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DFNA2 Nonsyndromic Hearing Loss

, MD and , PhD.

Author Information

Initial Posting: ; Last Update: August 20, 2015.

Summary

Clinical characteristics.

DFNA2 nonsyndromic hearing loss is characterized by symmetric, predominantly high-frequency sensorineural hearing loss (SNHL) that is progressive across all frequencies. At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies; in older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. Although the hearing impairment is often detected during routine hearing assessment of a school-age child, it is likely that hearing is impaired from birth, especially at high frequencies. Most affected persons initially require hearing aids to assist with sound amplification between ages ten and 40 years. By age 70 years, all persons with DFNA2 nonsyndromic hearing loss have severe-to-profound hearing impairment.

Diagnosis/testing.

The diagnosis of DFNA2 nonsyndromic hearing loss is established in an individual with a characteristic audioprofile, a family history consistent with autosomal dominant inheritance, and identification of a deafness-related variant in KCNQ4.

Management.

Treatment of manifestations: Hearing aids for those with mild-to-moderate hearing loss; consideration of cochlear implants when hearing loss is severe to profound; special assistance in school for hearing-impaired children and adolescents.

Surveillance: At least annual audiogram to follow progression of hearing loss.

Agents/circumstances to avoid: Avoiding exposure to loud noise may reduce the rate of progression of high-frequency SNHL.

Evaluation of relatives at risk: Determining in infancy or early childhood whether a family member of the proband has inherited a deafness-related variant in KCNQ4 allows early support and management of the child and family.

Genetic counseling.

DFNA2 nonsyndromic hearing loss is inherited in an autosomal dominant manner. Most individuals with DFNA2 nonsyndromic hearing loss have a parent with hearing loss; the proportion of individuals with a de novo deafness-related variant is unknown. Each child of an individual with DFNA2 nonsyndromic hearing loss has a 50% chance of inheriting the deafness-related variant. Prenatal testing for pregnancies at increased risk is possible if the KCNQ4 deafness-related variant has been identified in a family member.

Diagnosis

Suggestive Findings

DFNA2 nonsyndromic hearing loss should be suspected in an individual with:

  • Symmetric, predominantly high-frequency sensorineural hearing loss (SNHL) that is progressive across all frequencies:
    • At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies.
    • In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies.
  • Normal physical examination
  • Family history of hearing loss consistent with autosomal dominant inheritance
  • Temporal bone imaging (i.e., CT of the inner ears) is normal. Specifically, abnormalities such as dilation of the vestibular aqueducts (also known as enlarged vestibular aqueducts) and Mondini dysplasia should be absent.

Establishing the Diagnosis

The diagnosis of DFNA2 nonsyndromic hearing loss is established in a proband with the above characteristic audioprofile and identification of a heterozygous deafness-related variant in KCNQ4 on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of KCNQ4 is performed first followed by gene-targeted deletion/duplication analysis if no deafness-related variant is found.
  • A multi-gene panel that includes KCNQ4 and other genes of interest (see Differential Diagnosis) may also be considered [Kothiyal et al 2010, Shearer et al 2010, Shearer & Smith 2015]. Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • More comprehensive genomic testing (when available) including whole-exome sequencing (WES), whole mitochondrial sequencing (WMitoSeq), and whole-genome sequencing (WGS) may be considered if serial single-gene testing (and/or use of a multi-gene panel that includes KCNQ4) fails to confirm a diagnosis in an individual with features of DFNA2 nonsyndromic hearing loss. For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in DFNA2 Nonsyndromic Hearing Loss

Gene 1Test MethodProportion of Probands with a Deafness-Related Variant 2 Detectable by This Method
KCNQ4Sequence analysis 3100% 4
Gene-targeted deletion/duplication analysis 5Unknown 6
1.
2.

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

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely deafness-related, or deafness related. Deafness-related 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.

4.

