Clinical characteristics.

Nonsyndromic hearing loss and deafness, DFNA3 is characterized by pre- or postlingual mild-to-profound progressive high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings.

Diagnosis/testing.

Diagnosis of DFNA3 depends on molecular genetic testing to identify a heterozygous pathogenic variant in GJB2 (encoding connexin 26 [Cx26]) or GJB6 (encoding connexin 30 [Cx30]).

Management.

Treatment of manifestations: Early diagnosis, habilitation with hearing aids or cochlear implantation, and educational programming diminishes the likelihood of long-term speech or educational delay.

Surveillance: Semiannual examination by a physician who is familiar with hereditary hearing impairment; repeat audiometry to confirm stability of hearing loss

Agents/circumstances to avoid: Environmental exposures known to cause hearing loss, such as repeated loud noises.

Evaluation of relatives at risk: Once the GJB2 or GJB6 pathogenic variant has been identified in an affected family member, molecular genetic testing can be used to clarify the genetic status of at-risk relatives in infancy or early childhood so that appropriate early support and management can be provided.

Genetic counseling.

DFNA3 is inherited in an autosomal dominant manner. Most individuals diagnosed as having DFNA3 have a deaf parent. Each child of an individual with DFNA3 has a 50% chance of inheriting the GJB2 or GJB6 pathogenic variant. Once the GJB2 or GJB6 pathogenic variant has been identified in a family member with DFNA3, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Nonsyndromic hearing loss and deafness, DFNA3 should be suspected in individuals with the following:

• Pre- or postlingual mild-to-profound progressive sensorineural hearing impairment [Denoyelle et al 2002]
  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 15 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 (71-90dB), or profound (>90dB). The frequency of hearing loss is designated as low (<500Hz), middle (501-2000Hz), or high (>2000Hz) (see Genetic Hearing Loss Overview).
• No related systemic findings identified by medical history and physical examination
• A family history of nonsyndromic hearing loss consistent with autosomal dominant inheritance

Establishing the Diagnosis

The diagnosis of DFNA3 is established in a proband by detection of a heterozygous pathogenic (or likely pathogenic) variant in GJB2 (encoding connexin 26) or GJB6 (encoding connexin 30) (see Table 1).

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]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous GJB2 or GJB6 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches in a person with hearing loss documented on audiogram can include a combination of gene-targeted testing (single-gene testing), multigene panels (including all genes implicated in nonsyndromic hearing loss), or genomic testing (e.g., exome or 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: a multigene panel of ALL genes implicated in nonsyndromic hearing loss and nonsyndromic mimics (recommended) or exome/genome sequencing (to consider).

Recommended Testing

A comprehensive deafness-specific multigene panel that includes all genes implicated in nonsyndromic hearing loss and nonsyndromic hearing-loss mimics (see Differential Diagnosis and Genetic Hearing Loss Overview) is recommended as the initial test in the evaluation of hearing loss following an audiogram that has documented the hearing loss [Sloan-Heggen et al 2016] (Figure 1).

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 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 is most likely 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. (4) All platforms used to identify deafness-causing genetic variants should include detection of copy number variants in the testing algorithm [Shearer et al 2014b].

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Nonsyndromic hearing loss and deafness, DFNA3 is characterized by progressive mild-to-severe high-frequency sensorineural hearing impairment (Figure 2). GJB2-related DFNA3 is associated with prelingual and postlingual onset of hearing loss while GJB6-related DFNA3 is associated with prelingual hearing loss [Weegerink 2013].

Figure 2.

This audioprofile surface shows the anticipated progression of DFNA3 hearing loss with age. Note that the hearing loss is typically congenital and slowly becomes more severe with age [Taylor et al 2016].

DFNA3 audioprofiles (visual plots of hearing loss severity across a range of frequencies measured by pure tone audiometry) may vary significantly, even within a family. Note that when the hearing loss is postlingual, individuals with DFNA3 may pass the newborn hearing screen.

Tests of vestibular function and computed tomography of the temporal bones in persons with DFNA3 are normal [Denoyelle et al 2002].

Individuals with DFNA3 have no other associated medical findings.

Phenotype Correlations by Gene

GJB2. The twelve pathogenic missense variants of GJB2 (Table 3) that cause deafness at the DFNA3 locus are associated with at least two different audioprofiles based on age of onset.

