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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
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.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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.
Disease characteristics. Nonsyndromic hearing loss and deafness (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 on 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. Clinically available molecular genetic testing of the GJB2 and GJB6 genes detects more than 99% of deafness-causing mutations in these genes.
Management. Treatment of manifestations: Hearing aids; enrollment in appropriate educational programs; cochlear implantation may be considered for individuals with profound deafness. Surveillance: Surveillance includes semi-annual examinations and repeat audiometry to confirm stability of hearing loss. Testing of relatives at risk: If both deafness-causing mutations have been identified in an affected family member, molecular genetic testing can clarify the genetic status of a child with a chance of having DFNB1 so that appropriate early support and management can be 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 mutations causing DFNB1 are detected in one family member, carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible.
Nonsyndromic hearing loss and deafness (DFNB1) is associated with the following:
Congenital, generally non-progressive sensorineural hearing impairment that is moderate to profound by auditory brain stem response testing (ABR) or pure tone audiometry
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 (501-2000 Hz), or high (>2000 Hz) (see Deafness and Hereditary Hearing Loss Overview).
No related systemic findings identified by medical history and physical examination
A family history of nonsyndromic hearing loss consistent with autosomal recessive inheritance
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 DFNB1 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 c.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).
Clinical testing
GJB2 (encoding connexin 26)
Sequence analysis. Sequence analysis of the entire coding region detects both mutations in 98% of persons with DFNB1, although 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 (see Molecular Genetics).
Targeted mutation analysis. Mutation analysis (looking for only one or several specific mutations) is generally not recommended because this type of analysis has an ethnic bias:
GJB6 (encoding connexin 30)
Targeted mutation analysis. Two large deletions that include a portion of GJB6 (![[increment]](corehtml/pmc/pmcents/x2206.gif)
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 deaf Spanish individuals with one identified GJB2 mutation had this deletion [Wu et al 2002, Stevenson et al 2003].
In another study, GJB6-D13S1830 was found in 16% of deaf 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.
| Gene Symbol | Proportion of DFNB1 Attributed to Mutations in This Gene | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability | |
|---|---|---|---|---|---|---|
| Two mutations | One mutation | |||||
| GJB2 | >>99% | Sequence analysis | GJB2 sequence alterations | 98% | ~2% 1 | Clinical
 |
| GJB6 | <<1% | 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 test 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 individuals heterozygous for c.35delG, 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 individuals [Azaiez et al 2004, del Castillo et al 2005].
Confirming the diagnosis in a proband. For individuals suspected of having DFNB1:
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 GJB6 deletions, GJB6-D13S1830 and GJB6-D13S1854, is warranted.
If no deafness-causing mutations of GJB2 are identified, targeted mutation analysis for the two GJB6 deletions, 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 individuals homozygous for these mutations. They represent less than 0.5% of all individuals with prelingual deafness and without mutations in GJB2 [Del Castillo et al 2003, del Castillo et al 2005].
Carrier testing for at-risk relatives requires prior identification of the deafness-causing mutations in the family.
Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deafness-causing mutations in the family.
Other phenotypes have been associated with mutations in GJB2 and GJB6:
DFNA3 is 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 is 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 is an autosomal dominant 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 age one year. Severe palmoplantar keratoderma and scarring alopecia occur 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 is 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 p.Met34Thr 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 [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 p.Met34Thr 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].
Hidrotic ectodermal dysplasia type 2 (Clouston syndrome) is characterized by ectodermal dysplasia, alopecia, and palmoplantar hyperkeratosis. Inheritance is autosomal dominant [Smith et al 2002].
Nonsyndromic hearing loss and deafness (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 allelic variants has a 91% chance of having severe-to-profound deafness and a 9% chance of having mild-to-moderate deafness.
If an affected person has mild-to-moderate deafness, an affected sibling with the same GJB2 deafness-causing allelic variants has a 66% chance of having mild-to-moderate deafness and a 34% chance of having severe-to-profound deafness.
A few reports describe children with GJB2 mutations who passed the newborn hearing screen and had somewhat later-onset hearing loss [Norris et al 2006, Orzan & Murgia 2007].
In a large cross-sectional analysis of GJB2 genotype and audiometric data from 1531 individuals with autosomal recessive, mild-to-profound, nonsyndromic deafness (median age 8 years; 90% within age 0 to 26 years) 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 of hearing loss in any individual [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. Snoeckx et al [2005] found a slight degree of asymmetry, although the difference in pure tone average at 0.5, 1.0, and 2.0 kHz between ears was less than 15 dB in 90% of individuals.
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.