Sequence analysis detects deafness-related variants in KCNQ4 in virtually all individuals with autosomal dominant nonsyndromic sensorineural hearing loss that maps to the DFNA2 locus.

5.

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

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

All families with DFNA2 nonsyndromic hearing loss have symmetric, predominantly high-frequency hearing loss that is progressive across all frequencies. A comprehensive review of the clinical presentation and prognosis of individuals diagnosed with DFNA2 nonsyndromic hearing loss has been provided by De Leenheer et al [2002a].

Onset of hearing loss is generally reported in early childhood or adolescence; however, it is likely that hearing is impaired from birth, especially at the high frequencies. The hearing loss is often detected during standard hearing assessment of a school-age child or less frequently during the evaluation of a child for delayed speech development.

In all affected individuals the hearing loss is more severe at the high frequencies, resulting in a characteristic downsloping audioprofile with hearing thresholds between 50 and 90 dB at 500 Hz and between 90 and 120 dB at 2 kHz and 4 kHz by age 50 years. A typical audiogram of an adolescent with DFNA2 nonsyndromic hearing loss is shown in Figure 1.

Figure 1. . Audiogram from a 12-year-old with DFNA2 hearing loss Note that the loss is greater in the high frequencies.

Figure 1.

Audiogram from a 12-year-old with DFNA2 hearing loss Note that the loss is greater in the high frequencies. With time, hearing at all frequencies progressively deteriorates.

Whereas onset age varies within families, deterioration of annual thresholds for families with DFNA2 nonsyndromic hearing loss has been calculated at a relatively uniform ~1 dB/year [Coucke et al 1999, Talebizadeh et al 1999, Ensink et al 2000, Van Hauwe et al 2000, Akita et al 2001, De Leenheer et al 2002a, De Leenheer et al 2002b, Van Camp et al 2002]. Most persons with DFNA2 nonsyndromic hearing loss are first fitted with hearing aids to assist with sound amplification between ages ten and 40 years [De Leenheer et al 2002a]. By age 70 years, all persons with hearing loss attributed to a deafness-related variant in KCNQ4 have severe-to-profound hearing loss.

Other findings

  • Vestibular function. Thirty percent of individuals in two families with DFNA2 nonsyndromic hearing loss (Dutch families 1 and 4; Table 3) had increased vestibulo-ocular reflex activity [Marres et al 1997, De Leenheer et al 2002b]. Vestibular problems have not been observed in any other families with DFNA2 nonsyndromic hearing loss.
  • Speech recognition scores. When measured in several Dutch families, speech recognition scores were relatively good given the pure-tone thresholds [De Leenheer et al 2002b, Van Camp et al 2002].

Genotype-Phenotype Correlations

The phenotype associated with KCNQ4 deafness-related missense variants is similar in all families: predominantly high-frequency sensorineural hearing loss (SNHL) that is detectable in childhood and progressive across all frequencies. At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies.

The phenotype associated with KCNQ4 truncating variants differs from that associated with KCNQ4 deafness-related missense variants. In two families, small frameshift deletions of KCNQ4 (c.211_223del and c.211delC) are predicted to result in a profoundly truncated protein that either does not interact with normal protein translated from the normal allele or may not remain in cells as a result of nonsense-mediated decay. The hearing loss associated with this dosage effect is milder in low and mid-frequencies, more severe in high frequencies, and later in onset than the hearing loss seen with deafness-related missense variants [Coucke et al 1999, Akita et al 2001].

Penetrance

The penetrance is complete. All individuals with a KCNQ4 deafness-related variant exhibit the hearing loss phenotype; onset age and severity are variable.

Prevalence

No data on prevalence of DFNA2 among families segregating autosomal dominant nonsyndromic hearing loss (ADNSHL) are available. Anecdotally, however, deafness-related variants in KCNQ4 are thought to account for up to 5% of ADNSHL [R Smith, personal communication].

Differential Diagnosis

See Deafness and Hereditary Hearing Loss Overview for complete differential diagnosis.

