Nonsyndromic Hearing Loss And Deafness, Dfna3

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2021-01-18

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Summary

Clinical characteristics.

Nonsyndromic hearing loss and deafness, DFNA3 is characterized by pre- or postlingual, mild-to-profound progressive high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings.

Diagnosis/testing.

Diagnosis of DFNA3 depends on molecular genetic testing to identify a heterozygous pathogenic variant in GJB2 (encoding connexin 26 [Cx26]) or GJB6 (encoding connexin 30 [Cx30]).

Management.

Treatment of manifestations: Early diagnosis, habilitation with hearing aids or cochlear implantation, and educational programming diminishes the likelihood of long-term speech or educational delay.

Surveillance: Semiannual examination by a physician who is familiar with hereditary hearing impairment; repeat audiometry to confirm stability of hearing loss

Agents/circumstances to avoid: Environmental exposures known to cause hearing loss, such as repeated loud noises.

Evaluation of relatives at risk: Once the GJB2 or GJB6 pathogenic variant has been identified in an affected family member, molecular genetic testing can be used to clarify the genetic status of at-risk relatives in infancy or early childhood so that appropriate early support and management can be provided.

Genetic counseling.

DFNA3 is inherited in an autosomal dominant manner. Most individuals diagnosed as having DFNA3 have a deaf parent. Each child of an individual with DFNA3 has a 50% chance of inheriting the GJB2 or GJB6 pathogenic variant. Once the GJB2 or GJB6 pathogenic variant has been identified in a family member with DFNA3, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Diagnosis

No formal diagnostic criteria have been published for DFNA3-related hearing loss.

Suggestive Findings

Nonsyndromic hearing loss and deafness, DFNA3 should be suspected in individuals with the following:

Pre- or postlingual, mild-to-profound progressive sensorineural hearing impairment [Denoyelle et al 2002]
Note: (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 15 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 (71-90dB), or profound (>90dB). The frequency of hearing loss is designated as low (<500Hz), middle (501-2000Hz), or high (>2000Hz) (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 dominant inheritance

Establishing the Diagnosis

The diagnosis of DFNA3 is established in a proband by detection of a heterozygous pathogenic variant in GJB2 (encoding connexin 26) or GJB6 (encoding connexin 30) (see Table 1).

Molecular genetic testing approaches in a person with hearing loss documented on audiogram can include a combination of gene-targeted testing (single-gene testing), multigene panels (including all genes implicated in nonsyndromic hearing loss), or genomic testing (e.g., exome or genome 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: a multigene panel of ALL genes implicated in nonsyndromic hearing loss and nonsyndromic mimics (recommended) or exome/genome sequencing (to consider).

Recommended Testing

A comprehensive deafness-specific multigene 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 test in the evaluation of hearing loss following an audiogram that has documented the hearing loss [Sloan-Heggen et al 2016] (Figure 1).

Figure 1.

Genetic diagnostic rates in 1119 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 is most likely 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. (4) All platforms used to identify deafness-causing genetic variants should include detection of copy number variants in the testing algorithm [Shearer et al 2014b].

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 and GJB6 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 and GJB6 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 (i.e., exome sequencing and genome sequencing) may be considered; however, given the huge number of variants that will be identified by these sequencing strategies, even if a trio (i.e., parents and child) is studied, it is extremely unlikely that either strategy will identify a cause for hearing loss. With exome and genome sequencing, appropriate genetic counseling is mandatory 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 Nonsyndromic Hearing Loss and Deafness, DFNA3

Gene ¹	Proportion of DFNA3 Attributed to Pathogenic Variants in This Gene	Proportion of Pathogenic Variants ² Detectable by This Method
Gene ¹		Sequence analysis ³	Gene-targeted deletion/duplication analysis ⁴
GJB2	>90%	100% ⁵	See footnote 5
GJB6	>10%	100%⁶	See footnote 5

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.: 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.
4.: 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.
5.: No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Nonsyndromic hearing loss and deafness, DFNA3 is characterized by progressive, mild-to-severe high-frequency sensorineural hearing impairment (Figure 2). GJB2-related DFNA3 is associated with prelingual and postlingual onset of hearing loss while GJB6-related DFNA3 is associated with prelingual hearing loss [Weegerink 2013].

Figure 2.

This audioprofile surface shows the anticipated progression of DFNA3 hearing loss with age. Note that the hearing loss is typically congenital and slowly becomes more severe with age [Taylor et al 2016].

DFNA3 audioprofiles (visual plots of hearing loss severity across a range of frequencies measured by pure tone audiometry) may vary significantly, even within a family. Note that when the hearing loss is postlingual, individuals with DFNA3 may pass the newborn hearing screen.

Tests of vestibular function and computed tomography of the temporal bones in persons with DFNA3 are normal [Denoyelle et al 2002].

Individuals with DFNA3 have no other associated medical findings.

Phenotype Correlations by Gene

GJB2. The twelve pathogenic missense variants of GJB2 (Table 3) that cause deafness at the DFNA3 locus are associated with at least two different audioprofiles based on age of onset.

The majority of pathogenic variants cause progressive prelingual hearing loss (Figure 2):

p.Trp44Cys. The audioprofile is characterized by a bilaterally symmetric sensorineural loss that varies from mild to profound, beginning with high-frequency hearing loss and progressing to loss at all frequencies.
p.Pro58Ala. Hearing loss is progressive, ranging from mild to severe.
p.Arg75Gln and p.Arg75Trp. Hearing loss is usually profound (average threshold for p.Arg75Gln is 105 dbHL).
p.Arg143Gln. Progressive and profound high-frequency hearing loss is observed.
c.551G>A (p.Arg184Gln). Audioprofiles are downsloping and consistent with severe-to-profound prelingual hearing loss [Janecke et al 2001, Löffler et al 2001, Tekin et al 2001, Denoyelle et al 2002, Feldmann et al 2005, Primignani et al 2007, Weegerink et al 2011].

