Auditory Neuropathy Panel (OTOF and DFNB59) Test Details
Auditory neuropathy spectrum disorder (ANSD) is a sensorineural hearing disorder characterized by an absent or severely abnormal auditory brainstem response (ABR) with preservation of cochlear outer hair cell function as measured by otoacoustic emission testing. Varying degrees of hearing loss are seen in individuals with ANSD but generally individuals have poor speech reception and do not perform well with hearing aids. In contrast, many individuals are successfully treated with cochlear implants. A variety of risk factors and etiologies are associated with this heterogeneous form of hearing loss. These include the following groups of causes: neonatal (hyperbilirubinemia, anoxia); infectious (mumps); hereditary (OTOF and DFNB59 variants, Friedreich’s ataxia, Charcot-Marie-Tooth disease, hereditary sensorimotor neuropathy, mitochondrial defects); immunological (Guillain-Barré syndrome). Still others are of unknown etiology.Read More...
Variants in the OTOF gene, encoding otoferlin, underlie the DFNB9 form of hearing loss, best characterized by nonsyndromic prelingual moderate-profound sensorineural hearing loss often presenting as ANSD. Individuals can lose their otoacoustic emissions making a diagnosis of ANSD difficult in some individuals. One variant corresponding to Gln829X appears particularly frequent in Spain (Rodriguez-Ballesteros 2003 PMID: 14635104). Some variants in OTOF are temperature sensitive and are associated with hearing loss that only occurs during febrile states (Varga 2006 PMID: 16371502 and Marlin 2010 PMID: 20230791).
Variants in the DFNB59 gene, encoding pejvakin, underlie the DFNB59 form of hearing loss (Delmaghani et al, 2006), characterized by either nonsyndromic prelingual sensorineural hearing loss presenting as ANSD or nonsyndromic severe-profound sensorineural hearing loss with abnormal outer hair cell function as assessed by OAE testing. Thus, variants in DFNB59 may cause either ANSD or non-ANSD sensorineural hearing loss.Less
The Auditory Neuropathy Panel is recommended for individuals with a diagnosis of nonsyndromic auditory neuropathy hearing loss.
This test is performed by next generation sequencing using Agilent SureSelect capture followed by sequencing of the coding regions and splice sites using Illumina sequencing technologies. Variant calls are generated using the Burrows-Wheeler Aligner followed by Genomic Analysis Tool Kit (GATK) analysis. Detection of copy number variants (CNVs) encompassing 1 or more exons is performed using VisCap™ analysis. Sanger sequencing is used to fill in regions with insufficient coverage. All clinically significant variants are confirmed by Sanger sequencing or droplet digital PCR. Variants classified as likely benign or benign are not confirmed. This test does not detect variants in non-coding regions that could affect gene expression, aside from the splice junctions, and a few exons have been excluded due to technical difficulties. CNV analysis is only performed when data meets necessary quality standards and may not be available for all cases.
Analytical and Clinical Sensitivity
This test is 100.00% sensitive (525/525 variants tested; 95% CI = 99.27-100.00% ) to detect variants changing a single base and 100.00% sensitive to detect insertion/deletions 1-21 bp in size (17/17 variants tested; 95% CI = 81.57-100.00%). Regions with high sequence homology are included in this test if a unique Sanger sequencing assay can be designed to rule out false positive calls. Analytical sensitivity in these regions may be reduced.
The frequency of variants in these genes in individuals with sensorineural hearing loss or ANSD is currently unknown. In Spain, Gln829X in OTOF is estimated to cause 3% of nonsyndromic recessive hearing loss.