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.

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.

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.

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).

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).

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 multigene 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 multigene sequencing panels for genetic diagnosis (see Evaluation Strategy).

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.)

Autosomal Dominant Inheritance – Risk to Family Members

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, the parent's 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.

Autosomal Recessive Inheritance – Risk to Family Members

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 (carriers) 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.

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

X-Linked Inheritance – Risk to Family Members

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 sex, 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.

Empiric Risk to Family Members

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 nonconsanguineous 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 the sib's 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant(s) have been identified in the family, prenatal and preimplantation genetic testing for deafness or 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.

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-to-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.

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 multigene 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 live
• 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 live
• 13 January 2003 (cd) Revision: test availability
• 24 April 2001 (me) Comprehensive update posted live
• 14 February 1999 (pb) Overview posted live
• 30 October 1998 (rjs) Original overview submission [Supported in part by grants 1RO1DC02842 and 1RO1DC03544 (RJHS) and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC).]

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 10-26-22.

Literature Cited

• Abdurehim Y, Lehmann A, Zeitouni AG. Predictive value of GJB2 mutation status for hearing outcomes of pediatric cochlear implantation. Otolaryngol Head Neck Surg. 2017;157:16–24. [PubMed: 28322114]
• 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]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• 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]
• Shearer AE, Kolbe DL, Azaiez H, Sloan CM, Frees KL, Weaver AE, Clark ET, Nishimura CJ, Black-Ziegelbein EA, Smith RJ. Copy number variants are a common cause of non-syndromic hearing loss. Genome Med. 2014;6:37. [PMC free article: PMC4067994] [PubMed: 24963352]
• Shearer AE, Smith RJH. Massively parallel sequencing for genetic diagnosis of hearing loss: the new standard of care. Otolaryngol Head Neck Surg. 2015;153:175–82. [PMC free article: PMC4743024] [PubMed: 26084827]
• 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]
• Smith RJH, Bale JF, White KR. Sensorineural hearing loss in children. Lancet. 2005;365:879–90. [PubMed: 15752533]
• 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 10-26-22.
• Yamasoba T, Lin FR, Someya S, Kashio A, Sakamoto T, Kondo K. Current concepts in age-related hearing loss: epidemiology and mechanistic pathways. Hear Res. 2013;303:30–8. [PMC free article: PMC3723756] [PubMed: 23422312]
• 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]