In contrast, deafness related to the pathogenic variants resulting in the substitutions p.Thr55Asn, p.Asp179Asn, and p.Cys202Phe is postlingual:

c.164C>A (p.Thr55Asn). Audioprofiles have a downsloping pattern and are consistent with a severe-to-profound postlingual hearing loss.
p.Asp179Asn. Age of onset for hearing loss ranges from the first to the third decade. The audioprofile shows a mild-to-moderate hearing loss, particularly at high frequencies.
p.Cys202Phe. Hearing loss is usually not detected until the second decade. Initially, the loss preferentially affects the high frequencies but progresses to affect the middle frequencies by middle age [Morlé et al 2000, Denoyelle et al 2002, Primignani et al 2003, Melchionda et al 2005].

Other:

p.Trp44Ser. Audioprofiles are not available.
p.Asp46Asn. Audioprofiles show intrafamilial variability with some individuals showing postlingual progressive hearing loss with onset in the first decade of life and some showing prelingual hearing loss.
p.Met163Leu. A mild-to-moderate high-frequency hearing loss is observed; age of onset was not reported [Hamelmann et al 2001, Marziano et al 2003, Matos et al 2008, Bazazzadegan et al 2011].

GJB6 (Table 4)

p.Thr5Met. The audioprofile of the one family reported [Grifa et al 1999] is characterized by middle- to high-frequency hearing loss. The degree of hearing loss is progressive and variable, ranging from mild to profound. The age of onset of hearing loss was not reported - and in the absence of linkage data, these results should be interpreted with caution [Friedman & Griffith 2003].
p.Ala40Val. The audioprofile and age of onset were not included in the one reported individual [Yang et al 2007, Wang et al 2011].

Penetrance

GJB2 and GJB6 pathogenic variants that cause DFNA3 are fully penetrant.

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

The relative prevalence of DFNA3 as a cause of autosomal dominant nonsyndromic hearing loss is not known, but it is extremely rare [Sloan-Heggen et al 2016]: 14 pathogenic variants have been described worldwide. The majority of these pathogenic variants are described only in single families or simplex cases (i.e., a single occurrence in a family) [Denoyelle et al 2002, Hilgert et al 2009].

Prevalence for different pathogenic variants varies by population [Abe et al 2000, Hamelmann et al 2001, Löffler et al 2001, Liu et al 2002, Shearer et al 2014a, Xiao & Xie 2004].

Differential Diagnosis

Other causes of postlingual, acquired forms of hearing loss need to be considered (see Deafness and Hereditary Hearing Loss Overview). Because the diagnosis of syndromic forms of hearing loss can be challenging, many multigene panels now include the more frequently diagnosed forms of autosomal dominant syndromic hearing loss [Sloan-Heggen et al 2016].

Autosomal dominant syndromic forms of hearing loss with:

Malformations of the head and neck. Branchiootorenal (BOR) syndrome is characterized by malformations of the outer, middle, and inner ear associated with: conductive, sensorineural, or mixed hearing impairment; branchial fistulae and cysts; and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis [Chang et al 2004]. Pathogenic variants in EYA1, SIX5, or SIX1 are causative.
Pigmentary anomalies. Waardenburg syndrome type 1 (WS1) is characterized by congenital sensorineural hearing loss and pigmentary disturbances of the iris, hair, and skin, along with dystopia canthorum (lateral displacement of the inner canthi) [DeStefano et al 1998].
Hearing loss occurs in approximately 57% and is congenital, sensorineural, typically non-progressive, and either unilateral or bilateral. Most commonly, hearing loss is bilateral and profound (>100 dB). The majority of individuals with WS1 have either a white forelock (45%) or graying of the scalp hair before age 30 years. Affected individuals may have complete heterochromia iridium, partial/segmental heterochromia, or hypoplastic or brilliant blue irides. The diagnosis is established by clinical findings. Diagnostic criteria rely on the presence of sensorineural hearing loss, pigmentary changes, and calculation of the W index to identify dystopia canthorum. Pathogenic variants in PAX3 are causative.

Management

Evaluations Following Initial Diagnosis

To establish the extent of involvement and needs in an individual diagnosed with nonsyndromic hearing loss, DFNA3, the following evaluations are recommended:

Complete assessment of auditory acuity using age-appropriate tests including ABR testing, auditory steady-state response (ASSR) testing, and/or pure tone audiometry (see Deafness and Hereditary Hearing Loss Overview).
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Early diagnosis, habilitation with hearing aids or cochlear implantation, and educational programming will diminish the likelihood of long-term speech or educational delay.

The following are indicated:

Fitting with appropriate hearing aids
Enrollment in an appropriate educational program for the hearing impaired
Consideration of cochlear implantation, an effective habilitation option for persons with preserved residual hearing [Gantz et al 2016]
Recognition that unlike with many clinical conditions, management and treatment of mild-to-profound deafness fall largely within the purview of the social welfare and educational systems rather than the medical care system [Smith et al 2005]

See Hereditary Hearing Loss and Deafness for more detailed discussion of management issues.

Surveillance

The following are appropriate:

Semiannual examination by a physician who is 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 is avoidance of repeated exposure to loud noises.

Evaluation of Relatives at Risk

If a GJB2 or GJB6 pathogenic variant has 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 access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be human trials for this condition.