DiagnosisClinical DiagnosisOTOF-related deafness (nonsyndromic hearing loss at the DFNB9 locus) is characterized by 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 becomes more consistent with a cochlear defect. Molecular Genetic TestingGene. OTOF-related deafness is caused by mutations in OTOF, encoding the protein otoferlin. Clinical testing Sequence analysis of OTOF. The mutation detection frequency for sequence analysis approaches 99%. Multi-gene panels. Although single-gene testing for OTOF is performed in a number of laboratories, in general genetic testing of hearing has advanced toward multi-gene testing methods in which new methods of DNA analysis can be used for the simultaneous analysis of numerous genes associated with hereditary hearing loss [Shearer et al 2010]. These panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation or mutations in any given individual also varies.Table 1. Summary of Molecular Genetic Testing Used in OTOF-Related DeafnessView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityOTOF} Sequence analysisSequence variants ^{299% Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. In a child with bilateral severe-to-profound congenital deafness in whom the clinical history and physical examination are consistent with the diagnosis of autosomal recessive nonsyndromic hearing loss, the following testing strategies rely on molecular genetic testing:Sequential molecular genetic testing of single genes:First perform molecular genetic testing of GJB2 (see Nonsyndromic Hearing Loss and Deafness, DFNB1); if only one GJB2 mutation is detected, perform deletion/analysis of GJB6If molecular genetic testing for mutations at the DFNB1 locus (GJB2 intragenic mutations and GJB6 deletions) does not identify two deafness-causing mutations, perform CT or MRI of the temporal bones to evaluate for dilation of the vestibular aqueduct (DVA) and Mondini dysplasia: The presence of either of these temporal bone anomalies warrants molecular genetic testing of SLC26A4. (See Pendred Syndrome/DFNB4.)If these temporal bone abnormalities are not present, molecular genetic testing of OTOF should be considered.AND / OR Use of a multigene panel that simultaneously analyzes multiple genes associated with hereditary hearing lossBecause electrophysiologic testing performed on a child with OTOF-related deafness during the first year or two of life can be consistent with auditory neuropathy, OTOF molecular genetic testing is warranted in all infants with congenital auditory neuropathy without a history of causative environmental factors (e.g., neonatal hyperbilirubinemia and neonatal hypoxia). However, the absence of electrophysiologic evidence of auditory neuropathy does not exclude OTOF-related deafness because with time OAEs disappear and results of electrophysiologic testing become more consistent with a cochlear defect. Carrier testing for at-risk relatives requires prior identification of the deafness-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive condition and are not at risk of developing the condition.Prenatal diagnosis for at-risk pregnancies requires prior identification of the deafness-causing mutations in the family. Genetically Related (Allelic) DisordersNonsyndromic hearing loss is the only phenotype known to be associated with mutations in OTOF.}

Natural HistoryThe 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 CorrelationsOnly limited genotype-phenotype correlations have been made, primarily involving reports of temperature-sensitive nonsyndromic auditory neuropathy (TS-NSAN). A missense allele, c.1544T>C (p.Ile515Thr), was found in the heterozygous state in an individual who was observed to have TS-NSAN [Varga et al 2006]. A deletion, c.5410_5412delGAG (p.Glu1804del), was reported to be homozygous in three members of a family with similar TS-NSAN [Marlin et al 2010]. An individual was found to have c.2975_2976delAG (p.Gln994Valfs*7) and c.4819C>T (p.Arg1607Trp) mutations in OTOF on workup for TS-NSAN [Wang et al 2006].

