Hereditary Hearing Loss and Deafness Overview

Shearer AE, Hildebrand MS, Smith RJH.

Publication Details

Summary

This overview focuses on the clinical features and molecular genetics of common syndromic and nonsyndromic types of hereditary hearing loss.

The goals of this overview on hereditary hearing loss and deafness are the following:

Goal 1.

Describe the clinical characteristics of hereditary hearing loss and deafness.

Goal 2.

Review the causes of hereditary hearing loss and deafness.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of hereditary hearing loss and deafness in a proband (when possible).

Goal 4.

Inform genetic counseling of family members of an individual with hereditary hearing loss and deafness.

Goal 5.

Review management of hereditary hearing loss and deafness.

Clinical Characteristics of Hereditary Hearing Loss and Deafness

Type

  • Conductive hearing loss results from abnormalities of the external ear and/or the ossicles of the middle ear.
  • Sensorineural hearing loss results from malfunction of inner ear structures (i.e., cochlea or auditory nerve).
  • Mixed hearing loss is a combination of conductive and sensorineural hearing loss.
  • Central auditory dysfunction results from damage or dysfunction at the level of the eighth cranial nerve, auditory brain stem, or cerebral cortex.

Onset

  • Prelingual hearing loss is present before speech develops. All congenital (present at birth) hearing loss is prelingual, but not all prelingual hearing loss is congenital.
  • Postlingual hearing loss occurs after the development of normal speech.

Severity of hearing loss. 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. Severity of hearing loss is graded as shown in Table 1.

Table 1.

Table 1.

Severity of Hearing Loss in Decibels (dB)

To calculate the percent hearing impairment, 25 dB is subtracted from the pure tone average of 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz. The result is multiplied by 1.5 to obtain an ear-specific level. Impairment is determined by weighting the better ear five times the poorer ear [JAMA 1979] (see Table 2).

Note: (1) Because conversational speech is at approximately 50-60 dB HL (hearing level), calculating functional impairment based on pure tone averages can be misleading. For example, a 45-dB hearing loss is functionally much more significant than 30% implies. (2) A different rating scale is appropriate for young children, for whom even limited hearing loss can have a great impact on language development [Northern & Downs 2002].

Table 2.

Table 2.

Percent Hearing Impairment

The frequency of hearing loss is designated as:

  • Low (<500 Hz)
  • Middle (501-2000 Hz)
  • High (>2000 Hz)

Other terminology

"Hearing impairment" and "hearing loss" are often used interchangeably by healthcare professionals to refer to hearing determined by audiometry to be below threshold levels for normal hearing.

Deaf (small "d") is a colloquial term that implies hearing thresholds in the severe-to-profound range by audiometry.

Deaf culture (always a capital "D"). Members of the Deaf community in the US are deaf and use American Sign Language. As in other cultures, members are characterized by unique social and societal attributes. Members of the Deaf community (i.e., the Deaf) do NOT consider themselves to be hearing "impaired," nor do they feel that they have a hearing "loss." Rather, they consider themselves deaf. Their deafness is not considered to be a pathology or disease to be treated or cured.

“Hard of hearing” is more functional than audiologic. It is used by the Deaf to signify that a person has some usable hearing – anything from mild to severe hearing loss. In the Deaf community persons who are deaf do not use oral language, while those who are hard of hearing usually have some oral language.

Diagnosing Deafness and Hearing Loss

Physiologic tests objectively determine the functional status of the auditory system and can be performed at any age. They include the following:

  • Auditory brain stem response testing (ABR, also known as BAER, BSER) uses a stimulus (clicks) to evoke electrophysiologic responses, which originate in the eighth cranial nerve and auditory brain stem and are recorded with surface electrodes. ABR "wave V detection threshold" correlates best with hearing sensitivity in the 1500- to 4000-Hz region in neurologically normal individuals; ABR does not assess low frequency (<1500 Hz) sensitivity.
  • Auditory steady-state response testing (ASSR) is like ABR in that both are auditory evoked potentials and they are measured in similar ways. ASSR uses an objective, statistics-based mathematical detection algorithm to detect and define hearing thresholds. ASSR can be obtained using broadband or frequency-specific stimuli and can offer hearing threshold differentiation in the severe-to-profound range. It is frequently used to give frequency-specific information that ABR does not give. Test frequencies of 500, 1000, 2000, and 4000 Hz are commonly used.
  • Evoked otoacoustic emissions (EOAEs) are sounds originating within the cochlea that are measured in the external auditory canal using a probe with a microphone and transducer. EOAEs reflect primarily the activity of the outer hair cells of the cochlea across a broad frequency range and are present in ears with hearing sensitivity better than 40-50 dB HL.
  • Immittance testing (tympanometry, acoustic reflex thresholds, acoustic reflex decay) assesses the peripheral auditory system, including middle ear pressure, tympanic membrane mobility, Eustachian tube function, and mobility of the middle ear ossicles.

Audiometry subjectively determines how the individual processes auditory information (i.e., hears). Audiometry consists of behavioral testing and pure tone audiometry.

