OTOF-Related Hearing Loss
Synonyms: DFNB9, Otoferlin-Related Hearing Loss
Hela Azaiez, PhD, Ryan K Thorpe, MD, Amanda M Odell, MS, LGC, and Richard JH Smith, MD.
Author Information and AffiliationsInitial Posting: February 29, 2008; Last Update: March 13, 2025.
Estimated reading time: 31 minutes
Summary
Clinical characteristics.
OTOF-related hearing loss is an auditory synaptopathy that results from defective synaptic transmission from normally functioning cochlear inner hair cells (IHCs) to the auditory nerve. Thus, newborn hearing screening (NBHS) that relies on otoacoustic emission (OAE) testing, which primarily assesses function of outer hair cells (OHCs), is usually normal, whereas hearing tests that rely on auditory brain stem response (ABR) testing are abnormal given the failure of signal transmission from IHCs to the auditory nerve. All individuals with OTOF-related hearing loss have severely impaired speech discrimination.
The two phenotypes comprising OTOF-related hearing loss are typical OTOF-related hearing loss and atypical OTOF-related hearing loss. Typical OTOF-related hearing loss is characterized by congenital or prelingual, typically severe-to-profound bilateral hearing loss (70 to ≥90 dB) associated with normal OAEs and abnormal ABRs. With age, OAEs decrease or disappear in 20%-80% of individuals. Atypical OTOF-related hearing loss is characterized by either temperature-sensitive OTOF-related hearing loss or progressive OTOF-related hearing loss. Temperature-sensitive OTOF-related hearing loss is characterized by hearing that ranges from normal hearing to moderate hearing loss (0-55 dB) at baseline body temperature and declines to bilateral hearing loss ranging from severe (71-90 dB) to profound (>90 dB) with an elevation of body temperature (approximately 0.5 °C or more). The increased hearing loss resolves typically within hours of baseline body temperature returning to normal. Progressive OTOF-related hearing loss ranges from mild to moderate at onset, and over the course of a few months or years could progress to profound. Rate of hearing loss progression is variable.
Management.
Treatment of manifestations: There is no cure for OTOF-related hearing loss. Early auditory intervention is critical to the development of speech and language. Habilitation options are tailored to the degree and frequency of hearing loss. While hearing aids may be trialed in persons with mild-to-severe hearing loss, these are unlikely to be beneficial due to auditory synaptopathy being the underlying cause. In contrast, cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. Educational and early intervention programs designed for individuals with hearing loss should start as early as possible. For individuals with atypical temperature-sensitive OTOF-related hearing loss, prevent febrile episodes and avoid exercise and/or ambient conditions that would cause body temperature to rise. Treat febrile episodes as quickly as possible.
Surveillance: To monitor the individual's response to supportive care and the emergence of new manifestations, the primary focus should be routine audiometric follow up. The frequency of follow up should be individualized and is likely to vary over time.
Agents/circumstances to avoid: For individuals with temperature-sensitive OTOF-related hearing loss, prevent fevers and other activities/ambient conditions that would cause body temperature to rise.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband shortly after birth by molecular genetic testing for the OTOF pathogenic variants found in the proband so that appropriate early support and management can be provided to the child and family.
Genetic counseling.
OTOF-related hearing loss is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an OTOF pathogenic variant, each sib of an affected individual has at conception a 25% chance of having OTOF-related hearing loss, a 50% chance of being a carrier and not having OTOF-related hearing loss, and a 25% chance of not being a carrier and not having OTOF-related hearing loss. Once the pathogenic variants have been identified in a family member with OTOF-related hearing loss, prenatal and preimplantation genetic testing for OTOF-related hearing loss are possible.
GeneReview Scope
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| OTOF-Related Hearing Loss: Included Phenotypes |
|---|
| Typical OTOF-related hearing loss |
| Atypical (temperature-sensitive or progressive) OTOF-related hearing loss |
Diagnosis
No consensus clinical diagnostic criteria for OTOF-related hearing loss have been published.