Because variants in KCNQ4 are a relatively common cause of high-frequency autosomal dominant nonsyndromic hearing loss (ADNSHL), KCNQ4 should be among the first genes tested in families with this type of hearing impairment.

Variants in the following genes also cause high-frequency ADNSHL:

  • GJB3 (DFNA3)
  • COCH (DFNA9)
  • POU4F3 (DFNA15)

Management

Evaluations Following Initial Diagnosis

To establish the extent of hearing loss and needs in an individual diagnosed with DFNA2 nonsyndromic hearing loss, the following are recommended:

  • Audiometry, including bone conduction testing
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

When hearing loss is mild to moderate, fitting of hearing aids to provide improved amplification is warranted.

When the hearing loss becomes severe to profound, cochlear implants (CIs) can be considered. In individuals with preserved or relatively good low-frequency hearing and severe-to-profound high-frequency loss, a short electrode may be considered. Short electrodes boost the high frequencies while preserving residual low-frequency hearing.

For school-age children or adolescents, special assistance for the hearing impaired may be warranted and, where available, should be offered.

Surveillance

Audiograms should be obtained on an annual basis to follow progression of hearing loss.

Agents/Circumstances to Avoid

The rate of progression of high-frequency hearing loss can be reduced by encouraging individuals with DFNA2 nonsyndromic hearing loss to avoid exposure to loud noise in the workplace and during recreation.

Evaluation of Relatives at Risk

Determining in infancy or early childhood whether a relative of a person with DFNA2 nonsyndromic hearing loss has inherited the KCNQ4 deafness-related variant allows for early support and management of the child and the family.

Evaluations may include:

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this condition.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DFNA2 nonsyndromic hearing loss is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with DFNA2 nonsyndromic hearing loss have a deaf parent.
  • A proband with DFNA2 nonsyndromic hearing loss may have deafness as the result of a de novo KCNQ4 variant. The proportion of individuals with a de novo KCNQ4 deafness-related variant is unknown.
  • If the deafness-related variant found in the proband cannot be detected in the leukocyte DNA of either parent, two possible explanations are a de novo deafness-related variant in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo deafness-related variant include audiometry and molecular genetic testing. Evaluation of parents may determine that one has hearing loss but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with DFNA2 nonsyndromic hearing loss have a deaf parent, in addition to failure to recognize hearing loss in family members, the family history may appear to be negative because of early death of the parent before the onset of hearing loss or late onset of hearing loss in a parent. (2) If the parent is the individual in whom the deafness-related variant first occurred, s/he may have somatic mosaicism for the deafness-related variant and have mild hearing loss.

Sibs of a proband. The probability that the sibs of the proband will be deaf depends on the genetic status of the proband's parents:

  • If a parent of the proband is deaf, each sib has a 50% chance of being deaf.
  • When the parents are hearing, the probability that a sib of the proband will be deaf appears to be low.
  • If the deafness-related variant found in the proband cannot be detected in the leukocyte DNA of either parent, the probability that a sib will be deaf is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with DFNA2 nonsyndromic hearing loss has a 50% chance of inheriting the deafness-related variant.

Other family members of a proband. The probability of deafness in other family members depends on the status of the proband's parents: if a parent is deaf, his or her family members may also be deaf or develop deafness.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating relatives of a proband for the purpose of early diagnosis and management.

Additional points to consider are the following:

  • Communication with individuals who are deaf requires the services of a skilled interpreter.
  • Some deaf persons may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition to be "prevented" or requiring a "treatment" or "cure." In fact, for some deaf individuals, having a deaf child may be preferred over having a child with normal hearing. Attitudes and preferences can vary depending on the type of hearing loss, personal experiences, and the communities with which individuals identify.
  • 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.

