Clinical characteristics.

GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) is the most common genetic cause of congenital (present at birth) severe-to-profound non-progressive sensorineural hearing loss in many world populations. In countries where available, newborn hearing screening (NBHS) typically identifies severe-to-profound hearing loss.

GJB2-AR NSHL can also be mild to moderate and is usually not progressive; however, it can progress. Congenital mild-to-moderate GJB2-AR NSHL is not detected by NBHS.

GJB2-AR NSHL has no related systemic findings.

Diagnosis/testing.

The diagnosis of GJB2-AR NSHL is established in a proband with suggestive findings and biallelic GJB2 pathogenic variants identified by molecular genetic testing. Of note: About 1% of individuals with GJB2-AR NSHL are compound heterozygotes for one GJB2 pathogenic variant and one of several different deletions that include sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression. Occasionally, the deletion also includes GJB2.

Management.

Treatment of manifestations: It is recommended that NBHS be completed by age one month, the genetic diagnosis be established by age three months, and early intervention begun by age six months. (This recommendation is also known as "the 1-3-6 benchmark.") In the United States, the states that recommend the 1-3-6 benchmark should actually strive for a "1-2-3" timeline.

Because children with severe-to-profound hearing loss who are candidates for cochlear implantation can attain levels of social functioning and education indistinguishable from those of normal-hearing peers, cochlear implantation should be performed as soon as possible.

Children with mild-to-moderate hearing loss can be treated with hearing aids customized to the child's age and severity of hearing loss.

Surveillance: Most children with severe-to-profound GJB2-AR NSHL who are cochlear implant recipients initially require frequent follow-up visits with their cochlear implant team (otolaryngologist, audiologist, and speech-language pathologist) for assessment of speech recognition and equipment check. Once the cochlear implant recipient and their family become comfortable with the cochlear implant, many of these tasks can be performed by the family at home.

All children with mild-to-moderate GJB2-AR NSHL require follow-up audiograms annually to detect any progression of hearing loss. Children using hearing aids typically have an annual evaluation by an otolaryngologist, audiologist, and hearing aid specialist to examine the ears, obtain an audiogram, and check hearing aid function.

Agents/circumstances to avoid: Individuals with mild-to-moderate hearing loss should avoid environmental exposures known to cause hearing loss. Most important for persons with GJB2-related mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises (i.e., >75 decibels), particularly secondary to earbud use. Note that the headphone safety feature built into many smartphones can be set to a maximum limit of decibels.

Evaluation of relatives at risk: With limited exceptions, it is appropriate to clarify the genetic status of sibs of a proband with GJB2-AR NSHL; early identification of infants and children with hearing loss allows appropriate support and management to be provided to the child and family.

Genetic counseling.

GJB2-AR NSHL is inherited in an autosomal recessive manner. The parents of a child with GJB2-AR NSHL are typically heterozygous for a GJB2 pathogenic variant. In populations with a high carrier rate, it is possible that either one or both parents of a child with GJB2-AR NSHL also have GJB2-AR NSHL. If both parents are known to be heterozygous for a pathogenic variant, each sib of an individual with GJB2-AR NSHL has at conception a 25% chance of inheriting biallelic pathogenic variants and having hearing loss, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial GJB2 pathogenic variants. Once the GJB2 pathogenic variants have been identified in a family member with GJB2-AR NSHL, prenatal and preimplantation genetic testing for GJB2-AR NSHL are possible.

Suggestive Findings

The diagnosis of GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) should be considered in two scenarios: an abnormal newborn hearing screening (NBHS) result and a symptomatic individual.

Establishing the Diagnosis

The diagnosis of GJB2-AR NSHL is established in a proband with suggestive findings who has EITHER of the following identified by molecular genetic testing (see Table 2):

• Biallelic GJB2 pathogenic (or likely pathogenic) variants (99%);

OR

• Compound heterozygosity for one GJB2 pathogenic (or likely pathogenic) variant and one of the following findings:
  • A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see Molecular Genetics, GJB2-specific laboratory technical considerations);
  • A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of GJB2; or
  • Mosaic uniparental disomy of GJB2.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. For expert specification of the ACMG/AMP variant interpretation for genetic hearing loss, see Oza et al [2018] (full text). Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of biallelic GJB2 variants of uncertain significance (or of one known GJB2 pathogenic variant and one GJB2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of GJB2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) is the most common genetic cause of congenital (present at birth) severe-to-profound non-progressive sensorineural hearing loss in many world populations. GJB2-AR NSHL can also be mild to moderate and is usually not progressive; however, there are exceptions.

Severe-to-profound GJB2-AR NSHL is typically congenital and diagnosed on newborn hearing screening (NBHS); however, there are occasional exceptions.