  • Behavioral testing includes behavioral observation audiometry (BOA) and visual reinforcement audiometry (VRA). BOA is used in infants from birth to age six months, is highly dependent on the skill of the tester, and is subject to error. VRA is used in children from age six months to 2.5 years and can provide a reliable, complete audiogram, but is dependent on the child's maturational age and the skill of the tester.
  • Pure-tone audiometry (air and bone conduction) involves determination of the lowest intensity at which an individual "hears" a pure tone, as a function of frequency (or pitch). Octave frequencies from 250 (close to middle C) to 8000 Hz are tested using earphones. Intensity or loudness is measured in decibels (dB), defined as the ratio between two sound pressures. 0 dB HL is the average threshold for a normal hearing adult; 120 dB HL is so loud as to cause pain. Speech reception thresholds (SRTs) and speech discrimination are assessed.
  • Air conduction audiometry presents sounds through earphones; thresholds depend on the condition of the external ear canal, middle ear, and inner ear.
  • Bone conduction audiometry presents sounds through a vibrator placed on the mastoid bone or forehead, thus bypassing the external and middle ears; thresholds depend on the condition of the inner ear.
  • Conditioned play audiometry (CPA) is used to test children from age 2.5 to five years. A complete frequency-specific audiogram for each ear can be obtained from a cooperative child.
  • Conventional audiometry is used to test individuals age five years and older; the individual indicates when the sound is heard.
  • Audioprofile refers to the recording of several audiograms on a single graph (Figure 1). These audiograms may be from one individual at different times, but more frequently they are from different members of the same family segregating deafness usually in an autosomal dominant fashion. By plotting numerous audiograms with age on the same graph, the age-related progression of hearing loss can be appreciated within these families. Often the composite picture is characteristic of specific genetic causes of autosomal dominant nonsyndromic hearing loss. One of the most characteristic audioprofiles is associated with DFNA6/14/38 hearing loss caused by a pathogenic variant in WFS1.
Figure 1.

Figure 1.

Audioprofile

Other

  • Congenital hearing loss can be identified by newborn hearing screening (NBHS), which has been advocated by the National Institutes of Health. NBHS is universally required by law or rule in 43 states plus the District of Columbia. In the remaining states, newborn hearing screening is offered but not required. The result is that in the United States 95% of all newborns undergo newborn hearing screening [NIH RePORT].
  • Parental concerns about possible hearing loss or observed delays in speech development require auditory screening in any child.

Differential Diagnosis of Hereditary Hearing Loss and Deafness

In children with delayed speech development, the auditory system should be assessed.

In the presence of normal audiometry associated with progressive loss of speech and temporal lobe seizures, the diagnosis of Landau-Kleffner syndrome should be considered.

Delayed speech suggesting possible hearing loss can also be seen in young children with autism spectrum disorder or specific speech and language disorders.

In developed countries approximately 80% of congenital hearing loss is due to genetic causes and the remainder to environmental (acquired) causes (Figure 2). Acquired causes should be differentiated from genetic causes to inform the evaluation and required ancillary testing (i.e., CT, MRI, and consultation with specialists) and to inform prognosis and treatment recommendations.

Figure 2.

Figure 2.

Causes of prelingual hearing loss in developed countries

Acquired hearing loss in children commonly results from prenatal infections from "TORCH" organisms (i.e., toxoplasmosis, rubella, cytomegalovirus, and herpes), or postnatal infections, particularly bacterial meningitis caused by Neisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae. Meningitis from many other organisms including Escherichia coli, Listeria monocytogenes, Streptococcus agalactiae, and Enterobacter cloacae can also cause hearing loss.

In developed countries, however, the most common environmental, non-genetic cause of congenital hearing loss is congenital cytomegalovirus (cCMV) infection. Its overall birth prevalence is approximately 0.64%; 10% of this number have symptomatic CMV, which is characterized by a variable number and degree of findings including neurologic deficits (death, seizures, cerebral palsy), hepatic insufficiency, and characteristic rash. Hearing loss affects approximately 50% of symptomatic individuals with cCMV. The remaining 90% of individuals with cCMV are considered “asymptomatic;” of these up to 15% develop unilateral or bilateral hearing loss. Thus, the majority of individuals with hearing loss due to cCMV are classified as “asymptomatic.”

The diagnosis of CMV hearing loss can be difficult to make, often can go unrecognized, and is characterized by variable-severity bilateral, asymmetric, or unilateral sensorineural hearing loss [Kenneson & Cannon 2007]. Testing for cCMV requires a high degree of suspicion and should be done within 21 days of birth given the ubiquity of the virus in the environment. Several states have introduced targeted testing for cCMV for newborns who fail their newborn hearing screen. Recognizing cCMV hearing loss is increasingly important given new studies that show improvement of hearing loss with antiviral therapy for persons with symptomatic CMV [Kimberlin et al 2015]. To date, however, the use of antivirals to treat hearing loss in persons with cCMV whose only manifestation is hearing loss is experimental.

Acquired hearing loss in adults, most often attributed to environmental factors, most likely reflects environmental-genetic interactions, the most frequent of which are age-related and noise-induced hearing loss. Although both of these types of hearing loss reflect complex “environmental-genetic” hearing loss, to date variants in only a few genes have been associated with these traits [Yamasoba et al 2013].