Considerations in families with an apparent de novo variant. When neither parent of a proband with DFNA2 nonsyndromic hearing loss has the deafness-related variant or clinical evidence of deafness, it is likely that the proband has a de novo variant. However, possible non-medical explanations could be explored including alternate paternity or maternity (i.e., with assisted reproduction) or undisclosed adoption.

Family planning

  • The optimal time for determination of genetic status and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of the probability that offspring will be deaf and reproductive options) to young adults who have DFNA2 nonsyndromic hearing loss.

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, allelic variants, and deafness will improve in the future, consideration should be given to banking DNA of individuals with DFNA2 nonsyndromic hearing loss.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the KCNQ4 deafness-related variant has been identified in a family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for DFNA2 nonsyndromic hearing loss are possible options.

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.

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.

  • National Library of Medicine Genetics Home Reference
  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org

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.

DFNA2 Nonsyndromic Hearing Loss: Genes and Databases

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

Table B.

OMIM Entries for DFNA2 Nonsyndromic Hearing Loss (View All in OMIM)

600101DEAFNESS, AUTOSOMAL DOMINANT 2A; DFNA2A
603537POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 4; KCNQ4

KCNQ4

Gene structure. KCNQ4 has a transcript length of 2,335 base pairs. The transcript consists of 14 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Variants of uncertain clinical significance. Two allelic variants that result in synonymous amino acid changes are of uncertain clinical significance (see Table 2). These nucleotide variants were detected on a screen of 185 individuals with nonsyndromic hearing loss. These individuals were reported as having nonsyndromic hearing loss; no information regarding family history was provided.

Table 2.

Selected KCNQ4 Variants of Uncertain Clinical Significance

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Protein DomainPopulationOnset of Symptoms 2Reference
c.648C>Tp.= 3
(Arg216Arg)
S4 transmembrane domainTaiwaneseChildhoodSu et al [2007]
c.1503C>Tp.= 3
(Thr501Thr)
Distal to S6 transmembrane domain

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Pathology was high-frequency hearing impairment and tissue-specific expression was in cochlear outer hair cells and brain for all deafness-related variants described in the table.

3.

For these variants, "p.=" indicates that no effect on protein level is expected.

Pathogenic allelic variants. Most deafness-related variants cluster in exons 5, 6, and 7 of KCNQ4. These exons encode highly conserved amino acid sequences that form the channel pore. The predominant deafness-related variants are missense variants that induce a dominant-negative effect. The p.Trp276Ser deafness-related variant appears to be most common and has been identified in four unrelated families, including three of five Dutch families with DFNA2 nonsyndromic hearing loss (see Table 3). The fourth family is Japanese. Congenital onset of DFNA2 nonsyndromic hearing loss has been reported in one of the Dutch families with the p.Trp276Ser variant [De Leenheer et al 2002b, Van Camp et al 2002], but not in other families with this deafness-related variant. The high-frequency hearing loss in this family was progressive without substantial loss of speech recognition during the first decades of life [De Leenheer et al 2002b].

Table 3.