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-inactivating (for example, missense mutations) and 36 as inactivating (for example, premature stop codons). By classifying mutations this way, the authors defined three genotype classes:
Biallelic inactivating (I/I) mutations. 1183 of the 1531 persons studied (77.3%) segregated two inactivating mutations that represented 64 different genotypes (36% of all genotypes found). The degree of hearing impairment in this cohort was: profound in 59% to 64% of individuals; severe in 25% to 28%; moderate in 10% to12%; and mild in 0% to 3%.
Biallelic non-inactivating (NI/NI) mutations. Ninety-five of the 1531 persons studied (6.2%) segregated two non-inactivating mutations that represented 42 different genotypes (24% of all genotypes found). The degree of hearing impairment was mild in 53% of individuals and severe to profound in 20% of individuals.
Compound heterozygous inactivating/non-inactivating (I/NI) mutations. Of the 1531 individuals studied, 253 (16.5%) segregated one inactivating and one non-inactivating mutation that represented 71 different genotypes (40% of all genotypes found). The degree of hearing impairment was profound in 24% to 30% of individuals and severe in 10% to 17% of individuals.
Scatter diagrams were constructed to show the binaural mean pure tone average (PTA) at 0.5, 1, and 2 kHz (PTA0.5,1,2 kHz) for each person within each genotype class, using individuals homozygous for the c.35delG allele as a reference group:
I/I: Only two genotypes differed significantly from the c.35delG homozygote reference group:
Individual doubly heterozygous for [GJB2:c.35delG]+[GJB6:del(GJB6-D13S1830)] had significantly greater hearing impairment (median PTA0.5,1,2 kHz = 108 dB; p < 0.0001)
Individuals who are GJB2 compound heterozygotes for [c.35delG]+[-3179G>A, also known as IVS1+1G→A] had significantly less hearing impairment (median PTA0.5,1,2 kHz = 64 dB; p < 0.0001).
I/NI: Nine genotypes differed significantly from the c.35delG homozygote reference group:
One GJB2 compound heterozygous genotype, [c.35delG]+[p.Arg143Trp], showed significantly greater hearing impairment.
Eight genotypes had significantly less hearing impairment. The three genotypes with the least hearing impairment were GJB2 compound heterozygotes [c.35delG]+[p.Val37Ile] (median PTA0.5,1,2 kHz = 40 dB, p < 0.0001), [c.35delG]+[p.Met34Thr] (median PTA0.5,1,2 kHz = 34 dB, p < 0.0001), and double heterozygotes [GJB6-D13S1830]+[GJB2:p.Met34Thr] (median PTA0.5,1,2 kHz = 25 dB, p < 0.0001). The finding in the T/NT genotypic class regarding the threshold distribution in persons with [c.35delG]+[p.Leu90Pro] suggested a bimodal distribution, as seven [c.35delG]+[p.Leu90Pro] GJB2 compound heterozygotes had a PTA0.5,1,2 kHz higher than 95 dB and 34 had a PTA0.5,1,2 kHz lower than 65 dB, with the PTA0.5,1,2 kHz of only one individual falling between these two values (65-95 dB).
NI/NI: Three genotypes differed significantly from the c.35delG homozygote reference group in having less hearing impairment: p.Met34Thr homozygotes (median PTA0.5,1,2 kHz = 30 dB, p < 0.0001), p.Val37Ile homozygotes (median PTA0.5,1,2 kHz = 27 dB, p < 0.0001), and [p.Met34Thr]+[p.Val37Ile] compound heterozygotes (median PTA0.5,1,2 kHz = 23 dB, p < 0.001).
DFNB followed by a suffix integer is used to designate loci for autosomal recessive nonsyndromic deafness.
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 80% of cases of nonsyndromic hearing loss are autosomal recessive; 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 an estimated 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 et al 2004], and an estimated 24% of Altaians from Siberia [Posukh et al 2005].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
See Deafness and Hereditary Hearing Loss 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.
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, individuals 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], SANS [USH1G]) have been identified.
Usher syndrome type II is characterized by congenital, bilateral sensorineural hearing loss (predominantly in the higher frequencies) ranging 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 age 18 months to two years because of vestibular involvement, whereas children with Usher syndrome type II usually begin walking at approximately age one year. 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; 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 individuals 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 with 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 the child has a history of syncope or seizure or a family history of sudden death before age 40 years. Homozygosity 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];
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:
Congenital 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
To establish the extent of involvment in an individual diagnosed with nonsyndromic hearing loss and deafness (DFNB1), the following evaluations are recommended:
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 retinitis pigmentosa, a manifestation of the three types of Usher syndrome, until near the end of the first decade of life.
The following are indicated:
Fitting with appropriate hearing aids
Enrollment in an appropriate educational program for the hearing impaired
Consideration of cochlear implantation (CI), 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]
The following are appropriate:
Semiannual examination by a physician familiar with hereditary hearing impairment
Repeat audiometry to confirm stability of hearing loss
Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important among these for persons with mild-to-moderate hearing loss caused by mutations in GJB2 is avoidance of repeated over-exposure to loud noises.