Suggestive Findings
OTOF-related hearing loss should be considered in two scenarios: an abnormal newborn hearing screening (NBHS) result and a symptomatic individual.
Scenario 1: Abnormal Newborn Hearing Screening (NBHS) Result
Universal NBHS using physiologic screening is required by law or rule in all 50 states in the US and is performed on >98% of children in the US typically within days after birth (see 2020 Summary of National CDC EHDI Data). NBHS uses either otoacoustic emissions (OAEs), which measure the response of cochlear outer hair cells (OHCs) to auditory stimuli, or automated auditory brain stem response (AABR) testing, which measures the physiologic response of cochlear inner hair cells (IHCs), auditory nerves, the brain stem, and the brain to auditory stimuli.
Typical OTOF-related hearing loss. Newborns with typical OTOF-related hearing loss have congenital severe-to-profound hearing loss characterized by normal OAEs, indicating normal OHC function, and an abnormal auditory brain stem response (ABR), indicating an abnormal IHC response and altered transmission of auditory signal from the IHCs to the brain. NBHS testing based only on OAEs will fail to detect typical OTOF-related hearing loss in most newborns [Kitao et al 2019, Thorpe et al 2022]. Typical OTOF-related hearing loss will be identified with physiologic NBHS only if AABR testing is used as part of the screen.
Atypical OTOF-related hearing loss includes temperature-sensitive hearing loss and progressive hearing loss.
Abnormal NBHS result. The following evaluations need to begin immediately on receipt of an abnormal NBHS result:
Confirmatory audiometric testing, typically diagnostic ABR testing. 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 loss in newborns with OTOF-related hearing loss ranges from moderate (41-55 dB) to moderately severe (56-70 dB) to severe (71-90 dB) to profound (>90 dB).
Medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss, who will perform examinations including: (1) otomicroscopic evaluation for other causes of hearing loss such as conductive hearing loss resulting from otitis media (fluid in the middle ear) and outer and middle ear abnormalities; and (2) evaluation for features of a syndrome that may be associated with hearing loss.
Scenario 2: Symptomatic Individual
Typical OTOF-related hearing loss
Clinical findings. Bilateral
congenital hearing loss with an otherwise unremarkable medical history and normal physical examination and inner ear imaging (if obtained)
Audiometric testing. Normal OAEs and abnormal ABR. The hearing loss is typically severe to profound [
Ford et al 2023]. The audiogram demonstrates flat hearing loss at all frequencies. In instances of severe hearing loss, progression to profound deafness is common [
Thorpe et al 2022].
Temperature-sensitive OTOF-related hearing loss
Progressive OTOF-related hearing loss
Suggestive findings. Bilateral hearing loss with variable onset, severity, and progression and an otherwise unremarkable medical history, normal physical examination, and inner ear imaging (if obtained)
Audiometric testing. Normal OAEs and abnormal ABRs. The hearing loss ranges from mild to moderate and progresses over time [
Ford et al 2023].
Family history. Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of OTOF-related hearing loss is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in OTOF identified by molecular genetic testing (see Table 1).
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic OTOF variants of uncertain significance (or of one known OTOF pathogenic variant and one OTOF variant of uncertain significance) does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include a combination of gene-targeted testing (various multigene panels) and comprehensive
genomic testing (exome sequencing, genome sequencing). Gene-targeted testing may require the clinician determine which gene(s) are likely involved, unless the multigene panel includes all genes known to be implicated in nonsyndromic hearing loss (see Option 1); comprehensive exome and genome sequencing does not (see Option 2).
Note: Single-gene testing (sequence analysis of OTOF, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
Option 1
A
multigene panel that includes OTOF and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which genes is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
To date, if annotating on the transcript NM_001287489.2, no deep intronic variants are reported. Therefore, the majority of OTOF pathogenic variants (e.g., missense, nonsense) are within the coding region and should be identified on any multigene panel that includes all genes implicated in nonsyndromic hearing loss and also by exome sequencing.
