Usher Syndrome Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10053 ADGRV1 81479,81479 Order Options and Pricing
CDH23 81408,81479
CIB2 81479,81479
CLRN1 81404,81479
MYO7A 81407,81479
PCDH15 81407,81406
PDZD7 81479,81479
USH1C 81407,81479
USH1G 81404,81479
USH2A 81408,81479
WHRN 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10053Genes x (11)81479 81404, 81406, 81407, 81408, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Usher syndrome is a clinically heterogeneous genetic disorder that is characterized by progressive retinitis pigmentosa (RP), sensorineural hearing impairment, and in some cases, vestibular abnormalities. Features of RP include night blindness progressing to constriction of the peripheral visual field with eventual loss of central vision, abnormal fundus with bone-spicule deposits/attenuated retinal vessels, and abnormal electroretinographic (ERG) findings (Daiger et al. 2007). Vestibular abnormalities often result in development delay in sitting and walking. Three clinical subtypes of Usher syndrome are currently recognized based on the age of onset, severity of symptoms, and vestibular involvement, although there is considerable variability within a subtype thus resulting in overlapping symptoms between subtypes. Usher syndrome type 1 (USH1) is the most common type and is distinguished by severe to profound congenital hearing loss, RP beginning in childhood, and abnormal vestibular function (Ahmed et al. 2013). Usher syndrome type 2 (USH2) involves moderate to severe hearing impairment, late-onset RP, and normal vestibular function. Usher syndrome type 3 (USH3) is characterized by progressive hearing loss and variable age of onset for retinal degeneration. The prevalence of Usher syndrome in the United States is 1 in 6,000 (Kimberling et al. 2010).

Genetics

Usher syndrome is a clinical heterogeneous autosomal recessive disorder that is caused by sequence variants in any one of the 11 genes that have so far been identified (Bolz and Roux 2011). USH1 is caused by pathogenic sequence variants in the following genes: cadherin-related family, member 23 (CDH23), which encodes for a 3,354-amino acid calcium ion-dependent transmembrane adhesion protein that contains ankyrin repeats; calcium- and integrin-binding protein 2 (CIB2), which encodes a calcium-binding actin-based protein that mediates intracellular calcium signaling; myosin VIIA (MYO7A), which encodes unconventional myosins with structurally conserved heads that move along actin filaments; protocadherin 15 (PCDH15), which encodes a 1,955-amino acid calcium ion-binding protein that contains 11 cadherin repeats and two domains that are proline-rich; Usher syndrome type 1C (USH1C), which encodes a 652-amino acid PDZ domain-containing protein called harmonin that is predominantly expressed in the sensory hair cells of the inner ear; and Usher syndrome type 1G (USH1G), which encodes a scaffold protein containing ankyrin repeats and a sterile alpha motif (SAM) called sans that is expressed in the cochlea (Ahmed et al. 2001; Riazuddin et al. 2012; Blanco-Sanchez et al. 2014).

USH2 is caused by causative sequence variants in the following genes: deafness, autosomal recessive 31 (WHRN), which encodes a PDZ domain-containing protein called whirlin that contains actin polymerization and the growth of stereocilia in the inner ear; G protein-coupled receptor 98 (GPR98), which encodes a 326-amino acid protein that is involved in neurotransmission and in the formation of synaptic contacts; PDZ domain-containing 7 (PDZD7), which encodes a binding protein that is expressed in the mechanosensory hair cells of the inner ear; and Usher syndrome type 2a (USH2A), which encodes a 1,551-amino acid protein that acts as a component of the basal lamina and extracellular matrices of the ears and eyes (Yang et al. 2010; Garcia-Garcia et al. 2013; Zou et al. 2014).

USH3 is caused by pathogenic sequence variants the clarin 1 (CLRN1) gene, which encodes a 232-amino acid transmembrane protein that is expressed in the inner and outer hair cells of the organ of Corti and the spiral ganglion cells; it possesses mechanotransduction channel activity and assists in the proper localization of synaptic components (Ogun and Zallocchi 2014).

