of the two deletions ( GJB6-D13S1830 and GJB6-D13S1854) truncating GJB6 that segregate in trans with GJB2 deafness-causing alleles, GJB6-D13S1830 is most frequent in Spain, France, the United Kingdom, Israel and Brazil (Portuguese origin), where it accounts for 5.9% to 8.3% of all the DFNB1 alleles. Its frequency is lower in Belgium and Australia (1.3-1.4%), and it has not been found among deaf Italian GJB2 heterozygotes. In the USA, its frequency is 1.6% to 4.0% [Del Castillo et al 2003].

GJB6-D13S1854 accounts for approximately 25 % of the deaf GJB2 heterozygotes, which remained unresolved after screening for GJB6-D13S1830 in Spain, 22.2% in the United Kingdom, 6.3% in Brazil, and 1.9% in Northern Italy. This deletion has not been found in deaf GJB2 heterozygotes from France, Belgium, Israel, the Palestinian Authority, the United States, or Australia. Haplotype analysis has revealed a common founder for the mutation in Spain, Italy, and the United Kingdom [Del Castillo et al 2005].

Resources

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References

Published Statements and Policies Regarding Genetic Testing

• American College of Medical Genetics (2002) Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel (pdf).
• American College of Medical Genetics (2000) Statement on universal newborn hearing screening (pdf)

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