An environmental interaction pertinent to medical care is the observation that aminoglycoside-induced hearing loss is more likely in persons with specific variants in the mitochondrial genome (mtDNA) (see Nonsyndromic Hearing Loss and Deafness, Mitochondrial).

Causes of Hereditary Hearing Loss and Deafness

Hereditary hearing loss and deafness can be regarded as syndromic or nonsyndromic (Figure 2). Syndromic hearing impairment is associated with malformations of the external ear, with malformations in other organs, or with medical problems involving other organ systems. Nonsyndromic hearing impairment has no associated visible abnormalities of the external ear or any related medical problems; however, it can be associated with abnormalities of the middle ear and/or inner ear.

Approximately 80% of prelingual deafness is genetic, most often autosomal recessive and nonsyndromic. The most common cause of severe-to-profound autosomal recessive nonsyndromic hearing loss in most populations is mutation of GJB2. The most common cause of mild-to-moderate autosomal recessive hearing loss is mutation of STRC; of note, there is ethnic-based variability [Sloan-Heggen et al 2016].

Syndromic Hearing Impairment

More than 400 genetic syndromes that include hearing loss have been described [Toriello et al 2004]. Although syndromic hearing impairment accounts for up to 30% of prelingual deafness, its relative contribution to all deafness is much smaller, commensurate with the occurrence and diagnosis of postlingual hearing loss. Syndromic hearing loss discussed here is categorized by mode of inheritance (Table 3).

Table 3.

Table 3.

Causes of Syndromic Hearing Impairment

Mitochondrial Syndromic Hearing Impairment

Mitochondrial DNA pathogenic variants have been implicated in a variety of diseases ranging from rare neuromuscular syndromes such as Kearns-Sayre syndrome (see Mitochondrial DNA Deletion Syndromes), MELAS, MERRF, and NARP (see Mitochondrial Disorders Overview), to common conditions such as diabetes mellitus, Parkinson disease, and Alzheimer disease. One pathogenic variant, the 3243 A-to-G transition in MTTL1, has been found in 2%-6% of individuals with diabetes mellitus in Japan; 61% of persons with diabetes mellitus and this pathogenic variant have hearing loss. The hearing loss is sensorineural and develops only after the onset of the diabetes mellitus. The same pathogenic variant is associated with MELAS, raising questions of penetrance and tissue specificity – issues further confounded by heteroplasmy.

Nonsyndromic Hearing Impairment

Nomenclature. For historical reasons, nonsyndromic hearing impairment may be referred to by the gene involved (e.g., OTOF-related deafness) or by the genetic locus (e.g., DFNB9). Nonsyndromic deafness loci are designated DFN (for DeaFNess) and further classified by mode of inheritance (DFNA: autosomal dominant; DFNB: autosomal recessive; DFNX: X-linked) and a number indicating the order of gene mapping and/or discovery).

Inheritance. The inheritance pattern among the disorders with prelingual nonsyndromic hearing loss is 80% autosomal recessive, 20% autosomal dominant, and 1%-1.5% X-linked, mitochondrial or other (Figure 2) [Smith et al 2005]. Although similar data are not available for the disorders with postlingual nonsyndromic hearing impairment, most reported families demonstrate autosomal dominant inheritance.

Genetic heterogeneity. Nonsyndromic hereditary hearing loss is characterized by extreme genetic heterogeneity: to date, more than 6,000 causative variants have been identified in more than 110 genes. In the largest study to date in which a multi-gene panel was used for comprehensive genetic testing, more than 40 causative genes were identified among the 440 individuals in whom a genetic diagnosis was established [Sloan-Heggen et al 2016]. This extreme genetic heterogeneity underscores the importance of use of multi-gene sequencing panels for genetic diagnosis (see Evaluation Strategy).

Autosomal Dominant Nonsyndromic Hearing Impairment

More than 25 genes have been associated with autosomal dominant nonsyndromic hearing loss. The genes implicated in autosomal dominant nonsyndromic hearing impairment and their clinical manifestations are summarized in Table 4. Note that the audioprofile can be distinctive and therefore guide genotype-phenotype correlations [Taylor et al 2013] (see Evaluation Strategy).

Most autosomal dominant loci cause postlingual hearing impairment.

  • Exceptions in which hearing loss is prelingual include GJB2 and GJB6 (DFNA3), TECTA (DFNA8/12), and DFNA19.
  • WFS1 (DFNA6/14/38) is noteworthy as the hearing loss primarily affects the low frequencies.
Table 4.

Table 4.

Autosomal Dominant Nonsyndromic Hearing Impairment: Genes and their Clinical Manifestations

Autosomal Recessive Nonsyndromic Hearing Impairment

Large studies have underscored the extreme genetic heterogeneity of autosomal recessive nonsyndromic deafness. The 70 genes implicated in autosomal recessive nonsyndromic hearing impairment and their clinical manifestations are summarized in Table 5.

While it is true that in some world populations, up to 50% of persons with severe-to-profound autosomal recessive nonsyndromic hearing loss have pathogenic variants in GJB2 (see DFNB1), recent studies have shown that the contribution of pathogenic variants in GJB2 to deafness varies considerably by ethnicity [Sloan-Heggen et al 2016]. For example, among individuals of African descent, pathogenic variants in GJB2 are very rare [Rudman et al 2017].