In two examples, a newborn passed his NBHS auditory brain stem response (ABR)-based test, but was diagnosed as deaf at age 15 months when an ABR test obtained at the request of his parents showed no responses through 90 dB. Another child had a normal free-field audiogram performed by an experienced audiologist at age five months, but at age nine months had ABR-confirmed severe hearing loss [Green et al 2000].

Severe-to-profound GJB2-AR NSHL is most frequently associated with truncating GJB2 variants (see Genotype-Phenotype Correlations).

Mild-to-moderate GJB2-AR NSHL may escape detection on the NBHS, especially when the hearing loss is mild. Most mild-to-moderate GJB2-AR NSHL is not progressive; however, an important exception is the unique trajectory of biallelic p.Val37Ile pathogenic variants, which has been well documented by Chen et al [2022] (see Genotype-Phenotype Correlations).

Mild-to-moderate GJB2-AR NSHL is most often associated with either biallelic missense variants or a missense variant in trans with a truncating variant (see Genotype-Phenotype Correlations).

Intrafamilial variability in the degree of GJB2-AR NSHL. The majority (67%) of sib pairs will have similar levels of hearing loss (within 20 dB); however, in a significant percentage (33%), there will be a prominent difference in hearing levels (>30 dB) between sibs [Fujioka et al 2020].

All GJB2-AR NSHL. 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, individuals with GJB2-AR NSHL are healthy; life span is normal.

Genotype-Phenotype Correlations

Nomenclature

GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) may also be referred by its genetic locus, DFNB1 (DFN for DeaFNess, B to indicate autosomal recessive inheritance, and 1 to indicate the relative order of hearing loss-related gene mapping). However, locus-based naming can be problematic when more than one gene is mapped to a given locus, as is the case with GJB2 and GJB6, which both map to the DFNB1 locus (13q12.11). For clarity, gene-based naming is used in this GeneReview rather than locus-based naming.

Prevalence

The prevalence of GJB2-AR NSHL and the carrier rate for pathogenic GJB2 variants are population dependent (see Figure 1). Some of this variability may reflect ascertainment bias. For example, although Adadey et al [2022] present the most comprehensive data of the landscape of genetic hearing loss to date, they note that in Africa the causes of genetic hearing loss are still to be investigated in a large majority of African countries. Based on currently available data, the highest carrier rate (8.3%) is reported in the East Asian population, in which the most common pathogenic variant is p.Val37Ile.

Figure 1.

The bar is the carrier frequency for a pathogenic variant in GJB2. Note that the carrier frequency for a pathogenic (or likely pathogenic) variant in GJB2 is highest in the East Asian population, reflecting the exceptionally high carrier frequency for (more...)

Evaluations Following Initial Diagnosis

To establish the extent of involvement and needs in an individual diagnosed with GJB2-AR NSHL, the following evaluations by an otolaryngologist are recommended:

• Comprehensive medical history focused on gestational and perinatal events, newborn hearing screen (NBHS) results, and cytomegalic virus (CMV) test results (if performed)
• Assessment of hearing using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure-tone audiometry to determine severity of hearing loss (see Table 1) and laterality (expected to be symmetric)
• Physical examination including an evaluation for syndromic features (which should be absent) and a thorough examination of the head and neck, including an otomicroscopic evaluation of the ear to evaluate for otitis media
• Ophthalmologic examination to identify refractive errors (unrelated to GJB2-AR NSHL) that require spectacle correction (glasses) to improve visual acuity
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of GJB2-AR NSHL in order to facilitate medical and personal decision making
• Assessment of need for family support and resources including community or online resources such as Parent to Parent, social work involvement for parental support, and home nursing referral

Treatment of Manifestations

Management of children with GJB2-AR NSHL involves discussion of the following issues with the family.

Uncorrected hearing loss (regardless of etiology) has consistent sequelae. Auditory deprivation during the first two years of life is associated with poor reading performance, poor communication skills, and poor speech production, deficiencies that cannot be completely remediated even with educational intervention. Early auditory intervention is effective – whether through cochlear implantation or amplification [Smith et al 2005].

To optimize intervention for children with hearing loss, the Joint Committee on Infant Hearing [2019] recommends universal NBHS be completed by age one month, diagnosis established by age three months, and early intervention begun by age six months (also known as "the 1-3-6 benchmark"). In the United States, the states that recommend the 1-3-6 benchmark should actually strive for a "1-2-3" timeline.

Children with severe-to-profound hearing loss who are candidates for cochlear implantation can attain levels of social functioning and education indistinguishable from those of normal-hearing peers [Loy et al 2010, Langereis & Vermeulen 2015]. Cochlear implantation performed as soon as possible is associated with significantly better long-term auditory performance and speech intelligibility than later cochlear implantation [Wu et al 2015, Eshraghi et al 2020]. Nonetheless, there is no upper age limit for cochlear implantation; however, at older ages habilitation outcomes are less predictable.

