Nonsyndromic Hearing Loss and Deafness, DFNB1

Richard JH Smith; Mary-Kayt N Jones

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Nonsyndromic Hearing Loss and Deafness, DFNB1

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

Richard JH Smith, MD and Mary-Kayt N Jones, BA.

Author Information and Affiliations

Initial Posting: September 28, 1998; Last Update: August 18, 2016.

Estimated reading time: 22 minutes

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 a pregnancy at increased risk, and preimplantation genetic testing 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 (501-2,000 Hz), or high (>2,000 Hz) (see Hereditary Hearing Loss and Deafness Overview).
No related systemic findings identified by medical history and physical examination
A family history of nonsyndromic hearing loss consistent with autosomal recessive inheritance

Establishing the Diagnosis

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

Individuals with DFNB1 are EITHER:

Homozygous or compound heterozygous for GJB2 pathogenic variants (99%); OR
Compound heterozygous for one GJB2 pathogenic variant and one of three large deletions that includes sequences upstream of GJB2 and a portion of GJB6 (<1%).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and/or a multigene panel) and genomic testing (comprehensive genomic 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 1,119 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 are likely to change over time [Shearer & Smith 2015]. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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 an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Testing to Consider

Single-gene testing can be considered if a deafness-specific multigene 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].

Comprehensive genomic testing including exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to warrant gene-targeted testing. Both exome sequencing and genome sequencing should be complemented with appropriate genetic counseling before and after testing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in DFNB1

Gene ¹	Method	Proportion of Probands with Pathogenic Variants ^2, ³ Detectable by Method
GJB2	Sequence analysis ⁴	>99%
GJB2	Gene-targeted deletion/duplication analysis ^5, ⁶	<1%

1.: See Table A. Genes and Databases for chromosome locus and protein.
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. 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 used may include a range of techniques such as 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 1,531 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 1,531 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 nontruncating (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 nontruncating (NT/NT) variants, and compound heterozygous truncating/nontruncating (T/NT) variants (Table 2).

Table 2.

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

GJB2 Genotype Class	Total of All DFNB1	Hearing Loss
GJB2 Genotype Class	Total of All DFNB1	Mild	Moderate	Severe	Profound
T/T	77.3% ¹	0%-3%	10%-12%	25%-28%	59%-64%
NT/NT	6.2% ²	53%	26%	8%	13%
T/NT	16.5% ³	29%-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 (PTA_0.5,1,2kHz) for each person within each genotype class, using individuals homozygous for the c.35delG allele as a reference group.
: NT/NT = biallelic predicted nontruncating variants; T/NT = compound heterozygous predicted truncating/nontruncating variants; T/T = biallelic predicted 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 [Green et al 1999, Azaiez et al 2004, Angeli 2008]. Its approximate prevalence in the general population is 14:100,000, based on the following calculation: the incidence of congenital hereditary hearing impairment is 1:2,000 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:

25% of Palestinian families [Shahin et al 2002]
An estimated 24% of Altaians from Siberia [Posukh et al 2005]
18% of Han Chinese [Duan et al 2015]
16% of the Iranian deaf population [Bazazzadegan et al 2012]
15% of Hui people [Duan et al 2015]
11% of Tibetan families [Duan et al 2015]

Genetically Related Disorders

Allelic disorders. The following autosomal dominant disorders are caused by heterozygous pathogenic variants in GJB2:

DFNA3 is characterized by progressive, moderate-to-severe sensorineural impairment. It is less commonly caused by heterozygous pathogenic variants in GJB6.
Palmoplantar keratoderma with deafness (OMIM 148350) is characterized by diffuse hyperkeratosis of the hands and feet [Richard et al 1998, Heathcote et al 2000].
Keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210) 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].
Hystrix-like ichthyosis-deafness (HID) syndrome (OMIM 602540) is a 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 [van Geel et al 2002].
Vohwinkel syndrome (OMIM 124500) is 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].
With some variants in GJB2, the epidermal disease and hearing loss cosegregate, while with other variants, the severity of the disease phenotype varies, suggesting that other factors modify gene expression [Kutkowska-Kaźmierczak et al 2015].

Other. A large deletion encompassing GJB2, the adjacent genes GJA3 and GJB6, and a portion of CRYL1 in trans with a GJB2 pathogenic variant was identified in an individual with a contiguous gene syndrome characterized by profound prelingual hearing loss, mental and psychomotor development delay, clinodactyly of the second toes, and a frontal tuft [Feldmann et al 2009].

Differential Diagnosis

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

Table 3.

Autosomal Recessive Syndromes Involving Hearing Loss

Syndrome	Distinctive Feature in Addition to Hearing Loss	Gene(s)	Hearing Loss	Comments
Usher syndrome type I	Retinitis pigmentosa ¹	See footnote 2.	Congenital bilateral profound sensorineural hearing loss	Vestibular areflexia w/delay in motor milestones (delayed sitting & walking) Unless fitted w/a cochlear implant, persons 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 II		USH2A 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 III		CLRN1	Postlingual 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 syndrome	Thyroid enlargement	SLC26A4 ³	Hearing 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 syndrome	Cardiac conduction defects; long QTc, usually >500 msec	KCNQ1 KCNE1	Congenital profound bilateral sensorineural hearing loss	Long QTc is assoc w/tachyarrhythmias, which may culminate in syncope or sudden death; >50% of untreated children w/JLNS die < age 15 yrs 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/history of syncope or seizure or family history of sudden death < age 40 yrs

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:

With a dilated vestibular aqueduct on thin-cut computed tomography (CT) of the temporal bones suggests DFNB4 [Azaiez et al 2007];
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 [Azaiez et al 2007].