Table 5.

Table 5.

Autosomal Recessive Nonsyndromic Hearing Impairment: Genes and their Clinical Manifestations

X-Linked Nonsyndromic Hearing Impairment

The genes implicated in X-linked nonsyndromic hearing impairment and their clinical manifestations are summarized in Table 6.

X-linked nonsyndromic hearing loss can be either pre- or postlingual; one disorder, DFNX3, has mixed hearing loss.

Table 6.

Table 6.

X-linked Nonsyndromic Hearing Impairment: Genes and their Clinical Manifestations

Nonsyndromic Hearing Loss and Deafness, Mitochondrial

The majority of pathogenic variants in mitochondrial genes cause a broad spectrum of maternally inherited multisystem disorders; however, variants in a subset of genes, mainly MT-RNR1 and MT-TS1, cause nonsyndromic hearing loss by a currently unknown mechanism [Fischel-Ghodsian 1998] (see Table 7 and Nonsyndromic Hearing Loss and Deafness, Mitochondrial).

MT-RNR1 encodes for the 12S ribosomal RNA. One variant in this gene, 1555G>A, is a frequent cause of maternally inherited nonsyndromic hearing loss. In some individuals with the 1555G>A variant, the hearing loss is induced by the administration of appropriate doses of aminoglycosides; however, phenotypic variation is great, consistent with the effect of modifier genes [Kokotas et al 2007].

MT-TS1 encodes for the transfer RNASer(UCN). Two families with heteroplasmy for an A-to-G transition at nt7445 of this gene have been identified; however, penetrance of hearing loss was low, and it has been suggested that MT-TS1 pathogenic variants on their own play an insignificant role in hearing loss.

MT-CO1 encodes cytochrome c oxidase subunit 1. Six individuals with severe-to-profound deafness showed cosegregation of a homoplasmic G-to-A transition at nt7444 of MT-CO1 and the 1555A>G pathogenic variant in MT-RNR1 [Pandya et al 1999]. Five of the six individuals showed maternal inheritance and two had a previous history of aminoglycoside use. As opposed to the variable hearing loss associated with MT-RNR1 1555A>G, all individuals with this double variant showed severe-to-profound impairment and penetrance was complete.

Table 7.

Table 7.

Mitochondrial Nonsyndromic Hearing Impairment: Genes and their Clinical Manifestations

Evaluation Strategy

Recent guidelines have underscored the importance of genetic testing in the evaluation of patients with hearing loss. See Alford et al [2014] (full text), Liming et al [2016] (full text), and Figure 3.

Figure 3.

Figure 3.

Diagnostic algorithm for presumed hereditary nonsyndromic sensorineural hearing loss

Because molecular genetic testing is the single type of test with the highest diagnostic rate, it should be offered first in evaluation of individuals with presumed hereditary sensorineural hearing loss and deafness unless past medical history, physical examination, and/or audiometric testing indicates a specific syndromic form of hearing loss (Figure 3 and Table 3).

Initial evaluation should always include the following:

  • Family history. Effort should be made to obtain a three-generation family history with attention to other relatives with hearing loss and associated findings. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or through review of their medical records, including audiograms, otologic examinations, and molecular genetic testing.
  • Clinical examination. All persons with hearing loss of unknown cause should be evaluated for features associated with syndromic deafness (see Table 3). Because variable expressivity is common among autosomal dominant syndromes with deafness, the correct diagnosis may depend on molecular genetic testing.
  • Audiometric testing. Hearing status can be determined at any age (see Diagnosing Deafness and Hearing Loss).
    • Individuals with progressive hearing loss should be evaluated for Alport syndrome, Pendred syndrome, and Stickler syndrome. In addition to genetic testing, temporal bone-computed tomography should be considered to evaluate for enlarged vestibular aqueduct.
    • Sudden or rapidly progressive hearing loss can be seen with temporal bone anomalies (as in Pendred syndrome and BOR syndrome), neoplasms (associated with NF2), and immunologic-related deafness, as well as trauma, infections (syphilis, Lyme disease), and metabolic, neurologic, or circulatory disturbances.

Subsequent evaluation should be directed based on findings from above. In cases of apparent nonsyndromic sensorineural hearing loss, genetic testing should be obtained prior to other (ancillary) testing (Figure 3).

Molecular genetic testing. Genes known to cause common syndromes with hereditary hearing loss and deafness are included in Table 3. Because variable expressivity is common among autosomal dominant syndromes with deafness, the correct diagnosis may depend on molecular genetic testing.

The diagnosis of nonsyndromic hereditary hearing loss and deafness is established in a proband by identification of pathogenic variant(s) in a given gene (see Tables 4, 5, 6, and 7).

Molecular genetic testing for hereditary hearing loss and deafness historically relied on single-gene testing; however, this testing approach has largely been supplanted by multi-gene panels, which are comprehensive (i.e., include all genes known to cause deafness or all genes known to cause either autosomal recessive or autosomal dominant hearing loss and deafness). Multi-gene testing panels have greatly improved the diagnostic rate regardless of presumed inheritance or ethnicity [Shearer & Smith 2015]. In select instances, exome sequencing has been used in a diagnostic setting and can provide a means for comprehensive genetic testing for hereditary hearing loss and deafness, although small copy number variants can be easily missed [Zazo Seco et al 2017].