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 OTOF-Related Hearing Loss
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| Gene 1 | Method | Proportion of Pathogenic Variants 2 Identified by Method |
|---|
|
OTOF
| Sequence analysis 3 | 98% 4 |
| Gene-targeted deletion/duplication analysis 5 | ~2% 4, 6 |
- 1.
- 2.
- 3.
- 4.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.
- 6.
Clinical Characteristics
Clinical Description
OTOF-related hearing loss is an auditory synaptopathy that results from defective synaptic transmission from normally functioning cochlear inner hair cells (IHCs) to the auditory nerve [Santarelli et al 2021]. Thus, newborn hearing screening (NBHS) that relies on otoacoustic emission (OAE) testing, which primarily assesses function of outer hair cells (OHCs), is usually normal, whereas hearing tests that rely on auditory brain stem response (ABR) testing are abnormal given the failure of signal transmission from IHCs to the auditory nerve. All individuals with OTOF-related hearing loss have severely impaired speech discrimination.
The two phenotypes comprising OTOF-related hearing loss are typical OTOF-related hearing loss and atypical OTOF-related hearing loss.
Typical OTOF-related hearing loss is characterized by congenital or prelingual, typically severe-to-profound bilateral hearing loss (70 to ≥90 dB) associated with normal OAEs and abnormal ABRs. Therefore, NBHS based only on OAEs will fail to detect OTOF-related hearing loss. With age, OAEs decrease or disappear in 20%-80% of affected individuals [Thorpe et al 2022, Ford et al 2023].
Atypical OTOF-related hearing loss is characterized by either temperature-sensitive OTOF-related hearing loss or progressive OTOF-related hearing loss.
Temperature-sensitive OTOF-related hearing loss is characterized by hearing that ranges from normal hearing to moderate hearing loss (0-55 dB) at baseline body temperature and declines to bilateral hearing loss ranging from severe (71-90 dB) to profound (>90 dB) with an elevation of body temperature (approximately 0.5 °C or more). The increased hearing loss resolves typically within hours of baseline body temperature returning to normal. (See
Genotype-Phenotype Correlations for
OTOF pathogenic variants known to be associated with this
phenotype.)
Progressive OTOF-related hearing loss ranges from mild to moderate at onset, and over the course of a few months or years could progress to profound. Rate of hearing loss progression is variable. (See
Genotype-Phenotype Correlations for
OTOF pathogenic variants known to be associated with this
phenotype.)
Genotype-Phenotype Correlations
Classes of pathogenic variants [Thorpe et al 2022]
All individuals with atypical temperature-sensitive OTOF-related hearing loss have either biallelic nontruncating pathogenic variants in OTOF or one truncating and one nontruncating pathogenic variant in OTOF.
Specific nontruncating pathogenic variants associated with atypical OTOF-related hearing loss include the following [Vona et al 2020]:
Temperature-sensitive OTOF-related
hearing loss. The 13 pathogenic variants associated with temperature-sensitive
OTOF-related hearing loss include the following: p.Ile515Thr, p.Gly541Ser, p.Gly614Glu, p.Leu795SerfsTer5, p.Glu841Lys, p.Gln994ValfsTer7, p.Arg1080Pro, p.Arg1116Ter, p.Arg1607Trp, p.Pro1628Thr, p.Glu1700Gln, p.Glu1804del, and c.(897+1_898-1)_(1579+1_1580-1)del. Three of these variants (p.Glu841Lys, p.Gln994ValfsTer7, and p.Gllu1700Gln) have also been reported in persons with typical
OTOF-related hearing loss and atypical progressive
OTOF-related hearing loss, suggesting compound heterozygosity for at least one temperature-sensitive
pathogenic variant results in this
phenotype (see
Table 3).
