DFNA2 Nonsyndromic Hearing Loss
Richard JH Smith, MD and Michael Hildebrand, PhD.
Author Information and AffiliationsInitial Posting: April 4, 2008; Last Update: May 10, 2018.
Estimated reading time: 18 minutes
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 heterozygous pathogenic 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 pathogenic variant in KCNQ4 allows for 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
KCNQ4 pathogenic variant is unknown. Each child of an individual with DFNA2 nonsyndromic hearing loss has a 50% chance of inheriting the KCNQ4 pathogenic variant. Once the KCNQ4 pathogenic variant has been identified in a family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for DFNA2 nonsyndromic hearing loss are possible.
Diagnosis
Suggestive Findings
DFNA2 nonsyndromic hearing loss should be considered in an individual with the following clinical, imaging, and family history findings:
Clinical findings
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
Imaging findings. Temporal bone imaging (i.e., CT of the inner ears) is normal. Specifically, abnormalities such as dilatation of the vestibular aqueducts (also known as enlarged vestibular aqueducts) and Mondini dysplasia should not be present.
Family history of hearing loss is present and consistent with autosomal dominant inheritance.
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 pathogenic variant in KCNQ4 on molecular genetic testing (see Table 1).
Because the phenotype of DFNA2 nonsyndromic hearing loss is indistinguishable from many other inherited disorders with hearing loss, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.
Note: Single-gene testing (sequence analysis of KCNQ4, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
A multigene hearing loss and deafness panel that includes KCNQ4 and other genes of interest (see Hereditary Hearing Loss and Deafness Overview) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic, particularly when evidence supports autosomal dominant inheritance.
For introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in DFNA2 Nonsyndromic Hearing Loss
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| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|
|
KCNQ4
| Sequence analysis 3 | 99% 4 |
| Gene-targeted deletion/duplication analysis 5 | 1% 6 |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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 pathogenic variants in KCNQ4 in virtually all individuals with autosomal dominant nonsyndromic sensorineural hearing loss mapping to the DFNA2 locus.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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.
Copy number variants (CNVs) can be detected in virtually any gene included in targeted sequencing panels for deafness. In sequential testing of 2,506 persons with hearing loss using OtoSCOPE, one CNV of KCNQ4 was identified [Author, personal observation].
Clinical Characteristics
Clinical Description
All individuals with DFNA2 nonsyndromic hearing loss have symmetric, predominantly high-frequency hearing loss that is progressive across all frequencies. Initially, high frequencies are affected; later in life, hearing loss becomes severe to profound 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 2-4 kHz by age 50 years. A typical audiogram of an adolescent with DFNA2 nonsyndromic hearing loss is shown in .
Audiogram from an individual age 12 years with DFNA2 hearing loss. Note that the loss is greater in the high frequencies at this age; 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 pathogenic 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.
Genotype-Phenotype Correlations
The phenotype associated with heterozygous KCNQ4 pathogenic 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.
Although 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], it has not been reported in other families with this 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].
The phenotype associated with heterozygous KCNQ4 truncating variants differs from that associated with KCNQ4 pathogenic 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 pathogenic missense variants [Coucke et al 1999, Akita et al 2001].
Penetrance
The penetrance is complete. All individuals with a heterozygous KCNQ4 pathogenic variant exhibit the hearing loss phenotype; onset age and severity are variable.
Prevalence
In a study conducted between 2012 and 2014, the Molecular Otolaryngology and Renal Research Laboratories performed clinical diagnostic testing on a total of 1,119 individuals with hearing loss using the comprehensive genetic testing panel OtoSCOPE. It was determined that among the 440 individuals in whom hearing loss was hereditary, KCNQ4 pathogenic variants accounted for 9.5% of autosomal dominant neurosensory hearing loss (ADNSHL) [Sloan-Heggen et al 2016].
Differential Diagnosis
See Hereditary Hearing Loss and Deafness for complete differential diagnosis. Note: Table 4 has a complete listing of the genes and clinical manifestations of autosomal dominant nonsyndromic hearing impairment.
Management
Evaluations Following Initial Diagnosis
To establish the extent of hearing loss and needs in an individual diagnosed with DFNA2 nonsyndromic hearing loss, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Audiometry, including bone conduction testing
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
See Hereditary Hearing Loss and Deafness Overview for complete discussion of treatment.
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 hybrid (short) cochlear implant may be considered. Hybrid implants combine two proven technologies – acoustic amplification and implant technology – to provide electroacoustic hearing. The acoustic component, which is coupled to the cochlear implant sound processor, amplifies residual low-frequency hearing; the electrical component uses cochlear implant technology to provide electrostimulation for high-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 pathogenic variant allows for early support and management of the child and the family.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise 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 pathogenic variant is not known. Of six clinically diagnosed individuals reported in the sequential series by
Sloan-Heggen et al [2016], five were verified to have autosomal dominant inheritance, whereas one represented a simplex case (i.e., a single occurrence in the family). Thus, it appears that in most instances
KCNQ4-related hearing loss is inherited from an affected parent [
Sloan-Heggen et al 2016].
Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include audiometry and molecular genetic testing.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
The family history of some individuals with DFNA2 nonsyndromic hearing loss may appear to be negative because of failure to diagnosis a parent with a milder phenotypic presentation, early death of the parent before the onset of hearing loss, or late onset of hearing loss in a parent. Therefore, an apparently negative family history cannot be confirmed until the appropriate clinical evaluation and molecular genetic testing have been performed on the parents of the proband.
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic 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.
If the
KCNQ4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the probability that a sib will have DFNA2 nonsyndromic hearing loss is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [
Rahbari et al 2016].
If the parents have not been tested for the KNCQ4 pathogenic variant but are both hearing, the probability that a sib of the proband will be deaf appears to be low. (Note: Sibs of a proband with clinically unaffected parents are presumed to have an increased probability of having DFNA2 nonsyndromic hearing loss because of the theoretic possibility of parental germline mosaicism.)
Offspring of a proband. Each child of an individual with DFNA2 nonsyndromic hearing loss has a 50% chance of inheriting the pathogenic variant.
Other family members. The probability of deafness in other family members depends on the status of the proband's parents: if a parent is deaf, the parent's family members may also be deaf or develop deafness.
Prenatal Testing and Preimplantation Genetic Testing
Once the KCNQ4 pathogenic variant has been identified in a family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for DFNA2 nonsyndromic hearing loss are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
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.
Medical Home Portal
MedlinePlus
Alexander Graham Bell Association for the Deaf and Hard of Hearing
Phone: 866-337-5220 (toll-free); 202-337-5221 (TTY)
Fax: 202-337-8314
Email: info@agbell.org
American Society for Deaf Children
Phone: 800-942-2732 (ASDC)
Email: info@deafchildren.org
BabyHearing.org
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
Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
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
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
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.
Variants of uncertain clinical significance. Two 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. To date these variants remain of uncertain clinical significance because to the authors' knowledge gene expression has not been tested (the hypothesis being that these variants disrupt exon-splice enhancers and interfere with normal gene splicing).
Table 2.
KCNQ4 Variants of Uncertain Clinical Significance Discussed in This GeneReview
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| DNA Nucleotide Change 1 | Predicted Protein Change 1 | Protein Domain | Population | Onset of Symptoms 2 | Reference |
|---|
| c.648C>T | p.Arg216= 3 | S4 transmembrane domain | Taiwanese | Childhood |
Su et al [2007]
|
| c.1503C>T | p.Thr501= 3 | Distal to S6 transmembrane domain |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
- 2.
Pathology was high-frequency hearing impairment and tissue-specific expression was in cochlear outer hair cells and brain for all pathogenic variants described in the table.
- 3.
No effect on protein level is expected.
Pathogenic variants. Most KCNQ4 pathogenic variants cluster in exons 5, 6, and 7, which encode highly conserved amino acid sequences that form the channel pore. The predominant pathogenic variants are missense variants that induce a dominant-negative effect. The variant p.Trp276Ser appears to be most common and has been identified in four unrelated families, including three of five Dutch families with DFNA2 nonsyndromic hearing loss and one Japanese family (see Table 3).
Table 3.
KCNQ4 Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.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 pathogenic variants described in the table.
Normal gene product. The protein encoded by KCNQ4 is 695 amino acids in length and forms a potassium channel with six transmembrane domains and a P-loop region, which 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]. Pathogenic variants cluster in the channel pore region and some (i.e., p.Gly285Ser and p.Gly285Cys) directly affect the selectivity filter.
Abnormal gene product. Most KCNQ4 pathogenic variants are missense alterations that cause hearing loss via a dominant-negative effect. 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 one pathogenic missense variant, 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. Most pathogenic 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 KCNQ4 pathogenic variants 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.
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 moderate hearing loss in the high frequencies.
The evidence associating GJB3 with hearing loss is neither substantial nor convincing:
In both families, other individuals with normal hearing had the reported pathogenic variants in GJB3, a finding inconsistent with complete penetrance, which is observed in virtually all types of autosomal dominant SNHL.
It is doubtful that KCNQ4 pathogenic variants have been excluded in these two families, which were reported in 1998, as KCNQ4 pathogenic variants were not implicated in autosomal dominant SNHL until 1999.
No other families with autosomal dominant SNHL have been reported to segregate GJB3 pathogenic variants.
Specific pathogenic variants in GJB3 cause erythrokeratodermia variabilis.
References
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Chapter Notes
Revision History
10 May 2018 (bp) Comprehensive update posted live
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 live
19 December 2007 (rjhs) Original submission