A multi-gene hearing loss and deafness panel that includes most of the genes listed in Tables 3, 4, 5, 6, and 7 is recommended. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the conditions discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. Clinicians should evaluate the genes included on the multi-gene testing panel and determine if the patient’s history and physical examination are consistent with apparent nonsyndromic hearing loss. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests. In the evaluation of hearing loss/deafness, a multi-gene panel that includes the identification of deletions and duplications is mandatory as copy number variants are a common cause of hereditary nonsyndromic hearing loss [Shearer et al 2014]. For more information on multi-gene panels click here.

Individuals with the distinctive findings of syndromic hearing loss (Table 3) may be diagnosed using gene-targeted testing. Of note, many multi-gene panels for hereditary hearing loss and deafness now include the most common causes of syndromic hearing loss, including those that masquerade as nonsyndromic hearing loss until secondary signs and symptoms present (e.g., Usher syndrome [blindness]; Pendred syndrome [thyroid goiter]).

Temporal bone CT or MRI. A dedicated thin cut CT or MRI of the temporal bones is useful for detecting malformations of the inner ear (i.e., Mondini deformity, Michel aplasia, enlarged/dilated vestibular aqueduct, dilation of the internal auditory canal), which should be considered in persons with progressive hearing loss.

Ancillary testing. Further testing including cardiac, renal, or ophthalmologic evaluation should not be routinely ordered unless there are concerning clinical findings or the results of genetic testing raise concerns about other organ system involvement.

Genetic Counseling

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. —ED.

Mode of Inheritance

Hereditary hearing loss may be transmitted in an autosomal dominant, autosomal recessive, or X-linked manner or by maternal inheritance.

(See Nonsyndromic Hearing Loss and Deafness, Mitochondrial for genetic counseling information about maternal inheritance.)

Risk to Family Members – Autosomal Dominant Hereditary Hearing Loss

Parents of a proband

  • Most individuals diagnosed as having autosomal dominant hereditary hearing loss have a deaf parent; the family history is rarely negative.
  • A proband with autosomal dominant hereditary hearing loss may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown but thought to be small.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include audiometry and molecular genetic testing.
  • Note: Although most individuals diagnosed with autosomal dominant hereditary hearing loss have a deaf parent, the family history may appear to be negative because of failure to recognize hereditary hearing loss in family members, late onset in a parent, reduced penetrance of the pathogenic variant in an asymptomatic parent, or a de novo variant for hereditary hearing loss.

Sibs of a proband

  • The risk to sibs depends on the genetic status of a proband's parents.
  • If one of the proband's parents has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
  • Depending on the specific diagnosis, clinical severity and phenotype may differ between individuals with the same variant; thus, age of onset and/or progression may not be predictable.

Offspring of a proband

  • Individuals with autosomal dominant hereditary hearing loss have a 50% chance of transmitting the pathogenic variant to each child.
  • Depending on the specific diagnosis, clinical severity and phenotype may differ between individuals with the same variant; thus, age of onset and/or progression may not be predictable.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, his or her family members may be at risk.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the causative variant identified in the proband or clinical evidence of the disorder, the variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Risk to Family Members – Autosomal Recessive Hereditary Hearing Loss

Parents of a proband

  • The parents of an individual diagnosed as having autosomal recessive hereditary hearing loss are obligate heterozygotes (i.e., carriers a single copy of a pathogenic variant).
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib has a 25% chance of being deaf, a 50% chance of having normal hearing and being a carrier, and a 25% chance of having normal hearing and not being a carrier.
  • Heterozygotes are asymptomatic.
  • Depending on the specific diagnosis, clinical severity and phenotype may differ between individuals with the same variants; thus, age of onset and/or progression of hearing loss may not be predictable. (Note: One exception is GJB2-related hearing loss; studies have shown that it is possible to predict phenotype based on GJB2 genotype (see Nonsyndromic Hearing Loss and Deafness, DFNB1).

Offspring of a proband. All offspring are obligate carriers.

Other family members. The sibs of obligate heterozygotes have a 50% chance of being heterozygotes.

Heterozygote (carrier) detection. Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Risk to Family Members – X-Linked Hereditary Hearing Loss

Parents of a proband

  • Male proband
    • The father of a male proband will not be hemizygous for the X-linked pathogenic variant identified in his son.
    • In a family with more than one individual with X-linked deafness, the mother of a deaf male is an obligate heterozygote (carrier). Note: If a woman has more than one deaf child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
    • If a male is the only deaf family member, the mother may be a heterozygote (carrier) or the deaf male may have a de novo pathogenic variant, in which case the mother is not a carrier.
  • Female proband
    • A female proband may have inherited the pathogenic variant from either her mother or her father, or the variant may be de novo.
    • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo variant from those with an inherited variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.

Sibs of a proband

  • Male proband. The risk to sibs depends on the genetic status of the mother: if the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be deaf; females who inherit the variant will be heterozygotes (carriers) and are likely to have normal hearing.
  • Female proband. The risk to sibs depends on the genetic status of the parents:
    • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be deaf; females who inherit the variant will be heterozygotes (carriers) and are likely to have normal hearing.
    • If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
  • Depending on the specific syndrome, clinical severity and phenotype may differ between individuals with the same pathogenic variant; thus, age of onset and/or progression may not be predictable.

