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OTOF-Related Deafness

Synonyms: DFNB9, DFNB9 Nonsyndromic Hearing Loss

, MD, PhD and , MD.

Author Information

Initial Posting: ; Last Update: July 30, 2015.

Estimated reading time: 16 minutes


Clinical characteristics.

OTOF-related deafness (DFNB9 nonsyndromic hearing loss) is characterized by two phenotypes: prelingual nonsyndromic hearing loss and, less frequently, temperature-sensitive nonsyndromic auditory neuropathy (TS-NSAN). The nonsyndromic hearing loss is bilateral severe-to-profound congenital deafness. In the first one or two years of life, OTOF-related deafness can appear to be an auditory neuropathy based on electrophysiologic testing in which auditory brain stem responses (ABRs) are absent and otoacoustic emissions (OAEs) are present. However, with time OAEs disappear and electrophysiologic testing is more consistent with a cochlear defect. The distinction between auditory neuropathy and a cochlear defect is important as cochlear implants may be of marginal value in persons with auditory neuropathy but have been shown to be effective for individuals with OTOF-related deafness. TS-NSAN is characterized by normal-to-mild hearing loss in the absence of fever and significant hearing loss ranging from severe to profound in the presence of fever. When the fever resolves, hearing returns to normal.


The diagnosis of OTOF-related deafness is suspected based on clinical findings, including results of ABR and OAE. The diagnosis is confirmed by identification of biallelic deafness-related variants in OTOF, the gene encoding the protein otoferlin.


Treatment of manifestations: In individuals with nonsyndromic bilateral congenital hearing loss, hearing aids as soon as possible, consideration of cochlear implants which have been shown to be effective for OTOF-related deafness, and educational programs designed for individuals with hearing impairment.

Prevention of primary manifestations: For individuals with TS-NSAN, prevent fevers and other activities/ambient conditions that would cause body temperature to rise.

Surveillance: In individuals with nonsyndromic bilateral congenital hearing loss, semiannual/annual examination by a physician familiar with hereditary hearing impairment, repeat audiometry initially every three to six months to determine if hearing loss is progressive.

Evaluation of relatives at risk: Evaluation of sibs as soon as possible after birth for hearing loss; if the OTOF deafness-related variants in the family are known, molecular genetic testing of sibs shortly after birth so that appropriate early support and management can be provided to the child and family.

Genetic counseling.

OTOF-related deafness is inherited in an autosomal recessive manner. At conception, each sib of an individual with OTOF-related deafness has a 25% chance of having OTOF-related deafness, a 50% chance of being a carrier, and a 25% chance of not having a deafness-related variant in OTOF. Carrier testing for relatives and prenatal testing for pregnancies are possible if the deafness-related variants in a family are known.

GeneReview Scope

OTOF-Related Deafness: Included Phenotypes 1
  • Prelingual nonsyndromic hearing loss
  • Temperature-sensitive nonsyndromic auditory neuropathy (TS-NSAN)

For synonyms and outdated names see Nomenclature.


For other genetic causes of these phenotypes see Differential Diagnosis.


Suggestive Findings

OTOF-related deafness should be suspected in individuals with:

  • Congenital auditory neuropathy without a history of causative environmental factors (e.g., neonatal hyperbilirubinemia and neonatal hypoxia);
  • Temperature-sensitive nonsyndromic auditory neuropathy.

Note: In the first one or two years of life, OTOF-related deafness can appear to be an auditory neuropathy based on electrophysiologic testing in which auditory brain stem responses (ABRs) are absent and otoacoustic emissions (OAEs) are present. However, with time OAEs disappear and electrophysiologic testing becomes more consistent with a cochlear defect.

Establishing the Diagnosis

The diagnosis of OTOF-related deafness is established in a proband with identification of biallelic deafness-related variants in OTOF on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of OTOF is performed first followed by gene-targeted deletion/duplication analysis if only one or no deafness-related variant is found.
  • A multigene panel that includes OTOF and other genes of interest (see Differential Diagnosis) may be considered if single-gene testing is negative or as a first-line test if single-gene testing is not available for OTOF. Note: 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) 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.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of OTOF-related deafness.
    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 Deafness

Gene 1Test MethodProportion of Probands with Deafness-Related Variants 2 Detectable by This Method
OTOFSequence analysis 399%
Gene-targeted deletion/duplication analysis 4Unknown 5

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely deafness-related, or deafness-related. Deafness-related variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications and may be performed as a single- or multigene panel. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or a gene-targeted microarray designed to detect single-exon deletions or duplications.