The majority of pathogenic variants cause progressive prelingual hearing loss (Figure 2):

• p.Trp44Cys. The audioprofile is characterized by a bilaterally symmetric sensorineural loss that varies from mild to profound, beginning with high-frequency hearing loss and progressing to loss at all frequencies.
• p.Pro58Ala. Hearing loss is progressive, ranging from mild to severe.
• p.Arg75Gln and p.Arg75Trp. Hearing loss is usually profound (average threshold for p.Arg75Gln is 105 dbHL).
• p.Arg143Gln. Progressive and profound high-frequency hearing loss is observed.
• c.551G>A (p.Arg184Gln). Audioprofiles are downsloping and consistent with severe-to-profound prelingual hearing loss [Janecke et al 2001, Löffler et al 2001, Tekin et al 2001, Denoyelle et al 2002, Feldmann et al 2005, Primignani et al 2007, Weegerink et al 2011].

In contrast, deafness related to the pathogenic variants resulting in the substitutions p.Thr55Asn, p.Asp179Asn, and p.Cys202Phe is postlingual:

• c.164C>A (p.Thr55Asn). Audioprofiles have a downsloping pattern and are consistent with a severe-to-profound postlingual hearing loss.
• p.Asp179Asn. Age of onset for hearing loss ranges from the first to the third decade. The audioprofile shows a mild-to-moderate hearing loss, particularly at high frequencies.
• p.Cys202Phe. Hearing loss is usually not detected until the second decade. Initially, the loss preferentially affects the high frequencies but progresses to affect the middle frequencies by middle age [Morlé et al 2000, Denoyelle et al 2002, Primignani et al 2003, Melchionda et al 2005].

Other:

• p.Trp44Ser. Audioprofiles are not available.
• p.Asp46Asn. Audioprofiles show intrafamilial variability with some individuals showing postlingual progressive hearing loss with onset in the first decade of life and some showing prelingual hearing loss.
• p.Met163Leu. A mild-to-moderate high-frequency hearing loss is observed; age of onset was not reported [Hamelmann et al 2001, Marziano et al 2003, Matos et al 2008, Bazazzadegan et al 2011].

GJB6 ( Table 4 )

• p.Thr5Met. The audioprofile of the one family reported [Grifa et al 1999] is characterized by middle- to high-frequency hearing loss. The degree of hearing loss is progressive and variable, ranging from mild to profound. The age of onset of hearing loss was not reported - and in the absence of linkage data, these results should be interpreted with caution [Friedman & Griffith 2003].
• p.Ala40Val. The audioprofile and age of onset were not included in the one reported individual [Yang et al 2007, Wang et al 2011].

Penetrance

GJB2 and GJB6 pathogenic variants that cause DFNA3 are fully penetrant.

Nomenclature

The different gene loci for nonsyndromic deafness are designated DFN (for deafness).

Loci are named based on mode of inheritance:

• DFNA. Autosomal dominant
• DFNB. Autosomal recessive
• DFN. X-linked

The number following the above designations reflects the order of gene mapping and/or discovery.

Prevalence

The relative prevalence of DFNA3 as a cause of autosomal dominant nonsyndromic hearing loss is not known, but it is extremely rare [Sloan-Heggen et al 2016]: 14 pathogenic variants have been described worldwide. The majority of these pathogenic variants are described only in single families or simplex cases (i.e., a single occurrence in a family) [Denoyelle et al 2002, Hilgert et al 2009].

Prevalence for different pathogenic variants varies by population [Abe et al 2000, Hamelmann et al 2001, Löffler et al 2001, Liu et al 2002, Shearer et al 2014a, Xiao & Xie 2004].

GJB2

DFNB1 is characterized by (generally) moderate-to-severe sensorineural impairment.

GJB2 is shared by an overlapping locus, DFNB1, which is associated with autosomal recessive nonsyndromic hearing loss. Variants in GJB2 may cause either autosomal dominant DFNA3-associated or autosomal recessive DFNB1-associated nonsyndromic hearing loss and deafness. The mode of inheritance is ultimately determined by how the variant affects the expression and function of the connexin 26 protein.

Palmoplantar keratoderma with deafness is characterized by diffuse hyperkeratosis of the hands and feet [Richard et al 1998, Heathcote et al 2000, Feldmann et al 2005, de Zwart-Storm et al 2008].

Keratitis-ichthyosis-deafness (KID) and hystrix-like ichthyosis-deafness (HID) syndromes are associated with the same pathogenic variant (p.Asp50Asn) in the first extracellular domain of the GJB2-encoded protein connexin 26 [van Geel et al 2002].