Clarifying the genetic status of a child with a 25% chance of having DFNB1 should be considered shortly after birth so that appropriate 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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this condition.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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.
Nonsyndromic hearing loss and deafness (DFNB1) is inherited in an autosomal recessive or digenic manner (see Risk to Family Members - Digenic 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.
Individuals who are heterozygous for a GJB2 deafness-causing allelic variant and one of the two GJB6 deletions, 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.
Parents of a proband
The parents are obligate heterozygotes; one parent carries a GJB2 deafness-causing mutation and the other parent carries one of the two GJB6 deletions, 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 allelic variant, a 25% chance of being a hearing carrier of one of the two GJB6 deletions, GJB6-D13S1830 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 testing is available once the mutations have been identified in the family.
See Management for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
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 versus risk; deaf and hard-of-hearing versus 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.
It is appropriate to offer genetic counseling to young adults who are deaf or are at risk of being carriers.
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
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies with a 25% chance of deafness is possible by analysis of DNA extracted from fetal cells obtained from amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 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, discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the deafness-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| GJB2 | 13q11-q12 | Gap junction beta-2 protein |
| GJB6 | 13q12 | Gap junction beta-6 protein |
Data are compiled from the following standard references: gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 121011 | GAP JUNCTION PROTEIN, BETA-2; GJB2 |
| 220290 | DEAFNESS, NEUROSENSORY, AUTOSOMAL RECESSIVE 1; DFNB1 |
| 604418 | GAP JUNCTION PROTEIN, BETA-6; GJB6 |
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| GJB2 | GJB2 | 2706 (MIM No. 121011) | GJB2 |
| GJB6 | GJB6 | 10804 (MIM No. 604418) | GJB6 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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 p.Met34Thr allelic 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 connexin 26 in Xenopus oocytes. This result, however, was later attributed to an artifact in the expression levels of mutant- and wild-type mRNA that were not controlled in the exogenous system [Skerrett et al 2004]. The p.Met34Thr allele has also been considered a pathologic autosomal recessive mutation [Wilcox et al 2000, Houseman et al 2001, Kenneson et al 2002, Wu et al 2002] and a benign allele [Griffith et al 2000, Feldmann et al 2004].
Assuming that the p.Met34Thr variant is a benign polymorphism, deaf persons who are compound heterozygotes for [c.35delG]+[p.Met34Thr] would be carriers of only one GJB2 mutation (c.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 individuals. However a recent study that included 38 individuals who were compound heterozygotes for [c.35delG]+[p.Met34Thr] showed that all had mild-to-moderate hearing loss with a median PTA0.5,1,2 kHz of 34 dB [Snoeckx et al 2005]. The 16 individuals homozygous for p.Met34Thr had an even lower median PTA0.5,1,2 kHz value (30 dB) [Snoeckx et al 2005].
The p.Val37Ile variant has also been reported as nonpathogenic [Kelley et al 1998, Kudo et al 2000, Hwa et al 2003, 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, Wilcox et al 2000, Kenna et al 2001, Lin et al 2001, Marlin et al 2001].
Pathologic allelic variants: See Table 2. 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 individuals of northern European descent is the c.35delG variant. This mutation has also been reported in individuals of Arabic, 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 c.35delG deafness gradient through the Persian Gulf countries [Najmabadi et al 2005] and a south-to-north c.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 c.35delG allele is common among Caucasians, with a carrier rate of 2% to 4% [Estivill et al 1998, Green et al 1999]; whereas c.235delC is most common in the Japanese population (carrier rate: 1% to 2%) [Abe et al 2000, Kudo et al 2000]; c.167delT is most common in the Ashkenazi Jewish population (carrier rate: 7.5%) [Morell et al 1998]; and p.Val37Ile is most common in Thailand (carrier rate: 11.6%) [Hwa et al 2003]. (For more information, see the Genomic Databases table.)
| DNA Nucleotide Change (Alias 1) | Protein Amino Acid Change | Reference Sequence |
|---|---|---|
| c.101T>C | p.Met34Thr 2 | NM_004004.4 NP_003995.2 |
| c.109G>A | p.Val37Ile 2 | |
| c.35delG | p.Gly12ValfsX1 | |
| c.35G>T | p.Gly12Val | |
| g.-3179G>A 3 (IVS1+1G>A) | -- | |
| c.56G>C | p.Ser19Thr | |
| c.167delT | p.Leu56ArgfsX26 | |
| c.235delC | p.Leu79CysfsX3 | |
| c.231G>A | p.Trp77Arg | |
| c.269T>C | p.Leu90Pro | |
| c.339T>G | p.Ser113Arg | |
| c.358_360delGAG | p.Glu120del | |
| c.427C>T | p.Arg143Trp | |
| c.487A>G | p.Met163Val | |
| c.551G>C | p.Arg184Pro |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
1. Variant designation that does not conform to current naming conventions
2. p.Met34Thr and p.Val37Ile are associated with normal-to-mild hearing loss
3. IVS1+1G>A is -3179 nucleotides from the beginning of exon 2 in the genomic sequence (Reference Sequence NC_000013.9)
Normal gene product: Connexin 26 is a beta-2 gap junction protein composed of 226 amino acids. 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.