There has been one report of a deletion involving OTOF [Zadro et al 2010] but a recent study evaluating CNVs in 686 individuals with hearing loss showed no copy number variants in OTOF [Shearer et al 2014] and therefore the detection rate is unknown.

Clinical Characteristics

Clinical Description

The two phenotypes observed in OTOF-related deafness are prelingual nonsyndromic hearing loss and, less frequently, temperature-sensitive nonsyndromic auditory neuropathy (TS-NSAN).

OTOF-related nonsyndromic hearing loss is characterized by prelingual, typically severe-to-profound deafness without inner-ear anomalies on MRI or CT examination of the temporal bones. Severe deafness is defined as hearing loss of 71-90 dB; profound deafness is a greater than 90-dB hearing loss.

TS-NSAN typically presents with normal-to-mild hearing loss when the individual is afebrile. With onset of fever, persons with TS-NSAN have significant hearing loss ranging from severe to profound; hearing returns to normal once the fever is resolved. Speech discrimination has been described as normal to slightly decreased at baseline with significant worsening during febrile periods.

Genotype-Phenotype Correlations

Only limited genotype-phenotype correlations have been made, primarily involving reports of temperature-sensitive nonsyndromic auditory neuropathy (TS-NSAN).


Nonsyndromic hearing loss caused by mutation of OTOF is likely to be classified as an auditory neuropathy when first detected in infants on hearing testing due to absence of auditory brain stem responses (ABRs) and presence of otoacoustic emissions (OAEs). However, this mismatch disappears over time such that deafness due to OTOF resembles a typical cochlear genetic deafness by several years of age. Auditory dyssynchrony is a historical term used to describe the mismatch between outer and inner hair cell activity reflected by the difference between ABR and OAE testing and auditory neuropathy or auditory neuropathy spectrum disorder is preferred.


The world-wide prevalence of OTOF deafness-related variants in persons with severe-to-profound congenital autosomal recessive nonsyndromic deafness remains unknown.

Differential Diagnosis

Congenital (or prelingual) inherited hearing impairment affects approximately one in 1,000 newborns; 30% of these infants have additional anomalies, making the diagnosis of a syndromic form of hearing impairment possible (see Hereditary Deafness and Hearing Loss Overview). In developed countries, approximately half of the remaining children (i.e., the 70% with nonsyndromic hearing impairment) segregate deafness-related variants in GJB2 [Smith et al 2005]. Variants in 28 genes (including OTOF) have been implicated in congenital autosomal recessive nonsyndromic deafness

Other nonsyndromic hereditary auditory neuropathies include the following:

OTOF deafness-related variants are extremely unlikely in a child with severe-to-profound hearing loss in only one ear and electrophysiologic responses consistent with auditory neuropathy. Instead, a cochlear defect should be considered; MRI is indicated [Buchman et al 2006].


Evaluations Following Initial Diagnosis

To establish the extent of involvement in an individual diagnosed with OTOF-related deafness, the following evaluations are recommended (see Hereditary Deafness and Hearing Loss Overview):

  • Assessment of auditory acuity (ABR emission testing, pure tone audiometry)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

See Hereditary Deafness and Hearing Loss Overview for details.

Hearing habilitation for those with nonsyndromic bilateral congenital hearing loss

  • Hearing aids should be fitted as soon as possible.
  • Cochlear implantation (CI) should be considered as soon as possible. Case reports have shown good outcomes of CI in individuals with OTOF-related deafness [Rouillon et al 2006, Wu et al 2011] and reviewed in Eppsteiner et al [2012].
    Note: In the first one or two years of life, OTOF-related deafness can appear to be an auditory neuropathy based on electrophysiologic testing; however, with time electrophysiologic testing becomes more consistent with a cochlear defect. Distinguishing between an auditory neuropathy and a cochlear defect is important as cochlear implants may be of marginal value in persons with auditory neuropathy such as that observed in deafness-dystonia-optic neuronopathy (DDON) [Brookes et al 2008] as well as individuals with deafness caused by pathogenic variants in spiral ganglion-expressed genes [Eppsteiner et al 2012].

Educational programs designed for individuals with hearing impairment are appropriate.