Children with mild-to-moderate hearing loss can be treated with hearing aids customized to the child's age and severity of hearing loss.

Surveillance

To monitor the individual's response to habituation and to identify any changes in severity of hearing loss, the following evaluations are recommended.

Most children with severe-to-profound GJB2-AR NSHL with a cochlear implant will initially have frequent evaluations recommended by their cochlear implant team (otolaryngologist, audiologist, and speech and language pathologist).

At follow-up appointments, the following may be performed: speech recognition testing, equipment checks (including device adjustment and troubleshooting), and provision of replacement or upgraded equipment [Cullington et al 2016].

As the cochlear implant recipient becomes comfortable with the cochlear implant, many of the above tasks can be performed by the family at home, obviating the need for routinely scheduled appointments unless the need for a clinic visit arises.

Children with mild-to-moderate GJB2-AR NSHL

• An annual evaluation by an otolaryngologist, audiologist, and hearing aid specialist is recommended to examine the ears, obtain an audiogram, and check hearing aid function.
• This annual follow up is essential, as progression of hearing loss can occur. For most GJB2 genotypes associated with mild-to-moderate hearing loss, hearing is stable; however, the variant p.Val37Ile is associated with progressive hearing loss. In one study, one of eight persons homozygous for the p.Val37Ile pathogenic variant underwent cochlear implantation due to progression of mild-to-moderate hearing loss; six of eight used hearing aids; and one of eight was not treated [Lee et al 2021].

Agents/Circumstances to Avoid

Individuals with hearing loss should avoid environmental exposures known to cause hearing loss.

Most important for persons with GJB2-related mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises, particularly secondary to earbud use. The headphone safety feature built into most smartphones can be set a maximum limit of 75 dB.

Headphone/earbud safety features can be found in the phone settings menu:

• In iPhones, under Settings > Sounds & Haptics > Headphone Safety
• In Android phones, under Settings > Sounds & Vibrations > Volume > Media volume limit

Also see these general resources on noise reduction:

• 6 Simple Ways To Check If Your Headphones Are Too Loud
• How Do I Prevent Hearing Loss from Loud Noise?

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of sibs of a proband with GJB2-AR NSHL if:

• A newborn sib has an abnormal result on universal NBHS;
• A newborn sib has a normal result on NBHS and the GJB2 pathogenic variants identified in the proband are associated with mild hearing loss (as NBHS may miss newborns with mild hearing loss); or
• A sib did not undergo NBHS and/or NBHS results are unknown.

Early identification of infants and children with hearing loss allows appropriate support and management to 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.

Mode of Inheritance

By definition, GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) is inherited in an autosomal recessive manner.

Note: Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) is reported in some families [Pampanos et al 2000, Tekin et al 2003] and is more likely to occur in populations with a high carrier rate (see Figure 1).

Risk to Family Members

Parents of a proband

• The parents of a child with GJB2-AR NSHL are typically heterozygous for a GJB2 pathogenic variant.
• In populations with a high carrier rate (e.g., the East Asian population, in which the carrier frequency for p.Val37Ile is 8.3% [see Figure 1]), it is possible that either one or both parents of a child with GJB2-AR NSHL also have GJB2-AR NSHL.
• Molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a GJB2 pathogenic variant and to allow reliable counseling regarding the likelihood of recurrence.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A deletion of a portion of GJB2 in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity [Abe et al 2018];
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) of a GJB2 pathogenic variant associated with autosomal recessive nonsyndromic hearing loss are asymptomatic.

Sibs of a proband

• If both parents are known to be heterozygous for a GJB2 pathogenic variant, each sib of an individual with GJB2-AR NSHL has at conception a 25% chance of inheriting biallelic GJB2 pathogenic variants and having hearing loss, a 50% chance of inheriting one GJB2 pathogenic variant, and a 25% chance of inheriting neither of the familial GJB2 pathogenic variants.
• Strong genotype-phenotype correlations are observed in GJB2-AR NSHL.
• The majority of sibs (67%) who inherit biallelic GJB2 pathogenic variants have a hearing threshold similar (within 20 dB) to that of the proband; a prominent difference (>30 dB) in hearing thresholds is seen in 33% of sib pairs [Snoeckx et al 2005, Fujioka et al 2020].
• Heterozygotes (carriers) of a GJB2 pathogenic variant associated with autosomal recessive nonsyndromic hearing loss are asymptomatic.

Offspring of a proband

• Unless an affected individual's reproductive partner also has GJB2-AR NSHL or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in GJB2.
• In populations with a high carrier rate (see Figure 1), the reproductive partner of the proband may have two GJB2 pathogenic variants or be heterozygous. Thus, the likelihood of GJB2-AR NSHL recurrence in offspring is most accurately determined after GJB2 molecular genetic testing of the proband's reproductive partner.

