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Nonsyndromic Hearing Loss and Deafness, DFNB1

Synonym: GJB2-Related DFNB 1 Nonsyndromic Hearing Loss and Deafness

, MD and , PhD.

Author Information
, MD
Department of Otolaryngology
University of Iowa Hospitals and Clinics
Iowa City, Iowa
, PhD
Department of Genetics
University of Antwerp
Antwerp, Belgium

Initial Posting: ; Last Update: January 2, 2014.

Summary

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 GJB2 and upstream cis-regulatiory elements that alter the gap junction beta-2 protein (connexin 26). Molecular genetic testing of GJB2 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 annual examinations and repeat audiometry to confirm stability of hearing loss.

Evaluation 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 who may have DFNB1 so that appropriate early support and management can be provided.

Genetic counseling. DFNB1 is inherited in an autosomal recessive 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.

Diagnosis

Clinical Diagnosis

Nonsyndromic hearing loss and deafness (DFNB1) is associated with the following:

  • Congenital, generally non-progressive sensorineural hearing impairment that is mild 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

Molecular Genetic Testing

Gene. GJB2, which encodes connexin 26, is the only gene in which mutations are known to cause 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].

    Data regarding association of the GJB2 variants p.Met34Thr and p.Val37Ile with DFNB1 are discussed in Molecular Genetics.

Approximately 2% of individuals with DFNB1 have one identifiable GJB2 mutation and one of three large deletions including sequences upstream of GJB2 and a portion of GJB6. Such deletions result in reduced express of the downstream GJB2 gene presumably due to deletion of a cis-regulatory element. Initially this involvement of partial GJB6 deletion was considered an example of digenic inheritance that is inactivation of GJB2 on one allele and inactivation of GJB6 on the second. Recent evidence confirms that digenic inheritance involving these two genes is not a factor in pathogenesis (see Molecular Genetics)

Clinical testing

  • Sequence analysis. Sequence analysis of exon 2, which harbors the entire coding region, detects both mutations in 98% of persons with DFNB1. Mutational analyses may include sequencing for additional rare mutations including the exon 1 splice site mutation and the upstream deletions involving GJB6 (see Molecular Genetics).

Table 1. Summary of Molecular Genetic Testing Used in DFNB1

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
Two mutationsOne mutation
GJB2Sequence analysisGJB2 sequence variants 4,598%~2% 6
Deletion/ duplication analysis 7(Multi)exonic or whole-gene deletions 8<<1%<<1%
Targeted mutation analysisDeletion of GJB2 upstream regulatory elements 9NA~2% 6

NA = not applicable

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on GJB2 variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Some mutations have an ethnic bias: c.35delG mutation is most common in populations of northern European ancestry; c.167delT mutation is most common in the Ashkenazi Jewish population; c.235delC mutation is most common in the Japanese and Chinese populations.

6. Percentages vary depending on ethnicity. Numbers in table reflect screening of a US population primarily of northern European ancestry.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. See Testing Strategy and Table 3.

9. Feldmann et al [2009] reported a contiguous gene deletion that included GJB2 and two contiguous connexin genes, GJA3 and GJB6, in addition to a portion of CRYL1 in trans with a known GJB2 deafness-causing mutation in an individual with profound prelingual hearing loss, mental and psychomotor development delay, clinodactyly of the second toes, and a frontal tuft [Feldmann et al 2009].

Interpretation of test results

  • The diagnosis of DFNB1 is established if an individual or affected sibling has recognized deafness-causing mutations in GJB2 or in known regulatory regions of the gene.
  • If only one GJB2 mutation is detected and a large deletion of known upstream regulatory region (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].

Testing Strategy

To confirm/establish the diagnosis in a proband. For individuals suspected of having DFNB1:

One testing strategy is analysis of GJB2:

  • The first step is sequence analysis of GJB2 exon 2 (the coding region of GJB2). If two deafness-causing mutations are identified, the diagnosis of DFNB1 is established.
  • If one deafness-causing mutation is identified, targeted mutation analysis for one of the two known large deletions of upstream of GJB2 (and including GJB2 regulatory sequences and GJB6), [increment]GJB6-D13S1830 and [increment]GJB6-D13S1854, is warranted.
  • If no deafness-causing mutations of GJB2 are identified, targeted mutation analysis for deletion of a GJB2 upstream regulatory sequence is not warranted. The frequency of these deletions in all populations is not high enough to result in a large number of deaf individuals homozygous for these mutations. They represent fewer than 0.5% of all individuals with prelingual deafness and without mutations in GJB2 [Del Castillo et al 2003, del Castillo et al 2005, Wilch et al 2010].