Progressive OTOF-related
hearing loss. Four pathogenic variants in
OTOF have been associated with hearing loss that is typically prelingual. The hearing loss ranged from mild to moderate at onset and in some individuals progressed over the course of a few months or years to reach profound (see
Table 3).
Homozygosity for
pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [
Yildirim-Baylan et al 2014].
Homozygosity for
pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [
Chiu et al 2010].
Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [
Matsunaga et al 2012].
Nomenclature
Auditory neuropathy can result from a variety of environmental, developmental, and genetic factors. The complex factors involved in the etiology and pathophysiology of auditory neuropathy led to a consensus to use the term auditory neuropathy spectrum disorder (ANSD) (see Guidelines for Identification and Management of Infants and Young Children with Auditory Neuropathy Spectrum Disorder).
ANSD can be caused by several different defects in the auditory system including the synaptic region (synaptopathy) and the auditory nerve (neuropathy). Because OTOF-related hearing loss is due to lesions at the presynaptic region of inner hair cells, the terms auditory synaptopathy or prelingual nonsyndromic ANSD are appropriate.
Temperature-sensitive OTOF-related hearing loss may be referred to as temperature-sensitive auditory neuropathy spectrum disorder (TS-ANSD).
Auditory dys-synchrony is a historical term used to describe the mismatch between outer hair cell and inner hair cell activity reflected by the difference between ABR and OAE testing.
Prevalence
The prevalence of OTOF pathogenic variants in persons with congenital autosomal recessive nonsyndromic hearing loss varies by ethnicity. Among individuals with congenital/prelingual autosomal recessive hearing loss, prevalence of biallelic OTOF pathogenic variants has been reported in the following populations:
56.5% of
OTOF-related hearing loss in the Korean population is due to the
pathogenic variant p.Arg1939Gln.
The prevalence of temperature-sensitive auditory neuropathy is unknown.
Differential Diagnosis
Due to the heterogeneity of auditory neuropathy spectrum disorder (ANSD), it is difficult to estimate the prevalence of environmental versus genetic causes. Environmental causes include cytotoxic agents (e.g., cisplatin), prematurity, hyperbilirubinemia, septicemia, loop diuretics, and aminoglycoside use [Harrison et al 2015]. Infants in the neonatal intensive care unit (NICU) are at particularly high risk for environmental factors, with the prevalence of ANSD approximately 5.6 in 1,000 [Xoinis et al 2007].
As of this writing, more than 85 genes have been associated with autosomal recessive nonsyndromic hearing loss and seven genes have been associated with nonsyndromic ANSD (see Table 2).
Up to 8% of congenital nonsyndromic hearing loss is associated with pathogenic variants in OTOF [Ford et al 2023]. Among individuals with ANSD, OTOF is found in 41%-91% of those tested [Zhang et al 2016a, Kim et al 2018].
For a list of selected genes associated with distinctive clinical features, see Genetic Hearing Loss Overview, Table 3. For a current, comprehensive list of all identified autosomal recessive nonsyndromic hearing loss genes, see Hereditary Hearing Loss Homepage.
Loss of otoacoustic emissions (OAEs) over time is found in other forms of genetic auditory neuropathy, such as with OPA1-related hearing loss [Kitao et al 2019].
Table 2.
Other Nonsyndromic Genetic Auditory Neuropathy Spectrum Disorders
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Note: Unilateral OTOF-related hearing loss has not been reported (i.e., severe-to-profound hearing loss in only one ear with electrophysiologic responses consistent with auditory neuropathy). A cochlear defect should be considered in individuals with unilateral hearing loss, and an MRI is indicated [Liddle et al 2022].
Differential diagnosis of temperature-sensitive auditory neuropathy spectrum disorder. Although other disorders, such as Muckle-Wells syndrome (cryopyrin-associated periodic syndrome; OMIM 191900), are associated with progressive deafness and intermittent fevers, the fever itself does not cause a fluctuating hearing loss [Kuemmerle-Deschner et al 2013].
