Otof-Related Deafness

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2021-01-18

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Gene_reviews

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OTOF, FER, GJB2, TMPRSS3, STRC

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Summary

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.

Diagnosis/testing.

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.

Management.

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.

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 ¹	Method	Proportion of Probands with Deafness-Related Variants ² Detectable by Method
OTOF	Sequence analysis ³	99%
OTOF	Gene-targeted deletion/duplication analysis ⁴	Unknown ⁵

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: 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.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications and may be performed as a single- or multigene panel. Methods used may 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.
5.: 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).

A pathogenic truncating variant, c.4467dupC (p.Ile1490HisfsTer19), caused a severe-to-profound hearing loss while a homozygous missense change, c.4718T>C (p.Ile1573Thr), caused a moderate hearing loss which was progressive [Yildirim-Baylan et al 2014].
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.Gln994ValfsTer7) and c.4819C>T (p.Arg1607Trp) deafness-related variants in OTOF on workup for TS-NSAN [Wang et al 2006].

Nomenclature

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.

Prevalence

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

Studies in Spanish populations suggest that OTOF may be responsible for 5%-8% of prelingual autosomal recessive hearing loss [Rodríguez-Ballesteros et al 2008].
A study in the Pakistani population suggests that the frequency of deafness-related variants is approximately 2.3% in persons with recessive congenital/prelingual-onset severe-to-profound deafness [Choi et al 2009].

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:

DFNB59, autosomal recessive auditory neuropathy caused by variants in PJVK, the gene encoding the protein pejvakin [Delmaghani et al 2006, Schwander et al 2007]
Autosomal dominant auditory neuropathy caused by variants in DIAPH3, the gene encoding protein diaphanous homolog 3

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].

Management

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.

Surveillance

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 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. Note: There may not be clinical trials for this condition.