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Nonsyndromic Hearing Loss and Deafness, DFNB1

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

, MD and , BA.

Author Information

Initial Posting: ; Last Update: August 18, 2016.

Summary

Clinical 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 biallelic pathogenic variants in GJB2 (sequence variants as well as variants in upstream cis-regulatory elements that alter expression of the gap junction beta-2 protein [connexin 26]).

Management.

Treatment of manifestations: Hearing aids; enrollment in appropriate educational programs; consideration of cochlear implantation 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 pathogenic variants have been identified in an affected family member, molecular genetic testing can be used to clarify the genetic status of an at-risk relative in childhood 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. When the GJB2 pathogenic variants causing DFNB1 are detected in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible.

Diagnosis

Suggestive Findings

Nonsyndromic hearing loss and deafness caused by biallelic pathogenic GJB2 variants (DFNB1) should be suspected in individuals 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

Establishing the Diagnosis

The diagnosis of DFNB1 is established in a proband with mild to profound congenital, generally non-progressive sensorineural hearing impairment and identification of biallelic pathogenic variants in GJB2 (encoding connexin 26) on molecular genetic testing (see Table 1).

Individuals with DFNB1 are EITHER:

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and/or a multi-gene panel) and genomic testing (comprehensive genome sequencing).

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved based on phenotypic data, while comprehensive genomic testing does not. Because of the overlapping phenotypes of the many causes of hereditary hearing loss and deafness, most individuals with hereditary hearing loss and deafness are diagnosed by one of two approaches: comprehensive genomic sequencing (recommended) or gene-targeted testing (to consider).

Recommended Testing

A comprehensive deafness-specific genetic panel that includes all genes implicated in nonsyndromic hearing loss and nonsyndromic hearing loss mimics (see Differential Diagnosis and Hereditary Hearing Loss and Deafness Overview) is recommended as the initial genetic test (Figure 1).

Figure 1. . Genetic diagnostic rates in 1119 sequentially accrued persons with hearing loss.

Figure 1.

Genetic diagnostic rates in 1119 sequentially accrued persons with hearing loss. No person was excluded based on phenotype, inheritance, or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 individuals (more...)

Note: (1) Genes included in available panels and the diagnostic sensitivity of the test used for each gene vary by laboratory and over time [Shearer & Smith 2015]. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests; detection of copy number variants must be included in hearing loss panels [Shearer et al 2014].

For more information on multi-gene panels click here.

Testing to Consider

Single-gene testing can be considered if a deafness-specific multi-gene panel is not available. However, performing sequence analysis of GJB2 alone is not cost-effective unless it is limited to persons with severe-to-profound congenital nonsyndromic hearing loss. Offering single-gene testing of GJB2 reflexively to everyone with congenital hearing loss without regard to the degree of hearing loss is not evidence based and not cost effective [Jayawardena et al 2015, Shearer & Smith 2015].

Exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to warrant gene-targeted testing. Both WES and WGS should be complemented with appropriate genetic counseling before and after testing. For more information on comprehensive genome sequencing click here.

Table 1.

Molecular Genetic Testing Used in DFNB1

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2, 3 Detectable by This Method
GJB2Sequence analysis 4> 99%
Gene-targeted deletion/duplication analysis 5, 6<1%
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Feldmann et al [2009]) may not be detected by these methods.

Clinical Characteristics

Clinical Description

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 sib with the same GJB2 pathogenic variants has a 91% chance of having severe-to-profound deafness and a 9% chance of having mild-to-moderate deafness [Tennessee Department of Health 2005].
  • If an affected person has mild-to-moderate deafness, an affected sib with the same GJB2 pathogenic variants has a 66% chance of having mild-to-moderate deafness and a 34% chance of having severe-to-profound deafness [Tennessee Department of Health 2005].
  • A few reports describe children with GJB2 variants who pass the newborn hearing screen and have 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 [Orzan et al 1999, Löffler 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] found a slight degree of asymmetry, 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 variants identified, 47 were predicted non-truncating (e.g., missense variants) and 36 were predicted truncating (e.g., premature stop codons). By classifying variants this way, the authors defined three genotype classes: biallelic truncating (T/T) variants, biallelic non-truncating (NT/NT) variants, and compound heterozygous truncating/non-truncating (T/NT) variants (Table 2).

Table 2.

Genotype-Phenotype Correlations by Variant Type in 1531 Persons with Biallelic GJB2 Pathogenic Variants

GJB2 Genotype ClassTotal of All DFNB1Hearing Loss
MildModerateSevereProfound
T/T77.3% 10%-3%10%-12%25%-28%59%-64%
NT/NT6.2% 253%26%8%13%
T/NT16.5% 329%-37%24%-29%10%-17%24%-30%

Based on Snoeckx et al [2005]. See full text, Figure 3 for scatter diagrams showing 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.