Prevention of Primary Manifestations

For individuals with TS-NSAN:

  • 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.
  • Educate individuals 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]. Appropriate precautions including avoidance of potentially dangerous or noisy situations should be encouraged.


For individuals with nonsyndromic bilateral congenital hearing loss:

  • Examine semiannually or annually by a physician familiar with hereditary hearing impairment.
  • Repeat audiometry initially every three to six months to determine whether hearing loss is progressive.

Agents/Circumstances to Avoid

Individuals with TS-NSAN. Avoid excessive body temperatures when possible. Follow-up studies have not demonstrated the success of preventative measures as an effective long-term treatment.

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 of the OTOF deafness-related variants found in the proband so that appropriate early support and management can be provided to the child and family.

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

Therapies Under Investigation

Search in the US and in Europe for access to information on clinical studies for a wide range of conditions. Note: There may not be clinical trials for this condition.

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

OTOF-related deafness is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of a child with OTOF-related deafness are obligate heterozygotes (i.e., carriers of one OTOF deafness-related variant).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an individual with OTOF-related deafness has a 25% chance of being deaf, a 50% chance of being a carrier, and a 25% chance of not having a deafness-related variant in OTOF.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with OTOF-related deafness are obligate heterozygotes (carriers of a deafness-related variant in OTOF).

Other family members of a proband. For each sib of the proband's parents, the probability of being a carrier of an OTOF deafness-related variant is 50%.

Carrier (Heterozygote) Detection

Carrier testing for relatives requires prior identification of the OTOF deafness-related variants in the family.

Related Genetic Counseling Issues

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

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 that offspring will be deaf and reproductive options) to young adults who have OTOF-related deafness, are carriers, or may be carriers.

The following points are noteworthy:

  • Communication with individuals who are deaf requires the services of a skilled interpreter.
  • Deaf persons 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." In fact, having a child with deafness may be preferred over having a child with normal hearing.
  • 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. As in all genetic counseling, it is important for the counselor to identify, acknowledge, and respect the individual's/family's questions, concerns, and fears.
  • The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "affected," "abnormal," and "disease-causing" should be avoided.

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 deafness will improve in the future, consideration should be given to banking DNA of deaf individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the OTOF deafness-related variants have been identified in a deaf family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for DFNB9-related deafness are possible.

Requests for prenatal testing for conditions which (like OTOF-related deafness) do not affect intellect or life span are not common. 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. While decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.


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
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
  • 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
    This site, developed with support from the National Institute on Deafness and Other Communication Disorders, provides information about newborn hearing screening and hearing loss.
  • 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
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease

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 Deafness: Genes and Databases

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.

Table B.

OMIM Entries for OTOF-Related Deafness (View All in OMIM)


Molecular Genetic Pathogenesis

Otoferlin belongs to a small family of membrane-anchored cytosolic proteins that includes dysferlin (encoded by DYSF), myoferlin (encoded by MYOF), and a predicted fourth member fer-1-like protein 4 (encoded by FER1L4). The ferlin genes are so named because of their structural similarity to a gene found in C. elegans, fer-1, which is required for normal maturation of spermatozoa.

With the exception of OTOF, hearing loss has not been associated with members of this gene family. DYSF is associated with three distinct types of distal myopathies: Miyoshi myopathy (MM), limb-girdle muscular dystrophy type 2B (LGMD2B), and distal myopathy with anterior tibial onset (DMAT) [Bashir et al 1998, Liu et al 1998, Weiler et al 1999] (see Dysferlinopathy). Myoferlin, which is encoded by MYOF, is required for normal myoblast fusion [Doherty et al 2005]. The function of fer-1-like protein 4 is not known (Figure 1).

Figure 1.

Figure 1.

Protein motif organization for the human ferlin gene family as determined by SMART [Schultz et al 1998, Letunic et al 2002] C2 (green) is the calcium-binding motif.

Gene structure. OTOF consists of 48 coding exons that extend over 100 kb of genomic DNA. The short isoforms have only three C2 domains. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. A number of non-pathogenic variants have been described. See Table 3 (pdf).