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 GJB2-AR NSHL requires prior identification of the GJB2 pathogenic variants in the family.

Related Genetic Counseling Issues

See 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:

• Clear communication between individuals with hearing loss, families, and health care providers is key. Deaf and hard-of-hearing persons may use a variety of communication methods, including spoken language, sign language, lip reading, and written notes. For deaf individuals and families who use sign language, a certified sign language interpreter must be used. Communication aids such as visual aids and verbal cues when changing topics can be helpful.
• It is important to ascertain and address the questions and concerns of the family/individual. Deaf and hard-of-hearing persons may be interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services. Others may seek information about the chance of deaf/hard-of-hearing children and information for family planning decisions.
• The use of neutral or balanced terminology can enhance the provision of services; for example: use of the term "chance" instead of "risk"; "deaf" or "hearing" instead of "affected" or "unaffected"; and "deaf" or "hard-of-hearing" instead of "hearing impaired." 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." Terms such as "handicap" should be avoided.

Family planning

• The optimal time for determination of genetic status and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of the probability of hearing loss in offspring and reproductive options) to young adults with hearing loss.
• Because GJB2-AR NSHL is associated with extensive allelic heterogeneity, reliable carrier testing for the reproductive partners of individuals with GJB2-AR NSHL (and individuals who are carriers of GJB2-AR NSHL) requires GJB2 sequence analysis. Note: Screening for the large deletions shown in Figure 2 is not universally recommended because of the very low frequency of these deletions.

Figure 2.

Schematic of large (>10 kilobase) pathogenic deletions associated with GJB2-related autosomal recessive nonsyndromic hearing loss Modified from Abe et al [2018]

Prenatal Testing and Preimplantation Genetic Testing

Once the GJB2 pathogenic variants have been identified in a family member with GJB2-AR NSHL, prenatal and preimplantation genetic testing for GJB2-AR NSHL are possible.

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.

Molecular Pathogenesis

GJB2 encodes gap junction beta-2 protein, also called connexin 26. Connexins aggregate in groups of six around a central 2.3-nm pore to form a connexon. Connexin 26 forms functional gap junctions with itself, connexin 32, connexin 46, and connexin 50.

Connexons from adjoining cells covalently bond, forming a channel between cells. 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 nonexcitable tissues.

Mechanism of disease causation. Loss of function

GJB2-specific laboratory technical considerations

• Large deletions have been described, such as sequences upstream of GJB2 (comprising either GJB6 and portions of CRYL1 or just portions of CRYL1) that delete cis-regulatory regions of GJB2, thereby abolishing GJB2 expression (see Figure 2) [Abe et al 2018].
• Uniparental disomy (UPD). Mosaicism for the GJB2 c.235delC variant has been reported in an individual with maternal UPD [Lin et al 2021].

Author Notes

Richard JH Smith, MD, is a pediatric otolaryngologist and human geneticist at the University of Iowa. He directs the Molecular Otolaryngology and Renal Research Laboratories (MORL), which offer comprehensive genetic testing for hearing loss. He is interested in collaborating with clinicians treating families affected by genetic hearing loss in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. He also is actively involved in research regarding individuals with GJB2-related autosomal recessive nonsyndromic hearing loss (GJB2-AR NSHL) and would be happy to communicate with persons who have any questions regarding diagnosis of GJB2-AR NSHL or other considerations. For questions about hearing loss and the diagnosis of GJB2-AR NSHL, email ude.awoiu@lrom. MORL website: morl.lab.uiowa.edu

Hela Azaiez, MS, PhD, is a human geneticist specializing in the molecular genetics and genomics of hearing loss at the Department of Otolaryngology at the University of Iowa. She is actively engaged in basic and translational research, with a focus on the genetic etiology of hearing loss. Her research aims to decode the molecular mechanisms of hearing and deafness, intending to translate this knowledge into improved clinical diagnostics and enhanced patient care. She also maintains a keen interest in collaborating with clinicians who treat families affected by genetic hearing loss, particularly when no causative variant has been identified through molecular genetic testing of known genes associated with hearing loss.

Acknowledgments

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

Author History

Hela Azaiez, MS, PhD (2023-present)
Kevin Booth, PhD (2023-present)
Mary-Kayt N Jones, BA; University of Iowa (2016-2023)
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

• 20 July 2023 (bp) Comprehensive update posted live
• 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
• 27 October 2003 (me) Comprehensive update posted live
• 24 April 2001 (me) Comprehensive update posted live
• 4 April 1998 (rjs) Original submission

Published Guidelines / Consensus Statements

• The Joint Committee on Infant Hearing. Year 2019 position statement: principles and guidelines for early hearing detection and intervention programs. Available online. Accessed 7-10-2023.

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