Offspring of a proband

  • Males with X-linked hereditary hearing loss will transmit the pathogenic variant to all of their daughters and none of their sons.
  • Females with X-linked hereditary hearing loss have a 50% chance of transmitting the pathogenic variant to each child.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being deaf.

Heterozygote (carrier) detection. Carrier testing for at-risk relatives requires prior identification of the pathogenic variant in the family.

Risk to Family Members – Empiric Risks

If a specific diagnosis cannot be established (and/or the mode of inheritance cannot be established in a person with a positive family history of deafness or hearing loss), the following empiric figures can be used.

The subsequent offspring of a hearing couple with one deaf child and an otherwise negative family history of deafness have an 18% empiric probability of deafness in future children [Green et al 1999].

  • If the deaf child does not have DFNB1 based on molecular genetic testing of GJB2 and GJB6, the recurrence risk is 14% for deafness unrelated to connexin 26 [Green et al 1999].
  • If the hearing couple is consanguineous or comes from a highly consanguineous community, the subsequent offspring have close to a 25% probability of deafness because of the high likelihood of autosomal recessive inheritance.

The offspring of a deaf person and a hearing person have a 10% empiric risk of deafness [Green et al 1999].

  • Most of the risk is attributed to autosomal dominant syndromic deafness.
  • If both syndromic deafness and a family history of autosomal dominant inheritance can be excluded, the risk of deafness is chiefly related to pseudodominant inheritance of recessive deafness. GJB2 testing can identify much of this risk (see DFNB1).

The child of a non-consanguineous deaf couple in whom autosomal dominant deafness has been excluded has an approximately 15% empiric risk for deafness [Green et al 1999].

  • If both parents have GJB2-related deafness, the risk to their offspring is 100%.
  • If the couple has autosomal recessive deafness known to be caused by deafness-causing variants at two different loci, the chance of deafness in their offspring is lower than that of the general population.

The child of a hearing sib of a deaf proband (presumed to have autosomal recessive nonsyndromic deafness) and a deaf person has a 1/200 (0.5%) empiric risk for deafness, or five times the general population risk.

GJB2 and GJB6 molecular genetic testing can clarify if the risks are higher. If the hearing sib is a carrier of a GJB2 deafness-causing variant or a GJB6 deafness-causing variant and his/her reproductive partner has DFNB1 deafness, the chance of having a deaf child is 50%.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

The following points are noteworthy:

  • Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.
  • Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a “treatment” or “cure,” or to be “prevented.”
  • 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. It is, therefore, important to ascertain and address the questions and concerns of the family/individual.
  • The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as “abnormal” should be avoided.

Family planning

  • The optimal time for determination of genetic status and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of the probability of deafness in offspring and reproductive options) to young adults who are deaf.

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, allelic variants, and hereditary hearing loss will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in the family, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for deafness or hearing loss are possible.

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 would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • My46 Trait Profile
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • my baby's hearing
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.

Management

Treatment of Manifestations

Ideally, the team evaluating and treating the deaf individual should consist of an otolaryngologist with expertise in the management of early childhood otologic disorders, an audiologist experienced in the assessment of hearing loss in children, a clinical geneticist, and a pediatrician. The expertise of an educator of the Deaf, a neurologist, and a pediatric ophthalmologist may also be required.

An important part of the evaluation is determining the appropriate habilitation option. Possibilities include hearing aids, vibrotactile devices, and cochlear implantation. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss.

The ultimate goal in the evaluation and treatment of a child with hereditary hearing loss and deafness is mainstream schooling. Research shows that diagnosis by age three months and habilitation by six months makes this goal possible for children with mild-moderate hearing loss. Cochlear implantation in children with severe-to-profound deafness who are part of mainstream education leads to social functioning and educational attainment that is indistinguishable from normal-hearing peers [Loy et al 2010, Langereis & Vermeulen 2015].

Recent research has focused on cochlear implant performance based on the gene involved. Due to the genetic heterogeneity of deafness, large sample sizes are difficult to obtain for performance on a per-gene basis. However, the data are clear that individuals with GJB2-related hearing loss (see Nonsyndromic Hearing Loss and Deafness, DFNB1) have excellent cochlear implant outcomes that are significantly better than those of individuals with environmental causes of deafness [Yoshida et al 2013, Abdurehim et al 2017].

In adults, cochlear implant performance may be compromised when the genetic defect affects the auditory nerve itself; however, this hypothesis requires further research [Shearer et al 2017].

DFNX3 is characterized by a mixed conductive-sensorineural hearing loss, the conductive component of which is caused by stapedial fixation. In contrast to other types of conductive hearing loss, surgical correction of DFNX3-related hearing loss can compromise hearing. An abnormal communication between the cerebrospinal fluid and perilymph can lead to fluid leakage ("perilymphatic gusher") at surgery and complete loss of hearing upon fenestration or removal of the stapes footplate.