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. The presumed importance of these six cysteines can be inferred from connexin 32 experiments in which any cysteine mutation completely blocks the development of gap-junction conductances between Xenopus oocyte pairs. The third transmembrane domain (M3) is amphipathic and lines the putative wall of the intercellular connexon channel. 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. Connexin 26 forms functional combinations with itself, connexin 32, connexin 46, and connexin 50.
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 more than 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 (p.Gly12Val, p.Ser19Thr, c.35delG, p.Leu90Pro), inability to induce formation of homotypic gap junction channels (p.Val37Ile, p.Trp77Arg, p.Ser113Arg, p.Glu120del, p.Met163Val, p.Arg184Pro and c.235delC), or interference with translation (p.Arg184Pro) [Snoeckx et al 2005].
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: See Table 3. Pathologic allelic variants of GBJ6 are associated with DFNB1, DFNA3, and hidrotic ectodermal dysplasia (Clouston syndrome). The pathologic variants associated with DFNB1 are large deletions (GJB6-D13S1830: ~309 kb; GJB6-D13S1854: ~232 kb) that include much of GJB6 and a large portion of the upstream region. Whether these deletions, which segregate in trans with GJB2 deafness-causing alleles, 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.)
The GJB6-D13S1830 mutation 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 US, its frequency is 1.6% to 4.0% [Del Castillo et al 2003].
The GJB6-D13S1854 mutation accounts for approximately 25% of deaf GJB2 heterozygotes that remained unresolved after screening for GJB6-D13S1830 in Spain; it accounts for 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 US, or Australia. Haplotype analysis has revealed a common founder for the mutation in Spain, Italy, and the United Kingdom [del Castillo et al 2005].
| DNA Nucleotide Change 1 | Protein Amino Acid Change | Reference Sequence |
|---|---|---|
| GJB6-D13S1830 | -- | NM_001110219.1NP_001103689.1 |
| GJB6-D13S1854 | -- |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://www.hgvs.org).
1. Designations are colloquial variants that do not conform to current naming conventions.
Normal gene product: Connexin 30 is a beta-6 gap junction protein. It shares an architecture that is common to all connexins (see GJB2).
Abnormal gene product: Haploinsufficiency for connexin 30 in carriers of either of the GJB6-including deletions is not associated with a recognized phenotype.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Nonsyndromic deafness, autosomal recessive
Nonsyndromic deafness
NCBI Genes and Disease
Deafness
Alexander Graham Bell Association for the Deaf and Hard of Hearing
3417 Volta Place Northwest
Washington, DC 20007
Phone: 866-337-5220; 202-337-5220; 202-337-5221 (TTY)
Fax: 202-337-8314
Email: info@agbell.org
www.agbell.org
American Society for Deaf Children
3820 Hartzdale Drive
Camp Hill PA 17011
Phone: 800-942-2732 (parent hotline); 717-703-0073 (business V/TTY)
Fax: 717-909-5599
Email: asdc@deafchildren.org
www.deafchildren.org
National Association of the Deaf
8630 Fenton Street Suite 820
Silver Spring, MD 20910
Phone: 301-587-1788 (voice); 301-587-1789 (TTY)
Fax: 301-587-1791
Email: NADinfo@nad.org
www.nad.org
Teaching Case-Genetic Tools
Cases designed for teaching genetics in the primary care setting.
Case 11. Parents Seek Reproductive Counseling Following the Diagnosis of DFNB1-Related Hearing Loss in Their Son
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Daryl A Scott, MD, PhD; University of Iowa (1998-2001)
Val C Sheffield, MD, PhD; University of Iowa (1998-2001)
Richard JH Smith, MD (1998-present)
Guy Van Camp, PhD (1998-present)
Supported in part by grant RO1-DC02842 from the NIDCD (RJHS)
11 July 2008 (me) Comprehensive update posted to live Web site
21 December 2005 (me) Comprehensive update posted to live Web site
14 March 2005 (rjs) Revision: information on GJB6 deletions
15 July 2004 (rjs) Revision: use of an interpreter
27 October 2003 (me) Comprehensive update posted to live Web site
24 April 2001 (me) Comprehensive update posted to live Web site
28 September 1998 (pb) Review posted to live Web site
4 April 1998 (rjs) Original submission (original acknowledgments)