T/T = biallelic predicted truncating variants

NT/NT = biallelic predicted non-truncating variants

T/NT = compound heterozygous predicted truncating/non-truncating variants

1.

64 different genotypes (36% of all genotypes)

2.

42 different genoytpes (24% of all genotypes)

3.

71 different genotypes (40% of all genotypes)

Nomenclature

DFNB with 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 [Angeli 2008, Azaiez et al 2004, 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 biallelic pathogenic variants in GJB2. 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 biallelic GJB2 pathogenic variants as a cause of hearing impairment is highly variable. For example, among families segregating autosomal recessive nonsyndromic hearing impairment, GJB2 variants are causally related to congenital hereditary hearing impairment in:

Differential Diagnosis

See Deafness and Hereditary Hearing Loss Overview for information on the genes causing nonsyndromic hereditary hearing loss and deafness.

Table 3.

Autosomal Recessive Syndromes Involving Hearing Loss

SyndromeDistinctive Feature in Addition to Hearing LossGene(s)Hearing LossComments
Usher syndrome type IRetinitis pigmentosa 1See footnote 2Congenital bilateral profound sensorineural hearing loss
  • Vestibular areflexia w/delay in motor milestones (delayed sitting & walking)
  • Unless fitted w/a cochlear implant, individuals w/Usher syndrome type 1 do not typically develop speech.
  • RP develops in adolescence, resulting in progressively constricted visual fields & impaired visual acuity
Usher syndrome type IIUSH2A
ADGRV1
DFNB31
Congenital bilateral sensorineural hearing loss: mild-moderate in low frequencies; severe-profound in higher frequencies
  • Intact vestibular responses w/no delay in motor milestones
  • Clinical distinction between Usher syndrome types I & II: children w/type I usually delayed in walking until age 18 mos – 2 yrs (because of vestibular involvement); children w/type II usually begin walking at ~1 yr
Usher syndrome type IIICLRN1Postlingual progressive sensorineural hearing loss
  • Late-onset RP
  • Variable impairment of vestibular function
  • Older individuals w/Usher syndrome type III may have profound hearing loss & vestibular disturbance resembling Usher syndrome type I
Pendred syndromeThyroid enlargementSLC26A4 3Hearing impairment usually congenital & often severe-profound (mild-moderate progressive hearing impairment also occurs)
  • Bilateral dilation of the vestibular aqueduct 4 w/ or w/out cochlear hypoplasia 5
  • Either an abnormal perchlorate discharge test or goiter
  • Thyroid abnormality variable 6
  • Vestibular function usually abnormal
Jervell and Lange-Nielsen syndromeCardiac conduction defects; long QTc, usually >500 msecKCNQ1
KCNE1
Congenital profound bilateral sensorineural hearing loss
  • Long QTc is associated w/tachyarrhythmias, which may culminate in syncope or sudden death; >50% of untreated children w/JLNS die before age 15 years 7
  • Classic presentation: deaf child who experiences syncopal episodes during periods of stress, exercise, or fright
  • Consider JLNS in any child w/congenital sensorineural deafness & negative DFNB1 testing – esp. w/a history of syncope or seizure or family history of sudden death before age 40 years
1.

Retinitis pigmentosa is a progressive bilateral symmetric degeneration of rod and cone functions of the retina.

2.

Pathogenic variants 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.

3.

Pendred syndrome and DFNB4 comprise a phenotypic spectrum caused by biallelic pathogenic variants in SLC26A4 (the most common cause), or double heterozygosity in either SLC26A4 and FOXI1 or SLC26A4 and KCNJ10.

4.

Also called enlarged vestibular aqueduct (EVA)

5.

DVA with cochlear hypoplasia is known as Mondini malformation or dysplasia.

6.

Goitrous changes are typically not present at birth but do develop in early puberty (40%) or adulthood (60%).

7.

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.

Autosomal recessive nonsyndromic hearing loss without an identifiable GJB2 variant 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 a 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

Management

Evaluations Following Initial Diagnosis

To establish the extent of involvement and needs in an individual diagnosed with nonsyndromic hearing loss and deafness caused by biallelic pathogenic variants in GJB2 (DFNB1), the following evaluations are recommended:

  • Complete assessment of auditory acuity using age-appropriate tests such as ABR testing, auditory steady-state response (ASSR) testing, and pure tone audiometry
  • Ophthalmologic evaluation for refractive errors
  • Consultation with a clinical geneticist and/or genetic counselor

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), an excellent 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]

Also see Hereditary Hearing Loss and Deafness for more detailed discussion of management issues.

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 DFNB1 and mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises.

Evaluation of Relatives at Risk

If both GJB2 pathogenic variants have been identified in the proband, it is appropriate to clarify the genetic status of at-risk sibs shortly after birth so that appropriate early support and management can be provided to the child and family.