Prevention of Primary Manifestations

Whenever a child presents with progressive sensorineural hearing loss and progressive ataxia, with or without neurologic or cutaneous symptoms, biotinidase deficiency should be considered, with initiation of treatment as early as possible to prevent irreversible sequelae.

Prevention of Secondary Complications

Regardless of its etiology, uncorrected hearing loss has consistent sequelae. Auditory deprivation through age two years is associated with poor reading performance, poor communication skills, and poor speech production. Educational intervention is insufficient to completely remediate these deficiencies. In contrast, early auditory intervention is effective – whether through amplification, otologic surgery, or cochlear implantation [Smith et al 2005].

Although decreased cognitive skills and performance in mathematics and reading are associated with deafness, examination of persons with hereditary hearing loss has shown that these deficiencies are not intrinsically linked to the cause of the deafness. For example, assessment of cognitive skills in individuals with GJB2-related hearing loss reveals a normal Hiskey IQ and normal reading performance after cochlear implantation [Bauer et al 2003]. Thus, early identification and timely intervention is essential for optimal cognitive development in children with prelingual deafness.

Surveillance

Sequential audiologic examinations are essential to:

  • Document the stability or progression of the hearing loss;
  • Identify and treat superimposed hearing losses, such as middle ear effusion.

In a person with autosomal recessive nonsyndromic hearing loss caused by pathogenic variants in SLC26A4, the hearing loss can progress and annual audiometric testing may be warranted. Additionally, thyroid function should be followed if the diagnosis is consistent with Pendred syndrome.

Agents/Circumstances to Avoid

Noise exposure is a well-recognized environmental cause of hearing loss. Since this risk can be minimized by avoidance, persons with documented hearing loss should be counseled appropriately.

Evaluation of Relatives at Risk

At a minimum, all children at risk for hereditary deafness and hearing loss should receive screening audiometry.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

References

Published Guidelines / Consensus Statements

  • Alford RL, Arnos KS, Fox M, Lin JW, Palmer CG, Pandya A, Rehm HL, Robin NH, Scott DA, Yoshinaga-Itano C; ACMG Working Group on Update of Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss; Professional Practice and Guidelines Committee. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Available online. 2014. Accessed 7-27-17. [PubMed: 24651602]

Literature Cited

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  • Bauer PW, Geers AE, Brenner C, Moog JS, Smith RJ. The effect of GJB2 allele variants on performance after cochlear implantation. Laryngoscope. 2003;113:2135–40. [PubMed: 14660916]

  • Fischel-Ghodsian N. Mitochondrial mutations and hearing loss: paradigm for mitochondrial genetics. Am J Hum Genet. 1998;62:15–9. [PMC free article: PMC1376819] [PubMed: 9443888]

  • Green GE, Scott DA, McDonald JM, Woodworth GG, Sheffield VC, Smith RJ. Carrier rates in the Midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999;281:2211–6. [PubMed: 10376574]

  • JAMA. Guide for the evaluation of hearing handicap. JAMA. 1979;241:2055–9. [PubMed: 430800]

  • Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007;17:253–76. [PubMed: 17579921]

  • Kimberlin DW, Jester PM, Sánchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri N, Englund JA, Estrada B, Jacobs RF, Romero JR, Sood SK, Whitworth MS, Abzug MJ, Caserta MT, Fowler S, Lujan-Zilbermann J, Storch GA, DeBiasi RL, Han JY, Palmer A, Weiner LB, Bocchini JA, Dennehy PH, Finn A, Griffiths PD, Luck S, Gutierrez K, Halasa N, Homans J, Shane AL, Sharland M, Simonsen K, Vanchiere JA, Woods CR, Sabo DL, Aban I, Kuo H, James SH, Prichard MN, Griffin J, Giles D, Acosta EP, Whitley RJ, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. NEJM. 2015;372:933–43. [PMC free article: PMC4401811] [PubMed: 25738669]

  • Kokotas H, Petersen MB, Willems PJ. Mitochondrial deafness. Clin Genet. 2007;71:379–91. [PubMed: 17489842]

  • Langereis M, Vermeulen A. School performance and wellbeing of children with CI in different communicative–educational environments. Int J Pediatr Otorhinolaryngol. 2015;79:834–9. [PubMed: 25840945]

  • Liming BJ, Carter J, Cheng A, Choo D, Curotta J, Carvalho D, Germiller JA, Hone S, Kenna MA, Loundon N, Preciado D, Schilder A, Reilly BJ, Roman S, Strychowsky J, Triglia JM, Young N, Smith RJ. International Pediatric Otolaryngology Group (IPOG) consensus recommendations: Hearing loss in the pediatric patient. Int J Pediatr Otorhinolaryngol. 2016;90:251–8. [PubMed: 27729144]

  • Loy B, Warner-Czyz AD, Tong L, Tobey EA, Roland PS. The children speak: an examination of the quality of life of pediatric cochlear implant users. Otolaryngol Head Neck Surg. 2010;142:247–53. [PMC free article: PMC2852181] [PubMed: 20115983]

  • Northern JL, Downs M. Hearing in Children. Baltimore, MD: Lippincott, Williams, and Wilkins; 2002.