Management
No clinical practice guidelines specific for OTOF-related hearing loss have been published.
Management ideally occurs in the context of a multidisciplinary clinic with specialists in otolaryngology, audiology, and genetic counseling. See Genetic Hearing Loss Overview, Management.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with OTOF-related hearing loss, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Assess auditory acuity:
Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [
Young et al 2023] and should be performed if not already done by the time the diagnosis of
OTOF-related hearing loss has been established in a newborn/infant.
Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [
Kileny et al 2020]. Standard pure-tone audiometry can be reliably performed in children only after about age five years [
Sommerfeldt & Kolb 2023]. Behavioral observation audiometry is used in children younger than age six months, while visual reinforcement audiometry is used between ages six months and two years. Conditioned play audiometry is used between ages two and five years.
Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for
OTOF-related hearing loss. Speech discrimination testing in noise may be worse than expected based on the severity of hearing loss [
Vona et al 2020].
Consult with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature,
mode of inheritance, and implications of
OTOF-related hearing loss and to facilitate medical and personal decision making.
Assess the need for family support and resources including community or online
resources and social work involvement for parental support.
See also Genetic Hearing Loss Overview.
Treatment of Manifestations
There is no cure for OTOF-related hearing loss.
Hearing habilitation. Early auditory intervention is critical to the development of speech and language. Habilitation options are tailored to the degree and frequency of hearing loss.
Hearing aids may be trialed in persons with mild-to-severe hearing loss; however, these are unlikely to be beneficial due to the etiology of auditory synaptopathy. A systematic review of 32 individuals with
OTOF-related hearing loss found that none derived benefit in speech perception from hearing aids [
Ford et al 2023].
Cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. A systematic review of 100 individuals with
OTOF-related hearing loss treated with cochlear implants found improvement in speech perception in the vast majority [
Zheng & Liu 2020,
Ford et al 2023].
Educational and early intervention programs designed for individuals with hearing loss are recommended (see Genetic Hearing Loss Overview, Management).
For individuals with atypical temperature-sensitive OTOF-related hearing loss:
Prevent febrile episodes.
Avoid the level of exercise and/or ambient conditions that would cause body temperature to rise.
Treat febrile episodes as quickly as possible to return body temperature to normal.
Inform individuals with
OTOF-related hearing loss and their caregivers that the onset of hearing loss may be the first sign of a pyretic/infectious event requiring treatment [
Starr et al 1998].
Surveillance
To monitor the individual's response to supportive care and the emergence of new manifestations, the primary focus should be routine audiometric follow up. The frequency of follow up should be individualized and is likely to vary over time. For example, initial follow up may include audiometry and speech discrimination testing every six months; however, if a child receives a cochlear implant, the scheduled follow up will change. Post implantation, there will be frequent evaluations as recommended by the cochlear implant team (otolaryngologist, audiologist, and speech-language pathologist). At subsequent follow-up appointments, assessments may include speech recognition testing, equipment checks, and provision of replacement or upgraded equipment [Cullington et al 2016]. As the cochlear implant recipient and family become comfortable with the cochlear implant, many of the above tasks can be performed at home, markedly decreasing the need for routinely scheduled appointments.
Agents/Circumstances to Avoid
Persons with temperature-sensitive OTOF-related hearing loss, avoid excessive body temperatures whenever possible (see Treatment of Manifestations).
Therapies Under Investigation
Gene therapy for OTOF-related hearing loss is advancing rapidly, with several clinical trials reporting promising results. The main approach involves adeno-associated virus (AAV)-mediated gene delivery, which aims to restore otoferlin expression in cochlear inner hair cells (IHCs).
The first AAV-
OTOF therapy in humans was performed in two children (ages 5 and 8 years) by delivering the therapy unilaterally through the round window membrane to assess safety, auditory recovery, and speech perception. The five-year-old child achieved full hearing restoration in the treated ear within one month. The eight-year-old child, while not reaching normal hearing levels, had significant improvement in auditory function and speech comprehension. No severe adverse effects were reported [
Qi et al 2024].
