GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of OTOF-related deafness is suspected based on clinical findings and confirmed by molecular genetic testing of OTOF, the gene encoding the protein otoferlin. OTOF is the only gene known to be associated with this disorder.
Management. Treatment of manifestations: Hearing aids as soon as possible, consideration of cochlear implants, and educational programs designed for individuals with hearing impairment. Surveillance: 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. Testing of relatives at risk: evaluation of sibs as soon as possible after birth for hearing loss; if the deafness-causing mutations 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 being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the deafness-causing mutations in a family are known.
OTOF-related deafness (nonsyndromic hearing loss at the DFNB9 locus) is characterized by bilateral severe-to-profound congenital deafness.
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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. OTOF-related deafness is caused by mutations in OTOF, encoding the protein otoferlin.
Clinical testing
Sequence analysis. The mutation detection frequency for sequence analysis approaches 99%.
Mutation scanning. The mutation detection rate by mutation scanning is technique dependent. For DHPLC it can approach 99% [Prasad et al 2004].
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|
| OTOF | Mutation scanning | Sequence variants | ~99% | Clinical
 |
| Sequence analysis | 99% |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirmatory diagnostic testing
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:
First perform molecular genetic testing of GJB2 (see Nonsyndromic Hearing Loss and Deafness, DFNB1)
If 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.
If these temporal bone abnormalities are not present, molecular genetic testing of OTOF should be considered.
Because electrophysiologic testing performed on a child with OTOF-related deafness during the first one or two years 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 disorder and are not at risk of developing the disorder.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the deafness-causing mutations in the family.
OTOF-related deafness is nonsyndromic with a very homogeneous phenotype characterized by prelingual, typically severe-to-profound deafness without inner ear anomalies as resolved by MRI or CT 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.
Only limited genotype-phenotype correlations have been made.
The different gene loci for nonsyndromic deafness are designated DFN (for deafness).
Loci are named based on mode of inheritance:
DFNA: autosomal dominant
DFNB: autosomal recessive
DFN: X-linked
The number following the above designations reflects the order of gene mapping and/or discovery.
The prevalence of OTOF mutations in persons with severe-to-profound congenital autosomal recessive nonsyndromic deafness is unknown.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Congenital (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].
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)
Thin-cut CT of the temporal bones to identify structural abnormalities
See Hereditary Deafness and Hearing Loss Overview for details.
Hearing habilitation
Hearing 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.
Affected individuals should be examined 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.
Consider CI.
At-risk relatives should be evaluated for hearing loss and auditory neuropathy (which can be present during infancy).
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.
Search 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 disorder.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
OTOF-related deafness is inherited in an autosomal recessive manner.
Parents of a proband
The parents of a child with OTOF-related deafness are obligate heterozygotes and therefore carry one deafness-causing allele.
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 being unaffected and not a carrier.
Once an at-risk sib is known to be hearing, the probability of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with OTOF-related deafness are obligate heterozygotes (carriers) for a deafness-causing mutation in OTOF.
Other family members of a proband. For each sib of the proband's parents, the probability of being a carrier is 50%.
Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the family.
See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring 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. 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, mutations, and genetic conditions will improve in the future, consideration should be given to banking DNA of individuals with OTOF-related deafness. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both deafness-causing alleles must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions that (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. Although decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the deafness-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Locus Name | Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|---|
| DFNB9 | OTOF | 2p23-p22 | Otoferlin | Deafness Gene Mutation Database Hereditary Hearing Loss Homepage |
OTOF |
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 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.
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.
CC (yellow) is a coiled-coil domain.
TM (blue) is the transmembrane domain.
DysFN (purple) is the dysferlin domain N terminal.
DysFC (brown) is the dysferlin domain C-terminal region.
).
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].
| DNA Nucleotide Change | Protein Amino Acid Change (Alias 1 ) | Reference Sequence |
|---|---|---|
| c.158C>T | p.Ala53Val | NM_194248.1NP_919224.1 |
| c.244C>T 2 | p.Arg82Cys | |
| c.372A>G 2 | p.= 3 (Thr124Thr) | |
| c.945G>A 2 | p.= (Lys315Lys) | |
| c.1723G>A | p.Val575Met | |
| c.1926C>T | p.= (Asn642Asn) | |
| c.2022C>T | p.= (Asp674Asp) | |
| c.2025G>A | p.= (Glu675Glu) | |
| c.2317C>T 2 | p.Arg773Ser | |
| c.2464C>T | p.Arg822Trp | |
| c.2580C>G 2 | p.= (Val860Val) | |
| c.2736G>C 2 | p.= (Leu919Leu) | |
| c.3189G>A | p.= (Ala1063Ala) | |
| c.3247G>C | p.Ala1083Pro | |
| c.3470G>A | p.Arg1157Gln | |
| c.3966C>G | p.Asp1322Glu | |
| c.4677G>A | p.= (Val1559Val) | |
| c.4767C>T | p.= (Arg1589Arg) | |
| c.4874G>A | p.Val1625Met | |
| c.4936C>T | p.Pro1646Ser | |
| c.5391C>T | p.= (Phe1797Phe) | |
| c.5655C>T | p.= (Arg1885Arg) | |
| c.5663G>A | p.Gly1888Asp |
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 conventions
2. Polymorphic allelic variations in bold have been described in both American and Spanish populations [Rodriguez-Ballesteros et al 2003, Varga et al 2003].
