Nonsyndromic Hearing Loss And Deafness, Dfnb1
Summary
Clinical characteristics.
Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital non-progressive mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.
Diagnosis/testing.
Diagnosis of DFNB1 depends on molecular genetic testing to identify biallelic pathogenic variants in GJB2 (sequence variants as well as variants in upstream cis-regulatory elements that alter expression of the gap junction beta-2 protein [connexin 26]).
Management.
Treatment of manifestations: Hearing aids; enrollment in appropriate educational programs; consideration of cochlear implantation for individuals with profound deafness.
Surveillance: Surveillance includes annual examinations and repeat audiometry to confirm stability of hearing loss.
Evaluation of relatives at risk: If both pathogenic variants have been identified in an affected family member, molecular genetic testing can be used to clarify the genetic status of an at-risk relative in childhood so that appropriate early support and management can be provided.
Genetic counseling.
DFNB1 is inherited in an autosomal recessive manner. In each pregnancy, the parents of a proband have a 25% chance of having a deaf child, a 50% chance of having a hearing child who is a carrier, and a 25% chance of having a hearing child who is not a carrier. When the GJB2 pathogenic variants causing DFNB1 are detected in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
Nonsyndromic hearing loss and deafness caused by biallelic pathogenic GJB2 variants (DFNB1) should be suspected in individuals with the following:
- Congenital, generally non-progressive sensorineural hearing impairment that is mild to profound by auditory brain stem response testing (ABR) or pure tone audiometryNote: (1) Hearing is measured in decibels (dB). The threshold or 0-dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 25 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90 dB), or profound (90 dB). The frequency of hearing loss is designated as low (<500Hz), middle (501-2,000 Hz), or high (>2,000 Hz) (see Hereditary Hearing Loss and Deafness Overview).
- No related systemic findings identified by medical history and physical examination
- A family history of nonsyndromic hearing loss consistent with autosomal recessive inheritance
Establishing the Diagnosis
The diagnosis of DFNB1 is established in a proband with mild to profound congenital, generally non-progressive sensorineural hearing impairment and identification of biallelic pathogenic variants in GJB2 (encoding connexin 26) on molecular genetic testing (see Table 1).
Individuals with DFNB1 are EITHER:
- Homozygous or compound heterozygous for GJB2 pathogenic variants (99%); OR
- Compound heterozygous for one GJB2 pathogenic variant and one of three large deletions that includes sequences upstream of GJB2 and a portion of GJB6 (<1%).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and/or a multigene panel) and genomic testing (comprehensive genomic sequencing).
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved based on phenotypic data, while comprehensive genomic testing does not. Because of the overlapping phenotypes of the many causes of hereditary hearing loss and deafness, most individuals with hereditary hearing loss and deafness are diagnosed by one of two approaches: comprehensive genomic sequencing (recommended) or gene-targeted testing (to consider).
Recommended Testing
A comprehensive deafness-specific genetic panel that includes all genes implicated in nonsyndromic hearing loss and nonsyndromic hearing loss mimics (see Differential Diagnosis and Hereditary Hearing Loss and Deafness Overview) is recommended as the initial genetic test (Figure 1).
Figure 1.
Genetic diagnostic rates in 1,119 sequentially accrued persons with hearing loss. No person was excluded based on phenotype, inheritance, or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 individuals (more...)
Note: (1) Genes included in available panels and the diagnostic sensitivity of the test used for each gene vary by laboratory and are likely to change over time [Shearer & Smith 2015]. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests; detection of copy number variants must be included in hearing loss panels [Shearer et al 2014].
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Testing to Consider
Single-gene testing can be considered if a deafness-specific multigene panel is not available. However, performing sequence analysis of GJB2 alone is not cost-effective unless it is limited to persons with severe-to-profound congenital nonsyndromic hearing loss. Offering single-gene testing of GJB2 reflexively to everyone with congenital hearing loss without regard to the degree of hearing loss is not evidence based and not cost effective [Jayawardena et al 2015, Shearer & Smith 2015].
Comprehensive genomic testing including exome sequencing and genome sequencing may be considered if the phenotype alone is insufficient to warrant gene-targeted testing. Both exome sequencing and genome sequencing should be complemented with appropriate genetic counseling before and after testing.
For an 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 DFNB1
| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2, 3 Detectable by Method |
|---|---|---|
| GJB2 | Sequence analysis 4 | > 99% |
| Gene-targeted deletion/duplication analysis 5, 6 | <1% |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Percentages vary depending on ethnicity. Numbers in table reflect screening of a US population primarily of northern European ancestry.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may 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.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Feldmann et al [2009]) may not be detected by these methods.
Clinical Characteristics
Clinical Description
Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital (present at birth) non-progressive sensorineural hearing impairment. Intrafamilial variability in the degree of deafness is seen.