Selected KCNQ4 Deafness-Related Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Protein DomainPopulationOnset of Symptoms 2Reference
c.211_223del13
(211del13)
p.Gln71ProfsTer64
(Q71fs*134)
N-terminal cytoplasmicBelgianAdolescenceCoucke et al [1999]
c.211delCp.Gln71SerfsTer68
(FS71)
N-terminal cytoplasmicJapaneseAdolescenceKamada et al [2006], Ishikawa et al [2014]
c.228_229dupGCp.His77ArgfsTer63N-terminal cytoplasmicJapaneseChildhoodNaito et al [2013]
c.546C>Gp.Phe182LeuS3 transmembrane domainTaiwaneseChildhoodSu et al [2007]
c.667_684del18
(664_681del)
p.Thr223_Gly228del
(Gly222_Leu227del)
Intra-membrane loopSouth KoreanChildhoodBaek et al [2011]
c.689T>Ap.Val230GluS4-S5 linkerJapaneseChildhoodNaito et al [2013]
c.778G>Ap.Glu260LysS5 transmembrane domainNorth AmericanChildhoodHildebrand et al [2008]
c.785A>Tp.Asp262ValS5 transmembrane domainNorth AmericanChildhoodHildebrand et al [2008]
c.725G>Ap.Trp242TerS5 transmembrane domainNorth AmericanChildhoodHildebrand et al [2008]
c.806_808delCCTp.Ser269delBetween S5 domain and pore helixCanadianChildhoodAbdelfatah et al [2013]
JapaneseAdulthoodWatabe et al [2013]
c.808T>Cp.Tyr270HisPore helixJapaneseCongenitalNamba et al [2012]
c.821T>Ap.Leu274HisP-loopDutchChildhoodVan Hauwe et al [2000], de Heer et al [2011]
c.823T>Cp.Trp275ArgP-loopHan ChineseChildhoodWang et al [2014]
c.827G>Cp.Trp276SerP-loopDutch, JapaneseChildhoodCoucke et al [1999], Van Camp et al [2002], Topsakal et al [2005]
c.842T>Cp.Leu281SerP-loopNorth AmericanChildhoodTalebizadeh et al [1999]
c.853G>Tp.Gly285CysP-loopNorth AmericanChildhoodCoucke et al [1999]
c.853G>Ap.Gly285SerP-loopNorthern European, Han ChineseChildhoodKubisch et al [1999], Wang et al [2014]
c.859G>Cp.Gly287ArgP-loopNorth AmericanChildhoodArnett et al [2011]
c.871C>Tp.Pro291SerChannel poreJapaneseAdulthoodNaito et al [2013]
c.872C>Tp.Pro291LeuChannel poreJapaneseAdolescenceNaito et al [2013]
c.886G>Ap.Gly296SerChannel poreSpanishChildhoodMencía et al [2008]
c.891G>Tp.Arg297SerS6 transmembrane domainJapaneseChildhoodNaito et al [2013]
c.961G>Ap.Gly321SerS6 transmembrane domainDutchChildhoodCoucke et al [1999]
c.1044_1051del8p.Ala349ProfsTer19C-terminal cytoplasmicJapaneseChildhoodWasano et al [2015]
c.2039C>Tp.Ser680PheC-terminal cytoplasmicHan ChineseChildhoodWu et al [2013]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Reference sequences for KCNQ4: NM_004700​.2, NP_004691​.2

1.

Variant designation that does not conform to current naming conventions

2.

Pathology was high-frequency hearing impairment and tissue-specific expression was in cochlear outer hair cells and brain for all deafness-related variants described in the table.

Normal gene product. The protein encoded by KCNQ4 is 695 amino acids in length. The protein forms a potassium channel that consists of six transmembrane domains and a P-loop region that forms the channel pore. A highly conserved glycine-tyrosine-glycine (GYG) signature sequence within the P-loop comprises the selectivity filter that provides discrimination of potassium ions for selective transport [Kubisch et al 1999]. Deafness-related variants have been shown to cluster in the channel pore region and some directly affect this selectivity filter (i.e., p.Gly285Ser and p.Gly285Cys).

Abnormal gene product. Most deafness-related KCNQ4 variants are missense alterations (Table 3) that cause hearing loss via a dominant-negative effect. These alleles are typically associated with progressive hearing loss with childhood or adolescent onset. Initially, high frequencies are predominately affected; later in life, hearing loss can become severe to profound across all frequencies. The phenotype reflects the consequence of defective KCNQ4 protein in the inner ear. This protein assembles as a tetramer to form a potassium channel made of four subunits. In a person with a deafness-related missense variant in one allele, half of the total amount of encoded protein is defective and consequently only one of every 16 channels comprises four normal protein subunits [Kubisch et al 1999]. Over time the result is hypothesized to be progressive loss in potassium recycling in the inner ear. Because potassium ions are crucial for hair cell transduction, the inability to recycle these ions results in hearing loss. These deafness-related variants affect amino acids located within or close to the channel pore. The presence of an abnormal protein subunit interferes with the assembly and/or function of the tetrameric channel protein in the inner ear. Some DFNA2-causing variants in KCNQ4 are deletions that result in haploinsufficiency. As a result, cells of the inner ear produce insufficient functional KCNQ4 protein and over time auditory function is compromised.

