Clinical Diagnosis

Nonsyndromic hearing loss and deafness, DFNA3, is 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 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 dominant inheritance

Molecular Genetic Testing

Gene. GJB2, which encodes connexin 26, and GJB6, which encodes connexin 30, are the only two genes in which mutations are known to cause deafness at the DFNA3 locus.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Nonsyndromic Hearing Loss and Deafness, DFNA3

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% of All DFNA3	Gene Symbol	Test Method	Mutations Detected	Test Availability
>90%	GJB2	Sequence analysis / mutation scanning 1	Sequence variants 2, 3	Clinical
		Targeted mutation analysis	Specified sequence variants 4
		Deletion / duplication analysis 5	Exonic or whole-gene deletions / duplications 6
<10%	GJB6	Sequence analysis	Sequence variants 2, 7, 8	Clinical
		Targeted mutation analysis	Specified sequence variants 4
		Deletion / duplication analysis 5	Exonic or whole-gene deletions / duplications 6
Multi-gene hearing loss / deafness panel 9				Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Sequence analysis of GJB2 identifies 100% of mutations, including p.Trp44Cys, p.Trp44Ser, p.Asp46Asn, p.Thr55Asn, p.Pro58Ala, p.Arg75Gln, p.Arg75Trp, p.Arg143Gln, p.Met163Leu, p.Asp179Asn, p.Arg184Gln, and p.Cys202Phe, the ten mutations reported to segregate in persons with DFNA3 [Denoyelle et al 1998, Morlé et al 2000, Hamelmann et al 2001, Janecke et al 2001, Löffler et al 2001, Marziano et al 2003, Primignani et al 2003, Feldmann et al 2005, Melchionda et al 2005, Piazza et al 2005, Primignani et al 2007, Matos et al 2008, Bazazzadegan et al 2011].

4. Variants included in targeted panels may vary by laboratory.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

6. No deletions or duplications involving GJB2 or GJB6 as causative of DFNA 3 Nonsyndromic Hearing Loss and Deafness have been reported.

7. Reported in an Italian family by Grifa et al [1999] and a Taiwanese individual by Yang et al [2007].

8. Two mutations in GJB6, p.Thr5Met and p.Ala40Val, have been reported in one family and one individual with DFNA3 [Grifa et al 1999, Yang et al 2007].

9. The genes included and the methods used in multi-gene panels vary by laboratory.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A and/or Pathologic allelic variants).

Testing Strategy

Establishing the diagnosis in a proband. For individuals suspected of having DFNA3:

• Auditory tests should be followed by a thorough physical examination to exclude distinctive features, skin disease, eye disease, and any other phenotypes that can segregate with syndromic forms of hearing loss [Hilgert et al 2009].

Alternative 1. Single gene testing

• The first step in the genetic diagnosis of DFNA3 is sequence analysis of GJB2 exon 2.
• If no deafness-causing mutations are identified in GJB2, consider sequencing ofGJB6, with the caveat that only two reported DFNA3-causing pathologic variants of GBJ6 have been reported.
• See relevant ACMG ACT sheet and algorithm:
  • 
  • 

Alternative 2. Multi-gene testing

• Consider using a multi-gene hearing loss / deafness panel that includes GJB2 and GJB6 as well as a number of genes associated with disorders associated with hearing loss described in Differential Diagnosis. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual also varies. For laboratories offering hearing loss / deafness panels, see [Shearer et al 2011].

Predictive testing for at-risk asymptomatic family members requires prior identification of the deafness-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deafness-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Other phenotypes associated with mutations in GJB2 and GJB6 include the following:

Natural History

Nonsyndromic hearing loss and deafness, DFNA3, is characterized by childhood-onset, progressive, moderate-to-severe high-frequency sensorineural hearing impairment. The audioprofile may vary significantly, even among family members. Individuals with DFNA3 have no other associated medical findings.

GJB2. The twelve missense mutations of GJB2 (p.Trp44Cys, p.Trp44Ser, p.Asp46Asn, p.Thr55Asn, p.Pro58Ala, p.Arg75Gln, p.Arg75Trp, p.Arg143Gln, p.Met163Leu, p.Asp179Asn, p.Arg184Gln, and p.Cys202Phe) that cause deafness at the DFNA3 locus are associated with at least two different audioprofiles based on age of onset.

The majority of DFNA3-causing mutations cause prelingual hearing loss (p.Trp44Cys, p.Pro58Ala, p.Arg75Gln, p.Arg75Trp, p.Arg143Gln and p.Arg184Gln):

• The p.Trp44Cys 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.
• Hearing loss related to the p.Pro58Ala mutation is progressive, ranging from mild to severe.
• The hearing loss associated with the p.Arg75Gln and p.Arg75Trp mutations is usually profound (average threshold for p.Arg75Gln is 105 dbHL).
• Individuals with the p.Arg143Gln mutation show a progressive profound high-frequency hearing loss.
• Audioprofiles for individuals with the c.551G>A (p.Arg184Gln) mutation 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 mutations resulting in the substitutions p.Thr55Asn, p.Asp179Asn and p.Cys202Phe is postlingual:

• Audioprofiles of individuals with the c.164C>A (p.Thr55Asn) mutation have a downsloping pattern and are consistent with a severe-to-profound postlingual hearing loss.
• Age of onset for hearing loss in individuals with the p.Asp179Asn mutation ranges from the first to the third decade. The audioprofile shows a mild-to-moderate hearing loss, particularly at high frequencies.
• Hearing loss in individuals with the p.Cys202Phe mutation 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:

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

GJB6. The p.Thr5Met mutation in GJB6 has been reported in one family. The audioprofile of this family 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.