An alternative genetic testing strategy is use of a multi-gene panel that includes GJB2 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Clinical Description

Natural History

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 is seen.

  • If an affected person has severe-to-profound deafness, an affected sibling with the same GJB2 deafness-causing 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 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 0-26 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; life span is normal.

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-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%-64% of individuals; severe in 25%-28%; moderate in 10%-12%; and mild in 0%-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 (I) and one non-inactivating (NI) mutation that represented 71 different genotypes (40% of all genotypes found). The degree of hearing impairment was profound in 24%-30% of individuals and severe in 10%-17% of individuals.

Scatter diagrams were constructed to show the binaural mean pure tone average (PTA) at 0.5, 1, and 2 kHz (PTA0.5,1,2kHz) 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 PTA0.5,1,2kHz = 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 PTA0.5,1,2kHz = 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 PTA0.5,1,2kHz = 40 dB, p < 0.0001), [c.35delG]+[p.Met34Thr] (median PTA0.5,1,2kHz = 34 dB, p < 0.0001), and double heterozygotes [[increment]GJB6-D13S1830]+[GJB2:p.Met34Thr] (median PTA0.5,1,2kHz = 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 PTA0.5,1,2kHz higher than 95 dB and 34 had a PTA0.5,1,2kHz lower than 65 dB, with the PTA0.5,1,2kHz 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 PTA0.5,1,2kHz = 30 dB, p < 0.0001)
    • p.Val37Ile homozygotes (median PTA0.5,1,2kHz = 27 dB, p < 0.0001)
    • [p.Met34Thr]+[p.Val37Ile] compound heterozygotes (median PTA0.5,1,2kHz = 23 dB, p<0.001)

Nomenclature

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

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 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 highly 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].

Differential Diagnosis

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 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, symmetric 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. Mutations in genes at a minimum of nine different loci cause Usher syndrome type I. Genes at six of these loci – MYO7A (USH1B), USH1C, CDH23 (USH1D), PCDH15 (USH1F), USH1G, and CIB2 (USH1J) – have been identified.

    Usher syndrome type II is characterized by congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies, intact vestibular responses, and retinitis pigmentosa (RP).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. Three genes are known to be associated with Usher syndrome type II: USH2A (accounting for 80% of cases), GPR98 (VLGR1) (~15% of cases), and DFNB31 (<5% of cases). A fourth locus has been provisionally mapped to 15q.

    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 SLC26A4 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 KCNQ1 or KCNE1 is confirmatory. Inheritance is autosomal recessive.

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

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

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of involvement and needs 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.
  • Medical genetics consultation

Treatment of Manifestations

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 with many clinical conditions, the management and treatment of severe-to-profound congenital deafness falls largely within the purview of the social welfare and educational systems rather than the medical care system [Smith et al 2005]

Surveillance

The following are appropriate:

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

Agents/Circumstances to Avoid

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 overexposure to loud noises.

Evaluation of Relatives at Risk

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.

Therapies Under Investigation

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.

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. —ED.

Mode of Inheritance

Nonsyndromic hearing loss and deafness (DFNB1) is inherited in an autosomal recessive manner.

Risk to Family Members

DFNB1 occurs in individuals who are:

  • Homozygotes or compound heterozygotes for GJB2 mutations;
  • Compound heterozygotes for large deletion of GJB2 5’-cis-regulatory sequences that 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 offspring are obligate carriers.

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

Carrier Detection

Carrier testing of at-risk family members is possible if the deafness-causing mutations have been identified in the family

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating 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 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 affected individuals.

Prenatal Testing

If the deafness-causing alleles have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this condition/gene or custom prenatal testing.

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." – from 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 an option for some families in which the deafness-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Library of Medicine Genetics Home Reference

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Nonsyndromic Hearing Loss and Deafness, DFNB1: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Nonsyndromic Hearing Loss and Deafness, DFNB1 (View All in OMIM)

121011GAP JUNCTION PROTEIN, BETA-2; GJB2
220290DEAFNESS, AUTOSOMAL RECESSIVE 1A; DFNB1A

Gene structure. 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.

Pathogenic 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 GJB2 pathogenic variants diverges substantially among populations as reflected by specific ethnic biases for common mutations. As mentioned above, the c.35delG allele is common among individuals of northern European origin, 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 Table A.)