• Keratitis-ichthyosis-deafness (KID) syndrome is an ectodermal dysplasia characterized by 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 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 manifestations; (2) the severity of keratitis; and (3) electron microscopic features.

Vohwinkel syndrome is classified as a "mutilating" diffuse keratoderma because circumferential hyperkeratosis of the digits can lead to autoamputation (termed "pseudoainhum"). Mild-to-moderate sensorineural hearing loss is often associated with the disease.

Bart-Pumphrey syndrome is characterized by palmoplantar keratoderma, knuckle pads, leukonychia, and sensorineural hearing loss. The clinical features partially overlap with Vohwinkel syndrome and KID syndrome.

Other. With the GJB2 pathogenic variants in which the epidermal disease and hearing loss cosegregate, the severity of the skin disease phenotype is highly variable, suggesting that other factors modify gene expression [Kelsell et al 2001, Feldmann et al 2005]. It is important to clinically assess each individual with autosomal dominant hearing loss for any syndromic features, which may be subtle or easily overlooked in affected relatives.

GJB6

Hidrotic ectodermal dysplasia 2 (Clouston syndrome) is characterized by hidrotic ectodermal dysplasia, alopecia, and palmoplantar hyperkeratosis [Smith et al 2002].

Evaluations Following Initial Diagnosis

To establish the extent of involvement and needs in an individual diagnosed with nonsyndromic hearing loss, DFNA3, the following evaluations are recommended:

• Complete assessment of auditory acuity using age-appropriate tests including ABR testing, auditory steady-state response (ASSR) testing, and/or pure tone audiometry (See Genetic Hearing Loss Overview.)
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Early diagnosis, habilitation with hearing aids or cochlear implantation, and educational programming will diminish the likelihood of long-term speech or educational delay.

The following are indicated:

• Fitting with appropriate hearing aids
• Enrollment in an appropriate educational program for the hearing impaired
• Consideration of cochlear implantation, an effective habilitation option for persons with preserved residual hearing [Gantz et al 2016]
• Recognition that unlike with many clinical conditions, management and treatment of mild-to-profound deafness fall largely within the purview of the social welfare and educational systems rather than the medical care system [Smith et al 2005]

See Genetic Hearing Loss Overview for more detailed discussion of management issues.

Surveillance

The following are appropriate:

• Semiannual examination by a physician who is 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 is avoidance of repeated exposure to loud noises.

Evaluation of Relatives at Risk

If a GJB2 or GJB6 pathogenic variant has 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 access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be human trials for this condition.

Mode of Inheritance

Nonsyndromic hearing loss and deafness, DFNA3 is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed as having DFNA3 have a deaf parent.
• The proportion of individuals with DFNA3 caused by a de novo GJB2 or GJB6 pathogenic variant is very small.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include (a) genetic testing to validate the de novo nature of the identified variant; (b) assessment of auditory acuity in the parents; and (c) medical history and physical examination to rule out other systemic findings in the family.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. While theoretically possible, germline mosaicism has not been reported.

Sibs of a proband

• The likelihood that a sib will have DFNA3 depends on the genetic status of the proband's parents: if one of the proband's parents has a GJB2 or GJB6 pathogenic variant, each sib has a 50% chance of inheriting the pathogenic variant.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If the GJB2 or GJB6 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with DFNA3 has a 50% chance of inheriting the GJB2 or GJB6 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is deaf, the parent's family members may also have DFNA3.

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. It is, therefore, important to ascertain and address the questions and concerns of the family/individual.
• 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 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 deafness in offspring and reproductive options) to young adults who are deaf.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the condition, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Prenatal Testing and Preimplantation Genetic Testing

Once the GJB2 or GJB6 pathogenic variant has been identified in a family member with DFNA3, prenatal and preimplantation genetic testing 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.

GJB2

Gene structure. Most connexin genes have a common architecture, with the entire coding region contained in a single large exon separated from the 5'-untranslated region by an intron of variable size. The coding sequence of GJB2 (exon 2) is 681 base pairs (including the stop codon) and is translated into a 226-amino acid protein, connexin 26 (Cx26). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Twelve pathogenic variants in GJB2 are known (see Table 3). The majority segregate in families; however, the p.Arg75Gln and p.Arg75Trp variants have also been identified as de novo variants in simplex cases (i.e., a single occurrence in a family). These two variants are implicated in both autosomal dominant nonsyndromic hearing loss and syndromic hearing loss associated with skin disorders (see Genetically Related Disorders) [Janecke et al 2001, Feldmann et al 2005].