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 nonhereditary 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 in the US and EU Clinical Trials Register in Europe for 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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 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/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling to young adults who are deaf or who may be carriers.

Prenatal Testing and Preimplantation Genetic Testing

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 testing 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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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.

Medical Home Portal
Hearing Loss and Deafness
Alexander Graham Bell Association for the Deaf and Hard of Hearing
Phone: 866-337-5220 (toll-free); 202-337-5221 (TTY)
Fax: 202-337-8314
Email: info@agbell.org
Listening and Spoken Language Knowledge Center
American Society for Deaf Children
Phone: 800-942-2732 (ASDC)
Email: info@deafchildren.org
www.deafchildren.org
BabyHearing.org
This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
www.babyhearing.org
MedlinePlus
Nonsyndromic hearing loss
National Association of the Deaf
Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
Fax: 301-587-1791
Email: nad.info@nad.org
www.nad.org

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

Locus Name	Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
DFNB1	GJB2	13q12.11	Gap junction beta-2 protein	Hereditary Hearing Loss Homepage (GJB2) CCHMC - Human Genetics Mutation Database (GJB2) The Connexin-deafness homepage (GJB2)	GJB2	GJB2

: Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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

121011	GAP JUNCTION PROTEIN, BETA-2; GJB2
220290	DEAFNESS, 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 noncoding 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 homepage.

Common GJB2 pathogenic variants:

c.35delG
- Carrier rate of 2%-4% in individuals of northern European descent [Snoeckx et al 2005]
- Also reported in individuals of Arabic, Bedouin, Indian, and Pakistani descent
c.235delC, the most common variant in the Japanese population (carrier rate: 1%-2%) [Abe et al 2000, Kudo et al 2000, Snoeckx et al 2005]
c.167delT, the most common variant in the Ashkenazi Jewish population (carrier rate: 7.5%) [Morell et al 1998]
p.Val37Ile, the most common variant in Thailand (carrier rate: 11.6%) [Hwa et al 2003]; associated with mild hearing loss [Abe et al 2000, Wilcox et al 2000, Kenna et al 2001, Lin et al 2001, Marlin et al 2001, Snoeckx et al 2005]
p.Met34Thr, which has a minor allele frequency of 1%-2% and is associated with mild hearing loss [Snoeckx et al 2005]

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.

~309-kb deletion (known as ∆GJB6-D13S1830) (see Note) that is common in the Spanish population (67% DFNB1 alleles in deaf Spanish individuals not detected by GJB2 sequence analysis) [Wu et al 2002, Del Castillo et al 2003, Stevenson et al 2003]
~232-kb deletion (known as ∆GJB6-D13S1854) (see Note) that is also relatively common in the Spanish population (25% of DFNB1 alleles in deaf Spanish individuals not detected by GJB2 sequence analysis or screening for the 309-kb deletion) [del Castillo et al 2005]
~131.4-kb deletion with a proximal breakpoint more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6; identified in a large German-American family with autosomal recessive congenital severe-to-profound nonsyndromic sensorineural hearing loss [Wilch et al 2010]. This family is an example of a common and a rare pathogenic variant segregating in a nonconsanguineous family comprising many individuals with an autosomal recessive disorder.

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 Change	Reference Sequences
c.35delG	p.Gly12ValfsTer1	NM_004004.4 NP_003995.2
c.35G>T	p.Gly12Val	NM_004004.4 NP_003995.2
c.-3179G>A ² (IVS1+1G>A)	--	NM_004004.4
c.56G>C	p.Ser19Thr	NM_004004.4 NP_003995.2
c.101T>C	p.Met34Thr ³
c.109G>A	p.Val37Ile ³
c.167delT	p.Leu56ArgfsTer26
c.235delC	p.Leu79CysfsTer3
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
∆GJB6-D13S1830		NM_004004.4
∆GJB6-D13S1854
del(chr13:19,837,344-19,968,698)

: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.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]

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 live
21 December 2005 (me) Comprehensive update posted live
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 live
24 April 2001 (me) Comprehensive update posted live
28 September 1998 (pb) Review posted live
4 April 1998 (rjs) Original submission

References

Published Guidelines / Consensus Statements

American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 5-25-22.
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 5-25-22. [PMC free article: PMC3110944] [PubMed: 12180152]

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Smith RJH, Jones MKN. Nonsyndromic Hearing Loss and Deafness, DFNB1. 1998 Sep 28 [Updated 2016 Aug 18]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.
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Nonsyndromic Hearing Loss and Deafness, DFNB1

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

Diagnosis

Suggestive Findings

Establishing the Diagnosis

Recommended Testing

Figure 1.

Testing to Consider

Table 1.

Clinical Characteristics

Clinical Description

Genotype-Phenotype Correlations

Table 2.

Nomenclature

Prevalence

Genetically Related Disorders

Differential Diagnosis

Table 3.

Management

Evaluations Following Initial Diagnosis

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

Therapies Under Investigation

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Carrier Detection

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Molecular Genetics

Table A.

Table B.

Table 4.

Chapter Notes

Acknowledgments

Author History

Revision History

References

Published Guidelines / Consensus Statements

Literature Cited

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