3. The designation p.= means that no amino acid change is expected.
Figure 2. Schematic of OTOF on chromosome 2p23. The OTOF genomic structure comprises 48 exons that are used to transcribe the long isoform (NM_194248.1; NP_919224.1). The short isoform does not include the first 19 exons, which are shown as blue bars. The protein structure includes calcium-binding domains (green hexagons), a coiled-coil domain (yellow circle), and a transmembrane domain (blue rectangle). Arrows represent mutations. The genomic structure shows the location of splice-site mutations as grey arrows, nonsense mutations as brown arrows, and missense mutations as black arrows. The protein structure shows location of only the nonsense and missense mutations.
).
| DNA Nucleotide Change (Alias 1 ) | Protein Amino Acid Change (Alias 1 ) | Reference | Reference Sequence |
|---|---|---|---|
| 709>T | p.Arg237X | Houseman et al 2001 | NM_194248.1NP_919224.1 |
| c.766-2A>G (IVS8-2A>G) | -- | Yasunaga et al 2000 | |
| 1469C>A | p.Pro490Gln | Mirghomizadeh et al 2002 | |
| 1544T>C | p.Ile515Thr | Mirghomizadeh et al 2002 | |
| c.1651delG | p.Glu551SerfsX5 | Varga et al 2003 | |
| c.1886dupA (1886_1887insA) | p.Pro630AlafsX5 (Lys629fs) | Varga et al 2006 | |
| c.2214+1G>T (IVS18+1G>T) | -- | Varga et al 2006 | |
| 2122C>T | p.Arg708X | Rodriguez-Ballesteros et al 2003 | |
| c.2348delG | p.Gly783AlafsX17 (G783fs) | Varga et al 2006 | |
| 2381G>A | p.Arg794His | Varga et al 2006 | |
| 2485C>T | p.Gln829X | Migliosi et al 2002, Rodriguez-Ballesteros et al 2003 | |
| c. 2991+1G>A (IVS24+1G>A) | -- | Adato et al 2000 | |
| 2887C>T | p.Arg963X | Hutchin et al 2005 | |
| 3032T>C | p.Leu1011Pro | Tekin et al 2005 | |
| c.3571-2A>C (IVS28-2A>C) | -- | Varga et al 2006 | |
| 4275G>A | p.Trp1425X | Rodriguez-Ballesteros et al 2003 | |
| c.4500+2T>G (IVS36+2T>G) | -- | Rodriguez-Ballesteros et al 2003 | |
| 4491T>A | p.Tyr1497X | Yasunaga et al 1999 | |
| 4559G>A | p.Arg1520Gln | Rouillon et al 2006 | |
| c.4960+1G>C (IVS39+1G>C) | -- | Varga et al 2003 | |
| 5473C>G | p.Pro1825Ala | Migliosi et al 2002 | |
| c.5712+1G>A (IVS44+1G>A) | -- | Rouillon et al 2006 | |
| 5816G>A | p.Arg1939Gln | Varga et al 2003 | |
| 5860_5862delATC 2 | Ile1954del | Rodriguez-Ballesteros et al 2003 | |
| 5960C>G | p.Pro1987Arg | Varga et al 2003 |
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 conventions
2. This mutation is present the cochlear-specific isoform and occurs in exon 48. Both brain and cochlea have alternatively spliced isoforms that differ in that exon 47 is expressed in brain and translation is terminated with this exon. In cochlea, exon 47 is skipped and translation terminates with exon 48 [Varga et al 2003].
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 and colleagues (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.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Web: webh01.ua.ac.be/hhh
The work in this manuscript was supported in part by grants 1RO1DC02842 and 1RO1DC03544 (RJHS).
29 February 2008 (me) Review posted to live Web site
15 October 2007 (rjhs) Original submission