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 caused by biallelic GJB2 pathogenic variants (DFNB1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of a child with DFNB1 are obligate heterozygotes (i.e., carriers of one GJB2 pathogenic variant).
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of an individual with DFNB1 are obligate heterozygotes (carriers) for a GJB2 pathogenic variant.

Other family members. Each sib of the proband’s parents has a 50% chance of being a carrier of a GJB2 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for relatives of an individual with DFNB1 requires prior identification of the GJB2 pathogenic variants 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 members of the Deaf community and who sign requires the services of a skilled interpreter.
  • Members of the Deaf community 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.”
  • 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.
  • The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as “abnormal” should be avoided.

Family planning

  • The optimal time for 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 who may be 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 and allelic variants will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GJB2 pathogenic variants have been identified in a family member with DFNB1, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for DFNB1 are possible.

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]

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.

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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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

Introduction

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. Most connexin genes have a common architecture, with the entire coding region contained in a single large exon separated from a non-coding exon by an intron of variable size. The gap junction protein connexin 26 is encoded by GJB2.

Gene structure. The coding sequence of GJB2 (exon 2) encodes a 226-amino acid protein. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 4. Numerous GJB2 pathogenic variants that result in autosomal recessive nonsyndromic hearing loss are listed on the Connexin-deafness Home page.

Common GJB2 pathogenic variants:

The following three large deletions, which include sequences upstream of GJB2 and a portion of GJB6, result in reduced GJB2 expression, presumably due to deletion of a cis-regulatory element.

*Note: These two deletions have also been identified at lower frequencies in other populations of European origin [Wu et al 2002, Del Castillo et al 2003, Stevenson et al 2003].

Table 4.

Selected GJB2 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.35delGp.Gly12ValfsTer1NM_004004​.4
NP_003995​.2
c.35G>Tp.Gly12Val
c.-3179G>A 2
(IVS1+1G>A)
--
c.56G>Cp.Ser19Thr
c.101T>Cp.Met34Thr 3
c.109G>Ap.Val37Ile 3
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
GJB6-D13S1830
GJB6-D13S1854
del(chr13:19,837,344-19,968,698)

Note on variant classification: Variants listed in the table have been provided by the authors. 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.

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

3.

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

Normal gene product. GJB2 encodes connexin 26, 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 and permit synchronization of activity in excitable tissues and the exchange of metabolites and signal molecules in non-excitable tissues. Connexin 26 forms functional combinations with itself, connexin 32, connexin 46, and connexin 50.

Abnormal gene product. GJB2 pathogenic variants result in one of the following:

  • Loss of connexin 26 function (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)
  • Interference with translation (p.Arg184Pro) [Snoeckx et al 2005]

References

Published Guidelines/Consensus Statements

  • American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 4-14-17.
  • Genetics Evaluation of Congenital Hearing Loss Expert Panel, American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available online. 2002. Accessed 4-14-17.

Literature Cited

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  • Arnos KS, Israel J, Cunningham M. Genetic counseling of the deaf. Medical and cultural considerations. Ann N Y Acad Sci. 1991;630:212–22. [PubMed: 1952592]
  • Angeli SI. Phenotype/genotype correlations in a DFNB1 cohort with ethnical diversity. Laryngoscope. 2008;118:2014–23. [PubMed: 18758381]
  • Azaiez H, Chamberlin GP, Fischer SM, Welp CL, Prasad SD, Taggart RT, del Castillo I, Van Camp G, Smith RJ. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004;24:305–11. [PubMed: 15365987]
  • Azaiez H, Yang T, Prasad S, Sorensen JL, Nishimura CJ, Kimberling WJ, Smith RJ. Genotype-phenotype correlations for SLC26A4-related deafness. Hum Genet. 2007;122:451–7. [PubMed: 17690912]
  • Bazazzadegan N, Nikzat N, Fattahi Z, Nishimura C, Meyer N, Sahraian S, Jamali P, Babanejad M, Kashef A, Yazdan H, Sabbagh Kermani F, Taghdiri M, Azadeh B, Mojahedi F, Khoshaeen A, Habibi H, Reyhanifar F, Nouri N, Smith RJ, Kahrizi K, Najmabadi H. The spectrum of GJB2 mutations in the Iranian population with non-syndromic hearing loss--a twelve year study. Int J Pediatr Otorhinolaryngol. 2012;76:1164–74. [PubMed: 22695344]
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Suggested Reading

  • Petit C, Levilliers J, Marlin S, Hardelin J. Hereditary hearing loss. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 254. New York, NY: McGraw-Hill. Available online.

Chapter Notes

Acknowledgments

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

Author History

Mary-Kayt N Jones, BA (2016-present)
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; University of Antwerp (1998-2016)

Revision History

  • 18 August 2016 (bp) Comprehensive update posted live
  • 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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