Of note, although the pathogenicity of the p.Arg75Trp variant had been questioned as it was reported in one of 77 Egyptian controls whose hearing status was not reported [Richard et al 1998], subsequent case reports, animal models, and functional studies strongly argue for the pathogenicity of this variant [Janecke et al 2001, Kudo et al 2003, Maeda et al 2005, Maeda et al 2009, Mani et al 2009, Yum et al 2010, Weegerink et al 2011, Zhang et al 2011].

Normal gene product. Connexin 26 (Cx26) is a beta-2 gap junction protein. Gap junctions are highly specialized organelles consisting of clustered channels that permit direct intercellular exchange of ions and molecules through central aqueous pores. Postulated roles include: the rapid propagation of electrical signals and synchronization of activity in excitable tissues; and the exchange of metabolites and signal molecules in non-excitable tissues [Evans & Martin 2002].

Each connexin protein contains two extracellular (E1-E2), four transmembrane (M1-M4), and three cytoplasmic domains (N-terminus, C-terminus, and a cytoplasmic loop located between M2 and M3) [Maeda et al 2009]. Each extracellular domain contains three cysteine residues joined between the E1 and E2 loops by at least one disulfide bond [Kovacs et al 2007, Yeager & Harris 2007]. The presumed importance of these six cysteines can be inferred from Cx32 experiments in which any Cys pathogenic variant completely blocks the development of gap-junction conductances between Xenopus oocyte pairs. The third transmembrane domain (M3) is amphipathic and lines the putative wall of the intercellular channel [Kovacs et al 2007, Yeager & Harris 2007], which is created by oligomerization of six connexins to form a hexameric structure called a connexon. Two connexons, one from each cell, join in the extracellular gap to complete the cell-to-cell pathway. If the connexons contributed by each cell are of identical composition, the channel is homotypic; if each connexon is formed by a different composition of connexins, it is termed heterotypic. Most connexins are phosphoproteins and undergo post-transcriptional modifications [Moreno 2005, Locke et al 2006]. Cx26 forms functional combinations with itself, Cx30, Cx31, Cx32, Cx46, and Cx50 [Cottrell & Burt 2005, Liu et al 2009].

Abnormal gene product. Gap-junction channels are permeable to ions and small metabolites with relative molecular masses up to approximately 1.2 kd [Harris & Bevans 2001]. Differences in ionic selectivity and gating mechanisms among gap junctions reflect the existence of more than 20 different connexin isoforms in humans. The abnormal gene product in DFNA3 causes deafness via a dominant-negative mechanism of action.

GJB6

Gene structure. GJB6 has three exons, of which only the third is coding. The translated protein, connexin 30 (Cx30), is 261 amino acids long. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Two GJB6 DFNA3-causing pathogenic variants are known: p.Thr5Met and p.Ala40Val [Grifa et al 1999, Yang et al 2007] (see Table 4).

Normal gene product. Connexin 30 (Cx30) is a beta-6 gap junction protein. It shares an architecture that is common to all connexins (see GJB2, Normal gene product).

Abnormal gene product. Like the abnormal gene products of GJB2-related DFNA3, the p.Thr5Met and p.Ala40Val variants of GJB6-related DFNA3 act via a dominant-negative mechanism to inhibit activity of wild-type Cx30 gap junction channels.

Additionally, the p.Ala40Val variant exerts a trans-dominant-negative effect on Cx26, impairing gap junction formation in the cochlea.

In functional studies with a mouse model, the p.Thr5Met variant was shown to exert its pathogenic effect through diminished biochemical coupling between cochlear cells [Grifa et al 1999, Schütz et al 2010, Wang et al 2011].

Acknowledgments

This work was originally supported in part by research grants 1RO1 DC02842 and DC003544 (RJHS), HG00457 and P50HG00835 (VCS), and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC).

Author History

Paul T Ranum, BA (2014-present)

Daryl A Scott, MD, PhD; University of Iowa (1998-2001)

Abraham M Sheffield, MD; University of Iowa (2009-2014)

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

• 7 September 2023 (ma) Chapter retired: outdated
• 22 December 2016 (bp) Comprehensive update posted live
• 12 June 2014 (me) Comprehensive update posted live
• 19 April 2012 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 29 December 2005 (me) Comprehensive update posted live
• 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

Published Guidelines / Consensus Statements

• American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available online. 2002. Accessed 8-18-23.
• American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 8-18-23.

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