Differential DiagnosisCongenital (or prelingual) inherited hearing impairment affects approximately one in 1,000 newborns. Thirty percent of these babies 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 mutations in GJB2 [Smith et al 2005].Mutations in 28 genes (including OTOF) have been implicated in congenital autosomal recessive nonsyndromic deafness. The prevalence of OTOF mutations in the congenitally deaf population is unknown; OTOF mutations may be a common cause of isolated auditory neuropathy during the first one or two years of life. However, it is important to note that with time OAEs disappear and results of electrophysiologic testing are more consistent with a cochlear defect.Other nonsyndromic hereditary auditory neuropathies include the following:DFNB59, autosomal recessive auditory neuropathy caused by mutations in PJVK, the gene encoding the protein pejvakin [Delmaghani et al 2006, Schwander et al 2007] Autosomal dominant auditory neuropathy that maps to the AUNA1 locus (chromosome 13q14-q21) [Kim et al 2004] OTOF mutations 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]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this condition, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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) Thin-cut CT of the temporal bones to identify structural abnormalities Treatment of ManifestationsSee Hereditary Deafness and Hearing Loss Overview for details.Hearing habilitation for those with nonsyndromic bilateral congenital hearing lossHearing aids should be fitted as soon as possible. Cochlear implantation (CI) should be considered. CI has been successfully accomplished in two children with OTOF-related deafness [Rouillon et al 2006].
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].Educational programs designed for individuals with hearing impairment are appropriate. Prevention of Primary ManifestationsFor 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.Make patients and caregivers aware that 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. SurveillanceIndividuals 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 and/or treat excessive body temperatures when possible. Follow-up studies have not demonstrated the success of preventative measures as an effective long-term treatment in this patient population. Continued evaluation and follow-up should be encouraged.Evaluation of Relatives at RiskAt-risk relatives should be evaluated for hearing loss and auditory neuropathy (which can be present during infancy).If the family-specific mutations are known, molecular genetic testing of sibs is appropriate shortly after birth so that appropriate and 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 InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this condition.

Molecular GeneticsInformation 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 DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDDFNB9OTOF2p23​.3OtoferlinDeafness Gene Mutation Database
Hereditary Hearing Loss Homepage
CCHMC - Human Genetics Mutation DatabaseOTOFData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for OTOF-Related Deafness (View All in OMIM) View in own window 601071DEAFNESS, AUTOSOMAL RECESSIVE 9; DFNB9 603681OTOFERLIN; OTOFMolecular Genetic PathogenesisOtoferlin 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 FER1L4 (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 FER1L3, is required for normal myoblast fusion [Doherty et al 2005]. The function of FER1L4 is not known (Figure 1).FigureFigure 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.
CC (yellow) is a coiled-coil domain.
TM (blue) is (more...)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]. In the cochlea, otoferlin is believed to play a role in exocytosis of synaptic vesicles at the auditory ribbon synapse of inner hair cells [Roux et al 2006].Normal allelic variants. OTOF consists of 48 coding exons that extend over 100 kb of genomic DNA. The short isoforms have only three C2 domains. A number of non-pathogenic allelic variants have been described (see Table 3). Pathologic allelic variants. The 24 pathologic mutations that have been reported in OTOF (see Table 4) are distributed throughout the gene. Most are predicted to be inactivating mutations 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 mutations have been reported to be more frequent in specific ethnic groups with the exception of c.2485C>T (p.Gln829*), 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). FigureFigure 2. Schematic of OTOF on chromosome 2p23. The OTOF genomic structure comprises 48 exons that are used to transcribe the long isoform (NM_194248.1; NP_919224.1). The short isoform does not include the first 19 exons, which are shown as blue bars. (more...)Table 2. Selected OTOF Pathologic Allelic VariantsView in own windowDNA Nucleotide Change
(Alias ¹) Protein Amino Acid Change
(Alias ¹)ReferencesReference Sequencesc.1544T>Cp.Ile515ThrMirghomizadeh et al [2002] NM_194248​.2
NP_919224​.1c.2485C>Tp.Gln829*Migliosi et al [2002], Rodríguez-Ballesteros et al [2003] c.2975_2976delAG
(2975_2978delAGp.Gln994Valfs*7
(Gln994Valfs*6)Wang et al [2010]c.4819C>Tp.Arg1607TrpWang et al [2010]c.5410_5412delGAGp.Glu1804delMarlin et al [2010]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal 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. Seventeen of the 24 known pathologic mutations are inactivating mutations that lead to grossly abnormal protein or, in the event of nonsense-mediated mRNA decay, no protein at all. Many persons with OTOF-related deafness have two inactivating mutations, suggesting that the profound deafness associated with this genotype reflects the total absence of otoferlin. In persons who are compound heterozygotes for two missense mutations, or an inactivating mutation and a missense mutation, the missense mutation 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.