The p.Ala40Val substitution in GJB6 has been identified in one individual with autosomal dominant nonsyndromic hearing loss; the audioprofile and age of onset were not reported [Grifa et al 1999, Yang et al 2007, Wang et al 2011].

Tests of vestibular function and computed tomography of the temporal bones in persons segregating these mutations have been normal [Denoyelle et al 2002].

Genotype-Phenotype Correlations

See Natural History.

Penetrance

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

Anticipation

Genetic anticipation has not been observed with DFNA3.

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. To date, 14 DFNA3-causing mutations have been described worldwide. The majority of these mutations 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 mutations varies by population [Abe et al 2000, Hamelmann et al 2001, Löffler et al 2001, Liu et al 2002, Xiao & Xie 2004].

Evaluations Following Initial Diagnosis

The following are recommended following diagnosis of nonsyndromic hearing loss and deafness, DFNA3:

• Complete assessment of auditory acuity using age-appropriate tests including ABR testing, auditory steady-state response (ASSR) testing, and/or pure tone audiometry
• Medical genetics consultation

Treatment of Manifestations

The following are indicated:

• Fitting with appropriate hearing aids
• Enrollment in an appropriate educational program for the hearing impaired
• Consideration of cochlear implantation, a promising habilitation option for persons with profound deafness [Connell et al 2007]
• 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]

Prevention of Secondary Complications

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

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

Molecular genetic testing is recommended for at-risk relatives of individuals with a known DFNA3-causing mutation. Individuals with known deafness-causing mutations should be followed semiannually by a physician who is familiar with hereditary hearing impairment.

Recommendations for the evaluation of at-risk family members when molecular genetic testing is unavailable include pure tone audiometry to assess auditory acuity and review of medical history and physical examination to rule out other systemic findings.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In mice deafened by expression of the p.Arg75Trp allelic variant of GJB2, RNA interference can prevent the development of hearing loss [Maeda et al 2005].

Search ClinicalTrials.gov 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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 family history is rarely negative.
• A proband with DFNA3 may have the condition as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is very small.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include assessment of auditory acuity using ABR emission testing and pure tone audiometry and medical history and physical examination to rule out other systemic findings.

Sibs of a proband

• The risk to sibs depends on the genetic status of the proband's parents.
• If one of the proband's parents has a deafness-causing allele, each sib has a 50% chance of inheriting the mutant allele.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• If a mutation causing DFNA3 cannot be detected in the DNA extracted from leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Offspring of an affected individual have a 50% chance of inheriting the mutant allele.

Other family members of a proband

• The risk to other family members depends on the status of the proband's parents.
• If a parent is deaf, his or her family members are at risk.

Related Genetic Counseling Issues

Establishing in infancy or early childhood whether a child at risk has inherited the altered GJB2 or GJB6 allele should be considered so that appropriate and early support and management can be provided to the child and the family. Molecular genetic testing for the mutation can only be considered if a deafness-causing mutation has been identified in an affected family member. Additional points to consider are the following:

• Communication with individuals who are deaf requires the services of a skilled interpreter.
• Deaf persons may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." In fact, having a deaf child may be preferred over having a child with normal hearing.
• Many deaf people are interested in obtaining information about the cause of their own deafness including information on medical, educational, and social services rather than information about prevention, reproduction, or family planning. As in all genetic counseling, it is important for the counselor to identify, acknowledge, and respect the individual's/family's questions, concerns, and fears.
• The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "affected," "abnormal," and "disease causing" should be avoided.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are deaf.

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

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing for pregnancies at 50% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The mutation in GJB2 or GJB6 causing DFNA3 in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as DFNA3 are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the deafness-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Published Guidelines/Consensus Statements

1. American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. (pdf) Available online. 2002. Accessed 2-27-13. [PMC free article: PMC3110944] [PubMed: 12180152]
2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 2-27-13.

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Suggested Reading

1. Nickel R, Forge A. Gap junctions and connexins in the inner ear: their roles in homeostasis and deafness. Curr Opin Otolaryngol Head Neck Surg. 2008;16:452–7. [PubMed: 18797288]
2. Zhao HB, Kikuchi T, Ngezahayo A, White TW. Gap junctions and cochlear homeostasis. J Membr Biol. 2006;209:177–86. [PMC free article: PMC1609193] [PubMed: 16773501]

Acknowledgments

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

Author History

Daryl A Scott, MD, PhD; University of Iowa (1998-2001)
Abraham M Sheffield (2009-present)
Val C Sheffield, MD, PhD; University of Iowa (1998-2001)
Richard JH Smith, MD (1998-present)
Guy Van Camp, PhD (1998-present)

Revision History

• 19 April 2012 (me) Comprehensive update posted live
• 30 April 2009 (me) Comprehensive update posted live
• 29 December 2005 (me) Comprehensive update posted to live Web site
• 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