Pathogenic variants. The 117 deafness-related variants that have been reported in OTOF are distributed throughout the gene; see Deafness Variation Database [MORL 2015] and Table 4 (pdf). Most are predicted to be inactivating variants and are associated with severe-to-profound deafness [Yasunaga et al 1999, Adato et al 2000, Yasunaga et al 2000, Houseman et al 2001, Migliosi et al 2002, Mirghomizadeh et al 2002, Rodríguez-Ballesteros et al 2003, Varga et al 2003, Hutchin et al 2005, Tekin et al 2005, Rouillon et al 2006, Varga et al 2006]. No deafness-related variants have been reported to be more frequent in specific ethnic groups with the exception of c.2485C>T (p.Gln829Ter), which is present in 3%-5% of the Spanish population with severe-to-profound nonsyndromic, prelingual deafness [Migliosi et al 2002, Rodríguez-Ballesteros et al 2003] (Figure 2).

Figure 2. . Schematic of OTOF on chromosome 2p23.

Figure 2.

Schematic of OTOF on chromosome 2p23. The OTOF genomic structure comprises 48 exons that are used to transcribe the long isoform (NM_194248.2; NP_919224.1). The short isoform does not include the first 19 exons, which are shown as blue bars. The protein (more...)

Table 2.

Selected OTOF Deafness-Related Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
ReferencesReference Sequences
c.1544T>Cp.Ile515ThrMirghomizadeh et al [2002]NM_194248​.2
c.2485C>Tp.Gln829TerMigliosi et al [2002], Rodríguez-Ballesteros et al [2003]
Wang et al [2010]
c.4467dupCp.Ile1490HisfsTer19Yildirim-Baylan et al [2014]
c.4718T>Cp.Ile1573ThrYildirim-Baylan et al [2014]
c.4819C>Tp.Arg1607TrpWang et al [2010]
c.5410_5412delGAGp.Glu1804delMarlin et al [2010]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. Alternatively spliced transcripts combined with the use of several different translation initiation sites result in multiple short and long isoforms of the protein [Yasunaga et al 1999, Yasunaga et al 2000]. The first 19 exons are unique to the long isoforms, which contain six calcium-binding structural modules called C2 domains essential for vesicle-membrane fusion, one coiled-coil domain, and one transmembrane domain. The long isoforms of otoferlin have 1997 amino acids with six C2 domains, a coiled-coil domain, and a transmembrane domain, and bear homology to the synaptic vesicle protein synaptotagamin. The C2 domains bind phospholipids in the presence of calcium and are implicated in membrane fusion. Roux et al [2006] hypothesize that otoferlin is required for the high rate of synaptic vesicle fusion in inner hair cells.

Abnormal gene product. 68 of the 117 known deafness-related variants are inactivating variants that lead to significantly abnormal protein or, in the event of nonsense-mediated mRNA decay, no protein at all. Many persons with OTOF-related deafness have two inactivating variants, suggesting that the profound deafness associated with this genotype reflects the total absence of otoferlin. In persons who are compound heterozygotes for two missense deafness-related variants, or an inactivating variant and a missense variant, the missense variant is predicted to function defectively. Whether defective function (a) alters the timing of synaptic vesicle fusion, thereby leading to a loss of temporal coding (auditory dyssynchrony), or (b) accumulates in the vesicles disrupting transport in the inner hair cells is not known. It is possible that functional differences may be associated with phenotypic differences reflected by differences in auditory acuity, although additional studies are needed to establish whether any phenotype-genotype correlations exist in association with abnormal otoferlin protein.

In mouse, otoferlin is expressed in cochlear, vestibular, and brain tissue [Yasunaga et al 1999]. Mouse brain and cochlea have distinct isoforms differing primarily in the inclusion of exons 6 and 47. The consequence of inclusion of the latter exon is a distinct C-terminal protein sequence. Except for the absence of a mouse short isoform, tissue-specific isoform expression is concordant between mouse and human [Yasunaga et al 2000].


Literature Cited

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Chapter Notes

Author Notes



The work in this manuscript was supported in part by grants 1RO1DC02842 and 1RO1DC03544 (RJHS).

Author History

Jose G Gurrola III, MD; University of Iowa (2007-2015)
Philip M Kelley, PhD; Boys Town National Research Hospital (2007-2015)
A Eliot Shearer, MD, PhD (2015-present)
Richard JH Smith, MD (2007-present)

Revision History

  • 30 July 2015 (me) Comprehensive update posted live
  • 14 June 2011 (cd) Revision: link to hearing loss/deafness panel listings in GeneTests Laboratory Directory provided
  • 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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