Usher Syndrome Panel (11 Genes) Test Details
Usher syndrome is the most common cause of deaf-blindness and its prevalence is estimated at 3-6.2 per 100,000. It is estimated that approximately 10% of individuals with congenital hearing loss have Usher syndrome (Cohen 2007 PMID: 17365059). The vision loss associated with Usher syndrome is caused by the eye disease retinitis pigmentosa (RP), which causes night-blindness and a loss of peripheral vision through progressive degeneration of the retina. Early identification of RP or a genetic cause of Usher syndrome allows for appropriate management of the anticipated dual sensory loss, initiation of therapeutic strategies that may slow down RP progression (vitamin A therapy, minimization of sun exposure to the eyes, etc.), and may even qualify individuals for clinical trials aimed at halting or correcting vision loss.Read More...
Usher syndrome is divided into three subtypes: Usher syndrome type I (USH1), Usher syndrome type II (USH2), and Usher syndrome type III (USH3). Traditionally these subtypes have been described clinically based on the severity and onset of the hearing impairment, RP, and the presence of vestibular dysfunction. However, variable expression within and among the three subtypes has been observed.
Usher syndrome type I (USH1) is characterized by congenital, profound sensorineural hearing loss, vestibular dysfunction (often manifested as delayed walking, >18 months), and the onset of RP by the age of ten. Usher syndrome type I is further subdivided into 5 types. Pathogenic variants in the MYO7A, USH1C, CDH23, PCDH15, and USH1G (SANS) genes cause Usher syndrome type 1B, type 1C, type 1D, type 1F and type 1G respectively. Recently, the CIB2 gene has been associated to USH1.
Individuals with Usher syndrome type II (USH2) typically have a sloping congenital hearing loss that is mild to moderate in the low frequencies and severe to profound in the high frequencies. Vestibular problems are absent in USH2, which distinguishes it from USH1. RP is still present with an onset typically sometime in adolescence. USH2 is also further subdivided into three types which have known gene locations associated with them: USH2A, GPR98 (VLGR1), and DFNB31 (WHRN).
Usher syndrome type III is characterized by later onset hearing loss, variable vestibular dysfunction and RP that can present between the second and fourth decade of life. Pathogenic variants in the CLRN1 (USH3A) gene are known to be causative for this type of Usher syndrome. Recently, the HARS gene has been associated with Usher syndrome type 3.
It should be noted that pathogenic variants in several Usher syndrome genes (CDH23, DFNB31, MYO7A, PCDH15, and USH1C) have been identified in individuals with nonsyndromic hearing loss, indicating that the presence of variants in these genes does not always predict the development of Usher syndrome. Usher syndrome is inherited in an autosomal recessive pattern. Two parents who are carriers of pathogenic variants in an Usher gene have a 25% (or 1 in 4) chance of having an affected child.Less
Read More for expanded gene table.Read More...
|DFNB31||Deafness, Autosomal Recessive 31||607084||9q32|
|GPR98||G Protein-Coupled Receptor 98||602851||5q13|
|USH1G||Usher Syndrome Type-1G Protein||607696||17q25.1|
|CIB2||Calcium and Integrin-Binding Family Member 2||605564||15q25.1|
|HARS||Histidine-tRNA Ligase, Cytoplasmic||142810||5q31.3|
The Usher Syndrome Panel is recommended for individuals with hearing loss and other features associated with Usher syndrome such as retinitis pigmentosa. Overlapping and atypical presentations have been described for all three types of Usher syndrome. Therefore, a panel approach is recommended for testing for Usher syndrome.Read More...
Since the onset of the RP varies, children with Usher syndrome may initially present with isolated hearing loss. In a child who appears to have a non-syndromic hearing loss, a negative Usher Syndrome Panel test reduces but does not eliminate the chance that the child has Usher syndrome.Less
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.Read More...
Ethnicity based screening is available, given that founder variants exist in several populations. The Arg245X Ashkenazi Jewish founder pathogenic variant in the PCDH15 gene has a carrier frequency of up to 2.5% in this population. The Tyr176X variant in CLRN1 is common in Finnish individuals. The 216G>A variant in USH1C and the 4338_4339delCT variant in USH2A are commonly found in Acadian/French Canadian individuals with Usher syndrome.Less