The p.Met34Thr 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].

There is strong evidence to classify the p.Met34Thr allele as a pathologic autosomal recessive mutation [Wilcox et al 2000, Houseman et al 2001, Kenneson et al 2002, Wu et al 2002]. Assuming the p.Met34Thr variant to be 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 study of 38 individuals who were compound heterozygotes for [c.35delG]+[p.Met34Thr] showed that all had mild-to-moderate hearing loss with a median PTA0.5,1,2kHz of 34 dB [Snoeckx et al 2005]. The 16 individuals homozygous for p.Met34Thr had an even lower median PTA0.5,1,2khz value (30 dB) [Snoeckx et al 2005].

The p.Val37Ile variant has also been reported as non-pathogenic [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 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].

Table 2. Selected GJB2 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.101T>Cp.Met34Thr 2NM_004004​.4
NP_003995​.2
c.109G>Ap.Val37Ile 2
c.35delGp.Gly12ValfsTer1
c.35G>Tp.Gly12Val
g.-3179G>A 3
(IVS1+1G>A)
--
c.56G>Cp.Ser19Thr
c.167delTp.Leu56ArgfsTer26
c.235delCp.Leu79CysfsTer3
c.231G>Ap.Trp77Arg
c.269T>Cp.Leu90Pro
c.339T>Gp.Ser113Arg
c.358_360delGAGp.Glu120del
c.427C>Tp.Arg143Trp
c.487A>Gp.Met163Val
c.551G>Cp.Arg184Pro

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. p.Met34Thr and p.Val37Ile are associated with normal hearing or mild hearing loss. See discussion in Pathogenic allelic variants.

3. IVS1+1G>A is -3179 nucleotides from the beginning of exon 2 in the genomic sequence (Reference Sequence NC_000013​.9)

The pathogenic variants associated with DFNB1 are large deletions that include much of GJB6 and a large portion of the upstream region. Nonsense or missense mutations of GJB6 that would be detected by sequence analysis have not been associated with DFNB1. The deletions are believed to affect transcription of GJB2 presumably by deleting a cis-regulatory element. (For more information, see Table A.)

The [increment]GJB6-D13S1830 deletion is the most common GJB6 mutation associated with DFNB1. This deletion 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. In one study, for example, 67% of deaf Spanish individuals with one identified GJB2 mutation carried this deletion [Wu et al 2002, Stevenson et al 2003]. 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 [increment]GJB6-D13S1854 mutation accounts for approximately 25% of deaf GJB2 heterozygotes that remained unresolved after screening for [increment]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].

A third deletion has been identified in a large German-American family in which 15 persons have recessively inherited congenital, severe-to-profound nonsyndromic sensorineural hearing loss. Eleven of these 15 persons are homozygous for the GJB2 35delG mutation; however, the remaining four carry only a single 35delG mutation. Reduced expression of both GJB2 and GJB6 mRNA from the allele carried in trans with that bearing the 35delG mutation in these four persons was consistent with the presence of an upstream deletion, which was confirmed by array comparative genome hybridization. This deletion – del(chr13:19,837,344-19,968,698) – is 131.4 kb. Its proximal breakpoint lies more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6 and it segregates as a completely penetrant DFNB1-causing allele in this family [Wilch et al 2010].

Table 3. cis-Regulatory 5’ GJB2 Pathogenic Variants

DNA Nucleotide Change 1Protein Amino Acid ChangeReference Sequences
[increment]GJB6-D13S1830--NM_001110219​.1
NP_001103689​.1
[increment]GJB6-D13S1854--
del(chr13:19,837,344-19,968,698)--Human genome reference sequence (NCBI Build 36.1 or UCSC version hg18)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Designations are colloquial variants in common use and do not conform to current naming conventions.

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 pathogenic 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].

References

Published Guidelines/Consensus Statements

  1. American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. (pdf) Available online. 2002. Accessed 12-17-13.
  2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 12-17-13.

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Suggested Reading

  1. Hardelin JP, Marlin S, Levilliers J, Petit C. Hereditary hearing loss. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 254. Available online. Accessed 12-17-13.

Chapter Notes

Acknowledgments

Supported in part by grant RO1-DC02842 from the NIDCD (RJHS)

Author History

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)

Revision History

  • 2 January 2014 (me) Comprehensive update posted live
  • 14 July 2011 (me) Comprehensive update posted live
  • 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
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Bookshelf ID: NBK1272PMID: 20301449
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