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.
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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.—ED.
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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of DFNA2 hearing loss is established in an individual with a characteristic audioprofile, a family history consistent with autosomal dominant inheritance, and a deafness-causing mutation in KCNQ4, the only gene known to be associated with DFNA2 hearing loss. Molecular genetic testing is available on a clinical basis.
Management. Treatment of manifestations: hearing aids for those with mild-to-moderate hearing loss; consideration of cochlear implants (CIs) 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. Testing of relatives at risk: Determining in infancy or early childhood whether a family member of the proband has inherited the altered KCNQ4 gene allows early support and management of the child and family.
Genetic counseling. DFNA2 hearing loss is inherited in an autosomal dominant manner. Most individuals with DFNA2 hearing loss have a hearing-impaired parent; the proportion of cases caused by de novo mutations is unknown. Each child of an individual with DFNA2 hearing loss has a 50% chance of inheriting the mutation. No laboratories offering molecular genetic testing for prenatal diagnosis of DFNA2 hearing loss are listed in the GeneTests Laboratory Directory; however, prenatal testing may be possible through a laboratory offering custom prenatal testing for families in which the deafness-causing mutation is known.
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.
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.—ED.
Gene. KCNQ4 is the only gene known to be associated with 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) as causative of DFNA2 hearing loss have not been substantiated.
GJB3 was suggested as a deafness-causing 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.
| Gene Symbol | Proportion of DFNA2 Hearing Loss Attributed to Mutations in This Gene | Test Method | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| KCNQ4 | 100% | Sequence analysis | 100% | Clinical
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Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To 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.
No other phenotypes are known to be caused by mutations in KCNQ4.
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, Ensink et al 2002; De Leenheer, Huygen et al 2002; 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, Ensink et al (2002).
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.
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, Ensink et al 2002; De Leenheer, Huygen et al 2002; 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, Ensink et al 2002]. By age 70 years, all persons with hearing loss attributed to a mutation in KCNQ4 have severe-to-profound hearing impairment.
Other findings
Speech recognition scores. When measured in several Dutch families speech recognition scores were relatively good given the pure-tone thresholds [De Leenheer, Huygen et al 2002; Van Camp et al 2002].
The penetrance is complete. All individuals with a mutated allele exhibit the hearing loss phenotype; onset age and severity are variable.
Anticipation does not occur.
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.
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].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
See Deafness and Hereditary Hearing Loss Overview for complete differential diagnosis.
Because mutation of KCNQ4 is a relatively common cause of high-frequency ADNSHL, this gene should be among the first genes tested in families with this type of hearing impairment.
Mutations in the following genes also cause high-frequency ADSNHL:
GJB3 (DFNA3)
COCH (DFNA9)
POU4F3 (DFNA15)
To establish the extent of involvment in an individual diagnosed with DFNA2 nonsyndromic hearing loss, audiometry including bone conduction testing is recommended.
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.
Audiograms should be obtained on an ongoing, preferably annual, basis to follow progression of hearing loss.
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.
Determining in infancy or early childhood whether a relative of an affected person has inherited the altered KCNQ4 gene 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.
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 disorder.
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.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
DFNA2 nonsyndromic hearing loss is inherited in an autosomal dominant manner.
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, the family history may appear to be negative because of failure to recognize hearing loss in family members, 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.
See Testing of Relatives at Risk for information on testing 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 probability is before pregnancy. It is appropriate to offer genetic counseling (including discussion of the potential for deafness in offspring and reproductive options) to young adults who are deaf.
DNA banking. 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.
No laboratories offering molecular genetic testing for prenatal diagnosis of DFNA2 nonsyndromic hearing loss are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the deafness-causing mutation has been identified. For laboratories offering custom prenatal testing, see
.
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 available for families in which the deafness-causing mutation has been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Locus Name | Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|---|
| DFNA2 | KCNQ4 | 1p34 | Potassium voltage-gated channel subfamily KQT member 4 | Deafness Gene Mutation Database | KCNQ4 |
| 600101 | DEAFNESS, AUTOSOMAL DOMINANT 2A; DFNA2A |
| 603537 | POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 4; KCNQ4 |
Normal allelic variants: The normal KCNQ4 gene has a transcript length of 2,335 base pairs. The transcript consists of 14 exons.
| DNA Nucleotide Change | Protein Amino Acid Change 1 (Alias 2 ) | Protein Domain | Population | Onset of Symptoms 3 | Reference |
|---|---|---|---|---|---|
| c.648C>T | p.= (Arg216Arg) | S4 transmembrane domain | Taiwanese | Childhood | Su et al 2007 |
| c.1503C>T | p.= (Thr501Thr) | Distal to S6 transmembrane domain |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
1. For these variants, "p.=" indicates that no effect on protein level is expected.
2. Variant designation that does not conform to current naming conventions
3. Pathology was high-frequency hearing impairment and tissue-specific expression was in cochlear outer hair cells and brain for all mutations described in the table.
| DNA Nucleotide Change (Alias 1 ) | Protein Amino Acid Change (Alias 1 ) | Protein Domain | Population | Onset of Symptoms 2 | Reference |
|---|---|---|---|---|---|
| c.211_223del (211del13) | p.Gln71ProfsX64 (Q71fsX134) | N-terminal cytoplasmic | Belgian | Adolescence | Coucke et al 1999 |
| c.211delC | p.Gln71SerfsX68 (FS71) | N-terminal cytoplasmic | Japanese | Adolescence | Kamada et al 2006 |
| c.546C>G | p.Phe182Leu | S3 transmembrane domain | Taiwanese | Childhood | Su et al 2007 |
| c.778G>A | p.Glu260Lys | S5 transmembrane domain | North American | Childhood | Hildebrand et al 2008, unpublished |
| c.785A>T | p.Asp262Val | S5 transmembrane domain | North American | Childhood | Hildebrand et al 2008, unpublished |
| c.821T>A | p.Leu274His | P-loop | Dutch | Childhood | Van Hauwe et al 2000 |
| c.827G>C | p.Trp276Ser | P-loop | Dutch; Japanese | Childhood | Coucke et al 1999, Topsakal et al 2005, Van Camp et al 2002 |
| c.842T>C | p.Leu281Ser | P-loop | North American | Childhood | Talebizadeh et al 1999 |
| c.853G>T | p.Gly285Cys | P-loop | North American | Childhood | Coucke et al 1999 |
| c.853G>A | p.Gly285Ser | P-loop | Caucasian | Childhood | Kubisch et al 1999 |
| c.886G>A | p.Gly296Ser | Channel pore | Spanish | Childhood | Mencia et al 2008 |
| c.961G>A | p.Gly321Ser | S6 transmembrane domain | Dutch | Childhood | Coucke et al 1999 |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
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 mutations described in table.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Molecular Otolaryngology Research Laboratories (MORL) Homepage: www.healthcare.uiowa.edu/labs/morl
Hereditary Hearing Loss Homepage: webh01.ua.ac.be/hhh
4 April 2008 (me) Review posted to live Web site
19 December 2007 (rjhs) Original submission