- If an affected person has severe-to-profound deafness, an affected sib with the same GJB2 pathogenic variants has a 91% chance of having severe-to-profound deafness and a 9% chance of having mild-to-moderate deafness [Tennessee Department of Health 2005].
- If an affected person has mild-to-moderate deafness, an affected sib with the same GJB2 pathogenic variants has a 66% chance of having mild-to-moderate deafness and a 34% chance of having severe-to-profound deafness [Tennessee Department of Health 2005].
- A few reports describe children with GJB2 variants who pass the newborn hearing screen and have somewhat later-onset hearing loss [Norris et al 2006, Orzan & Murgia 2007].
In a large cross-sectional analysis of GJB2 genotype and audiometric data from 1,531 individuals with autosomal recessive mild-to-profound nonsyndromic deafness (median age 8 years; 90% within age 0-26 years) from 16 countries, linear regression analysis of hearing thresholds on age in the entire study and in subsets defined by genotype did not show significant progression of hearing loss in any individual [Snoeckx et al 2005]. This finding is in concordance with prior studies [Orzan et al 1999, Löffler et al 2001]; however, progression of hearing loss cannot be excluded definitively given the cross-sectional nature of the regression analysis.
Although Snoeckx et al [2005] found a slight degree of asymmetry, the difference in pure tone average at 0.5, 1.0, and 2.0 kHz between ears was less than 15 dB in 90% of individuals.
Vestibular function is normal; affected infants and young children do not experience balance problems and learn to sit and walk at age-appropriate times.
Except for the hearing impairment, affected individuals are healthy; life span is normal.
Genotype-Phenotype Correlations
Numerous studies have shown that it is possible to predict phenotype based on genotype. The largest study to date involved a cross-sectional analysis of GJB2 genotype and audiometric data from 1,531 persons from 16 different countries with autosomal recessive mild-to-profound nonsyndromic deafness [Snoeckx et al 2005]. Of the 83 different variants identified, 47 were predicted nontruncating (e.g., missense variants) and 36 were predicted truncating (e.g., premature stop codons). By classifying variants this way, the authors defined three genotype classes: biallelic truncating (T/T) variants, biallelic nontruncating (NT/NT) variants, and compound heterozygous truncating/nontruncating (T/NT) variants (Table 2).
Table 2.
Genotype-Phenotype Correlations by Variant Type in 1531 Persons with Biallelic GJB2 Pathogenic Variants
| GJB2 Genotype Class | Total of All DFNB1 | Hearing Loss | |||
|---|---|---|---|---|---|
| Mild | Moderate | Severe | Profound | ||
| T/T | 77.3% 1 | 0%-3% | 10%-12% | 25%-28% | 59%-64% |
| NT/NT | 6.2% 2 | 53% | 26% | 8% | 13% |
| T/NT | 16.5% 3 | 29%-37% | 24%-29% | 10%-17% | 24%-30% |
Based on Snoeckx et al [2005]. See full text, Figure 3 for scatter diagrams showing the binaural mean pure tone average (PTA) at 0.5, 1, and 2 kHz (PTA0.5,1,2kHz) for each person within each genotype class, using individuals homozygous for the c.35delG allele as a reference group.
NT/NT = biallelic predicted nontruncating variants; T/NT = compound heterozygous predicted truncating/nontruncating variants; T/T = biallelic predicted truncating variants
- 1.
64 different genotypes (36% of all genotypes)
- 2.
42 different genoytpes (24% of all genotypes)
- 3.
71 different genotypes (40% of all genotypes)
Nomenclature
DFNB with a suffix integer is used to designate loci for autosomal recessive nonsyndromic deafness.
Prevalence
DFNB1 accounts for approximately 50% of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss in the United States, France, Britain, and New Zealand/Australia [Green et al 1999, Azaiez et al 2004, Angeli 2008]. Its approximate prevalence in the general population is 14:100,000, based on the following calculation: the incidence of congenital hereditary hearing impairment is 1:2,000 neonates, of which 70% have nonsyndromic hearing loss. Seventy-five to 80% of cases of nonsyndromic hearing loss are autosomal recessive; of these, 50% result from biallelic pathogenic variants in GJB2. Thus, 5:10,000 x 0.7 x 0.8 x 0.5 = 14:100,000.
Given the extreme heterogeneity of autosomal recessive nonsyndromic hearing impairment, it is not surprising that epidemiologic studies in other populations have shown that the frequency of biallelic GJB2 pathogenic variants as a cause of hearing impairment is highly variable. For example, among families segregating autosomal recessive nonsyndromic hearing impairment, GJB2 variants are causally related to congenital hereditary hearing impairment in:
- 25% of Palestinian families [Shahin et al 2002]
- An estimated 24% of Altaians from Siberia [Posukh et al 2005]
- 18% of Han Chinese [Duan et al 2015]
- 16% of the Iranian deaf population [Bazazzadegan et al 2012]
- 15% of Hui people [Duan et al 2015]
- 11% of Tibetan families [Duan et al 2015]
Differential Diagnosis
See Hereditary Hearing Loss and Deafness Overview for information on the genes causing nonsyndromic hereditary hearing loss and deafness.