A single-arm trial with AAV1-hOTOF therapy (AAV serotype 1 carrying human
OTOF transgene) was performed in six individuals (ages 1-18 years) with severe-to-profound
congenital deafness due to confirmed
biallelic OTOF pathogenic variants. Five experienced significant hearing gains, with ABR thresholds improving by 40-57 dB at 26 weeks. A participant who received a lower dose of AAV1-hOTOF showed gradual improvement from >95 dB at baseline to 45 dB at 26 weeks, while those receiving a higher dose achieved thresholds of 38-55 dB. No dose-limiting toxicity occurred, though mild, transient adverse events (e.g., low neutrophil counts) were reported. Speech perception improved [
Lv et al 2024].
A bilateral AAV1-hOTOF
gene therapy trial in five children between ages one and six years with
OTOF-related hearing loss showed no serious adverse events and significant hearing restoration. ABR thresholds improved from >95 dB to 55-85 dB at 26 weeks, with enhanced speech perception and sound localization [
Wang et al 2024].
Five ongoing clinical trials are recruiting individuals with OTOF-related hearing loss:
NCT05821959 by Akouos, Inc - Gene Therapy Trial for Otoferlin Gene-Mediated Hearing Loss. This trial is currently enrolling children (ages 2-17 years) in sites in the United States, United Kingdom, and Taiwan.
NCT05788536 by Regeneron Pharmaceuticals - A Study of DB-OTO, an Adeno-Associated Virus (AAV)-Based Gene Therapy, in Children/Infants with Hearing Loss due to Otoferlin Mutations (CHORD). The CHORD trial is an ongoing, Phase I/II first-in-human, multicenter, open-label trial to evaluate the safety, tolerability, and preliminary efficacy of DB-OTO in infants, children, and adolescents with pathogenic variants in
OTOF. It is currently enrolling children (age <18 years) across sites in the United States, United Kingdom, and Spain.
NCT05901480 by Otovia Therapeutics - An Investigator-Initiated Study for OTOV101N+OTOV101C Injection
NCT06722170 by Fudan University, China - A Study of EH002 Gene Therapy for Otoferlin Gene Mutation-Mediated Hearing Loss
NCT06370351 by Sensorion - A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe-to-Profound Hearing Loss Due to Otoferlin (
OTOF) Mutations (AUDIOGENE). This study intends to assess safety, tolerability, and efficacy of SENS-501 in children between ages six and 31 months with prelingual
OTOF-related hearing loss.
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 conditions.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Risk to Family Members
Parents of a proband
Molecular genetic testing is recommended for the parents of the
proband to confirm that both parents are
heterozygous for an
OTOF pathogenic variant and to allow reliable recurrence assessment.
If a
pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the
proband occurred as a
de novo event in the proband or as a
postzygotic de novo event in a mosaic parent [
Jónsson et al 2017]. If the proband appears to have
homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
Sibs of a proband
If both parents are known to be
heterozygous for an
OTOF pathogenic variant, each sib of an affected individual has at conception a 25% chance of having
OTOF-related hearing loss, a 50% chance of being a
carrier and not having
OTOF-related hearing loss, and a 25% chance of not being a carrier and not having
OTOF-related hearing loss.
Typical
OTOF-related hearing loss is severe to profound, and
interfamilial variability is not reported. Interfamilial variability can be seen in atypical progressive
OTOF-related hearing loss.
Offspring of a proband. Unless the proband's reproductive partner also has OTOF-related hearing loss or is a carrier of an OTOF pathogenic variant, offspring will be obligate heterozygotes (i.e., carriers of an OTOF pathogenic variant).
Other family members. Each sib of the proband's parents has a 50% chance of being a carrier of an OTOF pathogenic variant.
