Clinical Diagnosis

The diagnosis of DFNA2 nonsyndromic hearing loss should be considered in persons with the following:

• 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
• A family history of hearing loss consistent with autosomal dominant inheritance

Audiometry. Standard audiometry is used to measure auditory acuity, with bone conduction to confirm the sensorineural nature of the loss, if necessary. (See Deafness and Hereditary Hearing Loss Overview for details about audiometry.)

Temporal bone imaging. CT of the inner ears is normal. Specifically, abnormalities such as dilation of the vestibular aqueducts (DVA; also known as enlarged vestibular aqueducts [EVAs]) and Mondini dysplasia should be absent.

The diagnosis of DFNA2 nonsyndromic hearing loss cannot be established by clinical examination alone because the hearing loss is similar to that caused by mutations in other genes. The diagnosis of DFNA2 nonsyndromic hearing loss can only be made by molecular genetic testing.

Molecular Genetic Testing

Gene. KCNQ4 is the only gene in which mutation is known to cause DFNA2 hearing loss.

Note: It is likely that KCNQ4 mutations account for all cases of DFNA2 hearing loss.

Other loci. Initial reports of GJB3 (encoding gap junction protein β-3, or connexin 31) mutations as causative of DFNA2 hearing loss have not been substantiated. No additional families with DFNA2 caused by GJB3 mutations 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 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 mutations with the hearing loss is neither substantial nor convincing:

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

Clinical testing

• Sequence analysis. Sequence analysis detects mutations in KCNQ4 in virtually all individuals with autosomal dominant nonsyndromic sensorineural hearing loss (ADNSHL) that maps to the DFNA2 locus.
• Sequence analysis of select exons. The exons sequenced vary by laboratory but may include exons 1,4,5,6, and 7.

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

Testing Strategy

To confirm/establish the diagnosis in a proband

• Clinical evaluation
  • Physical examination revealing no findings that could be associated with SNHL
  • Audiometry revealing a characteristic pattern of progressive hearing loss
• Molecular genetic testing. Identification of a KCNQ4 deafness-causing mutation

Predictive testing for at-risk infants or children 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.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be caused by mutations in KCNQ4.

Natural History

All families with DFNA2 nonsyndromic hearing loss have symmetric, predominantly high-frequency hearing loss that is progressive across all frequencies [Coucke et al 1999, Kubisch 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]. A comprehensive review of the clinical presentation and prognosis of individuals diagnosed with DFNA2 has been provided by De Leenheer et al [2002a].

Onset of hearing impairment 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 impairment 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 impairment 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 hearing loss is shown in Figure 1.

Figure

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 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 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 mutation in KCNQ4 have severe-to-profound hearing impairment.

Other findings

• Vestibular function. Thirty percent of individuals in two families with DFNA2 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.
• 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 missense mutations 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 mutations differs from that associated with KCNQ4 missense mutations. In two families small deletions of KCNQ4 (p.Gln71Profs*64 and p.Gln71Serfs*68) are frameshift mutations 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 is the hearing loss seen with missense mutations [Coucke et al 1999, Akita et al 2001].

Penetrance

The penetrance is complete. All individuals with a mutated allele exhibit the hearing loss phenotype; onset age and severity are variable.

Anticipation

Anticipation does not occur.

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

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

Evaluations Following Initial Diagnosis

To establish the extent of involvement in an individual diagnosed with DFNA2 nonsyndromic hearing loss, audiometry including bone conduction testing is recommended.

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 ongoing, preferably 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 an affected person has inherited the deafness-causing mutation in KCNQ4 allows for early support and management of the child and the family. Molecular genetic testing can only be considered if a deafness-causing mutation has been identified in an affected family member.

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.

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 hearing loss may have deafness as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
• If the deafness-causing mutation found in the proband cannot be detected in the DNA 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.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include audiometry and molecular genetic testing. Evaluation of parents may determine that one has hearing loss but has escaped previous diagnosis because of failure by health care professionals to recognize the symptoms and/or 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 symptoms or late onset of the hearing loss in a parent. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

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-causing mutation found in the proband cannot be detected in the 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 mutation.

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

Family planning

• The optimal time for determination of genetic risk 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 affected or at risk.

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.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased 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 deafness-causing mutation of an affected family member must be identified in the family 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 DFNA2 nonsyndromic hearing loss 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 consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the deafness-causing mutation has been identified.

Literature Cited

1. 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]
2. 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]
3. 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]
4. 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]
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6. De Leenheer EM, Huygen PL, Coucke PJ, Admiraal RJ, van Camp G, Cremers CW. Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family. Ann Otol Rhinol Laryngol. 2002b;111:267–74. [PubMed: 11915881]
7. Ensink RJ, Huygen PL, Van Hauwe P, Coucke P, Cremers CW, Van Camp G. A Dutch family with progressive sensorineural hearing impairment linked to the DFNA2 region. Eur Arch Otorhinolaryngol. 2000;257:62–7. [PubMed: 10784363]
8. Hildebrand MS, Tack D, McMordie SJ, DeLuca A, Hur IA, Nishimura C, Huygen P, Casavant TL, Smith RJ. Audioprofile-directed screening identifies novel mutations in KCNQ4 causing hearing loss at the DFNA2 locus. Genet Med. 2008;10:797–804. [PMC free article: PMC3337550] [PubMed: 18941426]
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10. Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell. 1999;96:437–46. [PubMed: 10025409]
11. Marres H, van Ewijk M, Huygen P, Kunst H, van Camp G, Coucke P, Willems P, Cremers C. Inherited nonsyndromic hearing loss. An audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2. Arch Otolaryngol Head Neck Surg. 1997;123:573–7. [PubMed: 9193215]
12. Mencia A, Gonzalez-Nieto D, Modamio-Hoybjor S, Etxeberria A, Aranguez G, Salvador N, Del Castillo I, Villarroel A, Moreno F, Barrio L, Moreno-Pelayo MA. A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Hum Genet. 2008;123:41–53. [PubMed: 18030493]
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15. Topsakal V, Pennings RJ, te Brinke H, Hamel B, Huygen PL, Kremer H, Cremers CW. Phenotype determination guides swift genotyping of a DFNA2/KCNQ4 family with a hot spot mutation (W276S). Otol Neurotol. 2005;26:52–8. [PubMed: 15699719]
16. Van Camp G, Coucke PJ, Akita J, Fransen E, Abe S, De Leenheer EM, Huygen PL, Cremers CW, Usami S. A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment. Hum Mutat. 2002;20:15–9. [PubMed: 12112653]
17. Van Hauwe P, Coucke PJ, Ensink RJ, Huygen P, Cremers CW, Van Camp G. Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet. 2000;93:184–7. [PubMed: 10925378]
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Suggested Reading

1. Hardelin JP, Marlin S, Levilliers J, Petit C. Hereditary hearing loss. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 254. Available online. Accessed 2-27-13.

Author Notes

Molecular Otolaryngology Research Laboratories home page: www.healthcare.uiowa.edu/labs/morl

Hereditary Hearing Loss home page: hereditaryhearingloss.org

Revision History

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