  • Pandya A, Xia X-J, Erdenetungalag R, Amendola M, Landa B, Radnaabazar J, Dangaasuren B, Van Tuyle G, Nance WE. Heterozygous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. Am J Hum Genet. 1999;65:1803–6. [PMC free article: PMC1288397] [PubMed: 10577941]

  • Rudman JR, Kabahuma RI, Bressler SE, Feng Y, Blanton SH, Yan D, Liu XZ. The genetic basis of deafness in populations of African descent. J Genet Genomics. 2017;44:285–94. [PubMed: 28642064]

  • Zazo Seco C, Wesdorp M, Feenstra I, Pfundt R, Hehir-Kwa JY, Lelieveld SH, Castelein S, Gilissen C, de Wijs IJ, Admiraal RJ, Pennings RJ, Kunst HP, van de Kamp JM, Tamminga S, Houweling AC, Plomp AS, Maas SM, de Koning Gans PA, Kant SG, de Geus CM, Frints SG, Vanhoutte EK, van Dooren MF, van den Boogaard MH, Scheffer H, Nelen M, Kremer H, Hoefsloot L, Schraders M, Yntema HG. The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands. Eur J Hum Genet. 2017;25:308–14. [PMC free article: PMC5315517] [PubMed: 28000701]

  • Shearer AE, Eppsteiner RW, Frees K, Tejani V, Sloan-Heggen CM, Brown C, Abbas P, Dunn C, Hansen MR, Gantz BJ, Smith RJH. Genetic variants in the peripheral auditory system significantly affect adult cochlear implant performance. Hear Res. 2017;348:138–42. [PMC free article: PMC5527292] [PubMed: 28213135]

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  • Sloan-Heggen CM, Bierer AO, Shearer AE, Kolbe DL, Nishimura CJ, Frees KL, Ephraim SS, Shibata SB, Booth KT, Campbell CA, Ranum PT, Weaver AE, Black-Ziegelbein EA, Wang D, Azaiez H, Smith RJ. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016;135:441–50. [PMC free article: PMC4796320] [PubMed: 26969326]

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  • Taylor KR, Deluca AP, Shearer AE, Hildebrand MS, Black-Ziegelbein EA, Anand VN, Sloan CM, Eppsteiner RW, Scheetz TE, Huygen PL, Smith RJ, Braun TA, Casavant TL. AudioGene: predicting hearing loss genotypes from phenotypes to guide genetic screening. Hum Mutat. 2013;34:539–45. [PMC free article: PMC3753227] [PubMed: 23280582]

  • Toriello HV, Reardon W, Gorlin RJ, eds. Hereditary Hearing Loss and Its Syndromes. New York: Oxford University Press; 2004.

  • Van Camp G, Smith RJH. The Hereditary Hearing Loss Homepage. Available online. 2017. Accessed 7-25-17.

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  • Yang T, Vidarsson H, Rodrigo-Blomqvist S, Rosengren SS, Enerback S, Smith RJ. Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4). Am J Hum Genet. 2007;80:1055–63. [PMC free article: PMC1867094] [PubMed: 17503324]

  • Yoshida H, Takahashi H, Kanda Y, Usami S. Long term speech perception after cochlear implant in pediatric patients with GJB2 mutations. Auris Nasus Larynx. 2013;40:435–9. [PubMed: 23477838]

Chapter Notes

Author History

Glenn Edward Green, MD; University of Arizona (1999-2005)
Michael S Hildebrand, PhD (2010-present)
A Eliot Shearer (2012-present)
Richard JH Smith, MD (1999-present)
Guy Van Camp, PhD; University of Antwerp (1999-2017)

Revision History

  • 27 July 2017 (bp) Comprehensive update posted live
  • 9 January 2014 (rjhs) Revision: DFNA41 and DFNB76 added
  • 3 January 2013 (cd) Revision: clinical testing available for DFNB79 and DFNX4 (DFN6)
  • 5 January 2012 (cd) Revision: clinical testing for mutations in MT-CO1 associated with hearing loss and multi-gene hearing loss/deafness panels now listed in the GeneTests™ Laboratory Directory
  • 14 October 2010 (me) Comprehensive update posted live
  • 2 December 2008 (rjs) Revision: DFNB23 added
  • 28 October 2008 (me) Comprehensive update posted live
  • 30 January 2007 (rjs) Revision: clinical testing and prenatal diagnosis available for DFNB9
  • 4 December 2006 (rjs) Revision: clinical testing available for DFNB21 and DFNA8/12
  • 22 August 2006 (rjs) Revision: to incorporate concerns of reader regarding hearing impairment scales
  • 30 December 2005 (me) Comprehensive update posted to live Web site
  • 18 February 2005 (rjs) Revision: clinical availability of testing, KCNQ4-related DFNA2
  • 15 July 2004 (rjs) Revision: use of an interpreter
  • 18 December 2003 (cd,rjs) Revision: change in test availability
  • 3 November 2003 (me) Comprehensive update posted to live Web site
  • 13 January 2003 (cd) Revision: test availability
  • 24 April 2001 (me) Comprehensive update posted to live Web site
  • 14 February 1999 (pb) Overview posted to live Web site
  • 30 October 1998 (rjs) Original overview submission [Supported in part by grants 1RO1DC02842 and 1RO1DC03544 (RJHS) and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC).]