Carrier Detection
Carrier testing for relatives requires prior identification of the OTOF pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
Once the OTOF pathogenic variants have been identified in a family member with OTOF-related hearing loss, prenatal and preimplantation genetic testing for OTOF-related hearing loss are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Alexander Graham Bell Association for the Deaf and Hard of Hearing
Phone: 202-337-5220
Email: info@agbell.org
American Society for Deaf Children
Phone: 800-942-2732 (ASDC)
Email: info@deafchildren.org
BabyHearing.org
This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
MedlinePlus
National Association of the Deaf
Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
Fax: 301-587-1791
Email: nad.info@nad.org
Newborn Screening in Your State
Health Resources & Services Administration
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
OTOF-Related Hearing Loss: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Molecular Pathogenesis
OTOF encodes otoferlin, a member of the FER-1 family of transmembrane proteins characterized by the presence of C2 domains [Yasunaga et al 1999]. Otoferlin contains six C2 domains (C2A-F), a transmembrane domain, and two Fer domains [Roux et al 2006, Lek et al 2010]. Otoferlin is a Ca2+ sensor that is expressed in cochlear inner hair cells (IHCs), where it plays a significant role in synaptic transmission by tethering glutamatergic synaptic vesicles to the plasma membrane and triggering their fusion and pool replenishment at ribbon synapses, processes essential for sound localization and speech comprehension [Strenzke et al 2016, Michalski et al 2017]. Because normal hearing relies on a temporally precise and sustained glutamate release at these ribbon synapses, defects in otoferlin compromise exocytosis of synaptic vesicles and their reformation, leading to impaired signal transmission to the auditory nerve. Consequently, individuals with biallelic OTOF pathogenic variants have congenital severe-to-profound hearing loss (see ) characterized by normal otoacoustic emissions (OAEs), indicating normal cochlear function, and abnormal auditory brain stem responses (ABRs), indicating altered transmission of auditory signal from the synapse to the brain and impaired speech discrimination.
Genetic spectrum of OTOF-related hearing loss A. Different types of pathogenic variants have been identified in OTOF, including missense, nonsense, frameshift, splice, inframe indels, and copy number variants (CNV).
Mechanism of disease causation. Loss of function
OTOF-specific laboratory technical considerations. Variants in OTOF should be annotated on transcript NM_001287489.2, the cochlea-specific transcript.
Table 3.
OTOF Pathogenic Variants Referenced in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
TS-OTOF-HL = atypical temperature-sensitive OTOF-related hearing loss
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Chapter Notes
Author Notes
The Hereditary Hearing Loss Homepage provides an up-to-date overview of the genetics of hereditary hearing impairment for researchers and clinicians, and lists data and links for all known gene localizations and identifications for monogenic nonsyndromic hearing impairment.
The Deafness Variation Database (DVD) [Azaiez et al 2018] collates, annotates, and classifies all genetic variants related to syndromic and nonsyndromic hearing loss. Data are collated from all major public databases and used to generate an evidence-based single classification for each variant, which is then curated by experts in hereditary hearing loss.
Acknowledgments
The work in this GeneReview was supported in part by grants R01s DC002842, DC012049, and DC017955 (RJHS) and 5T32DC000040 (RKT).
Author History
Hela Azaiez, PhD (2021-present)
Jose G Gurrola III, MD; University of Iowa (2007-2015)
Philip M Kelley, PhD; Boys Town National Research Hospital (2007-2015)
Amanda M Odell, MS, LGCA (2025-present)
Eliot Shearer, MD, PhD; University of Iowa (2015-2021)
Richard JH Smith, MD (2007-present)
Ryan K Thorpe, MD (2021-present)
Revision History
13 March 2025 (bp) Comprehensive update posted live
21 January 2021 (ha) Comprehensive update posted live
30 July 2015 (me) Comprehensive update posted live
26 April 2011 (me) Comprehensive update posted live
29 February 2008 (me) Review posted live
15 October 2007 (rjhs) Original submission
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