Table 3.
Autosomal Recessive Syndromes Involving Hearing Loss
| Syndrome | Distinctive Feature in Addition to Hearing Loss | Gene(s) | Hearing Loss | Comments |
|---|---|---|---|---|
| Usher syndrome type I | Retinitis pigmentosa 1 | See footnote 2 | Congenital bilateral profound sensorineural hearing loss |
|
| Usher syndrome type II | USH2A ADGRV1 DFNB31 | Congenital bilateral sensorineural hearing loss: mild-moderate in low frequencies; severe-profound in higher frequencies |
| |
| Usher syndrome type III | CLRN1 | Postlingual progressive sensorineural hearing loss |
| |
| Pendred syndrome | Thyroid enlargement | SLC26A4 3 | Hearing impairment usually congenital & often severe-profound (mild-moderate progressive hearing impairment also occurs) |
|
| Jervell and Lange-Nielsen syndrome | Cardiac conduction defects; long QTc, usually >500 msec | KCNQ1 KCNE1 | Congenital profound bilateral sensorineural hearing loss |
|
- 1.
Retinitis pigmentosa is a progressive bilateral symmetric degeneration of rod and cone functions of the retina.
- 2.
Pathogenic variants in genes at a minimum of nine different loci cause Usher syndrome type I. Genes at six of these loci – MYO7A (USH1B), USH1C, CDH23 (USH1D), PCDH15 (USH1F), USH1G, and CIB2 (USH1J) – have been identified.
- 3.
Pendred syndrome and DFNB4 comprise a phenotypic spectrum caused by biallelic pathogenic variants in SLC26A4 (the most common cause), or double heterozygosity in either SLC26A4 and FOXI1 or SLC26A4 and KCNJ10.
- 4.
Also called enlarged vestibular aqueduct (EVA)
- 5.
DVA with cochlear hypoplasia is known as Mondini malformation or dysplasia.
- 6.
Goitrous changes are typically not present at birth but do develop in early puberty (40%) or adulthood (60%).
- 7.
Treatment involves use of beta-adrenergic blockers, cardiac pacemakers, and implantable defibrillators as well as avoidance of drugs that cause further prolongation of the QT interval and of activities known to precipitate syncopal events.
Autosomal recessive nonsyndromic hearing loss without an identifiable GJB2 variant and with progression of hearing loss:
- With a dilated vestibular aqueduct on thin-cut computed tomography (CT) of the temporal bones suggests DFNB4 [Azaiez et al 2007];
- With a Mondini malformation on thin-cut CT of the temporal bones suggests Pendred syndrome. A perchlorate test and molecular genetic testing of SLC26A4 should be considered [Azaiez et al 2007].
Other causes of congenital severe-to-profound hearing loss should be considered in children who represent single cases in a family:
- Congenital CMV (cytomegalovirus), the most common cause of congenital nonhereditary hearing loss
- Prematurity, low birth weight, low Apgar scores, infection, and any illness requiring care in a neonatal intensive care unit
Management
Evaluations Following Initial Diagnosis
To establish the extent of involvement and needs in an individual diagnosed with nonsyndromic hearing loss and deafness caused by biallelic pathogenic variants in GJB2 (DFNB1), the following evaluations are recommended:
- Complete assessment of auditory acuity using age-appropriate tests such as ABR testing, auditory steady-state response (ASSR) testing, and pure tone audiometry
- Ophthalmologic evaluation for refractive errors
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
The following are indicated:
- Fitting with appropriate hearing aids
- Enrollment in an appropriate educational program for the hearing impaired
- Consideration of cochlear implantation (CI), an excellent habilitation option for persons with profound deafness
- Recognition that, unlike with many clinical conditions, the management and treatment of severe-to-profound congenital deafness falls largely within the purview of the social welfare and educational systems rather than the medical care system [Smith et al 2005]
Also see Hereditary Hearing Loss and Deafness for more detailed discussion of management issues.
Surveillance
The following are appropriate:
- Annual examination by a physician familiar with hereditary hearing impairment
- Repeat audiometry to confirm stability of hearing loss
Agents/Circumstances to Avoid
Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important among these for persons with DFNB1 and mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises.
Evaluation of Relatives at Risk
If both GJB2 pathogenic variants have been identified in the proband, it is appropriate to clarify the genetic status of at-risk sibs shortly after birth so that appropriate early support and management can be provided to the child and 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 information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this condition.