Evidence for locus heterogeneity. Initial reports of GJB3 (encoding gap junction protein β-3, or connexin 31) variants as causative of DFNA2 nonsyndromic hearing loss have not been substantiated. No additional families with DFNA2 caused by GJB3 variants have been reported since the original Chinese families in 1998.

GJB3 was suggested as a deafness-associated gene at the DFNA2 locus based on two different GJB3 sequence variants identified in two small Chinese families [Xia et al 1998]. Individuals from both families had bilateral sensorineural hearing loss (SNHL) characterized by a gently downsloping audiogram from normal hearing thresholds below 1,000 Hz to a moderate hearing loss in the high frequencies.

However, the evidence associating the GJB3 variants with the hearing loss is neither substantial nor convincing:

  • In both families, other individuals with normal hearing had the reported deafness-related variants, a finding inconsistent with complete penetrance, which is observed in virtually all types of autosomal dominant SNHL.
  • It is doubtful that KCNQ4 deafness-related variants have been excluded in these two families reported in 1998, as KCNQ4 deafness-related variants were not implicated in autosomal dominant SNHL until 1999.
  • No other families with autosomal dominant SNHL have been reported to segregate GJB3 deafness-related variants.
  • Specific deafness-related variants in GJB3 cause erythrokeratodermia variabilis.

References

Literature Cited

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  2. Akita J, Abe S, Shinkawa H, Kimberling WJ, Usami S. Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese. J Hum Genet. 2001;46:355–61. [PubMed: 11450843]
  3. Arnett J, Emery SB, Kim TB, Boerst AK, Lee K, Leal SM, Lesperance MM. Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene. Arch Otolaryngol Head Neck Surg. 2011;137:54–9. [PMC free article: PMC3278911] [PubMed: 21242547]
  4. Baek JI, Park HJ, Park K, Choi SJ, Lee KY, Yi JH, Friedman TB, Drayna D, Shin KS, Kim UK. Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology. Biochim Biophys Acta. 2011;1812:536–43. [PubMed: 20832469]
  5. Coucke PJ, Van Hauwe P, Kelley PM, Kunst H, Schatteman I, Van Velzen D, Meyers J, Ensink RJ, Verstreken M, Declau F, Marres H, Kastury K, Bhasin S, McGuirt WT, Smith RJ, Cremers CW, Van de Heyning P, Willems PJ, Smith SD, Van Camp G. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet. 1999;8:1321–8. [PubMed: 10369879]
  6. de Heer AM, Schraders M, Oostrik J, Hoefsloot L, Huygen PL, Cremers CW. Audioprofile-directed successful mutation analysis in a DFNA2/KCNQ4 (p.Leu274His) family. Ann Otol Rhinol Laryngol. 2011;120:243–8. [PubMed: 21585154]
  7. De Leenheer EM, Ensink RJ, Kunst HP, Marres HA, Talebizadeh Z, Declau F, Smith SD, Usami S, Van de Heyning PH, Van Camp G, Huygen PL, Cremers CW. DFNA2/KCNQ4 and its manifestations. Adv Otorhinolaryngol. 2002a;61:41–6. [PubMed: 12408061]
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Suggested Reading

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

Chapter Notes

Revision History

  • 20 August 2015 (me) Comprehensive update posted live
  • 20 June 2013 (me) Comprehensive update posted live
  • 17 February 2011 (me) Comprehensive update posted live
  • 4 April 2008 (me) Review posted to live Web site
  • 19 December 2007 (rjhs) Original submission
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