The mutational spectrum of the 11 genes implicated in Usher syndrome mainly include missense, nonsense, and splicing sequence variants, as well as some small deletions, duplications, and insertions. The most common sequence variants that have been reported as pathogenic for Usher syndrome occur in the following genes: USH2A (697 reported sequence variants), MYO7A (338 reported sequence variants), CDH23 (227 sequence variants), GPR98 (100 sequence variants), and PCDH15 (78 sequence variants). On the other hand, only a few pathogenic sequence variants have been reported for the USH1C (37 sequence variants), CLRN1 (25 sequence variants), USH1G (15 sequence variants), WHRN (19 sequence variants), CIB2 (7 sequence variants), and PDZD7 (4 sequence variants) genes (Stenson et al. 2003).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in any of the eleven genes in this NextGen panel may be responsible for 11.3% to 91% of Usher syndrome cases, depending on the combination of genes utilized in the NextGen assay and the specific population being screened. A German study that performed sequencing of 9 out of the 11 genes in our NextGen panel showed that all 42 Usher syndrome patients (100%) harbored causative sequence variants (Krawitz et al. 2014). In a French study that involved sequencing of 9 of the 11 genes listed in our NextGen panel, 49 out of 54 (91%) Usher syndrome patients showed pathogenic sequence variants (Bonnet et al. 2011). On the other hand, a Spanish study that conducted sequencing of 10 of the 11 genes included in our NextGen panel reported that 22 out of 32 (69%) Usher syndrome patients tested positive for causative pathogenic sequence variants (Aparisi et al. 2014). A US-based study that performed sequencing of 5 of the 11 genes listed in our NextGen panel showed that 15 out of 133 (11.3%) hard-of-hearing or deaf pediatric patients harbored pathogenic sequence variants (Kimberling et al. 2010).

Large-scale copy number variants may be responsible for around 6% of Usher syndrome alleles. The most frequent CNVs have been detected in the USH2A (42 gross deletions, 4 gross insertions/deletions, 2 complex rearrangements), MYO7A (6 gross deletions, 1 gross insertion/deletion, 1 complex rearrangement), CDH23 (33 gross deletions), GPR98 (3 gross deletions, 1 gross insertion/deletion), and PCDH15 (13 gross deletions and 2 gross insertions/deletions) genes (Stenson et al. 2003).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients with combined congenital sensorineural hearing loss, RP, and vestibular areflexia.

Genes

Official Gene Symbol OMIM ID
ADGRV1 602851
CDH23 605516
CIB2 605564
CLRN1 606397
MYO7A 276903
PCDH15 605514
PDZD7 612971
USH1C 605242
USH1G 607696
USH2A 608400
WHRN 607928
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Ahmed ZM, Frolenkov GI, Riazuddin S. 2013. Usher proteins in inner ear structure and function. Physiological Genomics 45(21): 987-989 PubMed ID: 24022220
  • Ahmed ZM, Riazuddin S, Bernstein SL, Ahmed Z, Khan S, Griffith AJ, Morell RJ, Friedman TB, Riazuddin S, Wilcox ER. 2001. Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. American Journal of Human Genetics 69(1): 25-34. PubMed ID: 11398101
  • Aparisi MJ, Aller E, Fuster-García C, García-García G, Rodrigo R, Vázquez-Manrique RP, Blanco-Kelly F, Ayuso C, Roux AF, Jaijo T, Millán JM. 2014. Targeted next generation sequencing for molecular diagnosis of Usher syndrome. Orphanet Journal of Rare Diseases 9:168. PubMed ID: 25404053
  • Blanco-Sánchez B, Clément A, Fierro J Jr, Washbourne P, Westerfield M. 2014. Complexes of Usher proteins preassemble at the endoplasmic reticulum and are required for trafficking and ER homeostasis. 2014. Disease Models and Mechanisms 7(5): 547-559. PubMed ID: 24626987
  • Bolz HJ, Roux AF. 2011. Clinical utility gene card for: Usher syndrome. European Journal of Human Genetics 19(8). PubMed ID: 21697857
  • Bonnet C, Grati M, Marlin S, Levilliers J, Hardelin JP, Parodi M, Niasme-Grare M, Zelenika D, Délépine M, Feldmann D, Jonard L, El-Amraoui A, Weil D, Delobel B, Vincent C, Dollfus H, Eliot MM, David A, Calais C, Vigneron J, Montaut-Verient B, Bonneau D, Dubin J, Thauvin C, Duvillard A, Francannet C, Mom T, Lacombe D, Duriez F, Drouin-Garraud V, Thuillier-Obstoy MF, Sigaudy S, Frances AM, Collignon P, Challe G, Couderc R, Lathrop M, Sahel JA, Weissenbach J, Petit C, Denoyelle F. 2011. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet Journal of Rare Diseases 6:21. PubMed ID: 21569298
  • Daiger SP, Bowne SJ, Sullivan LS. 2007. Perspective on genes and mutations causing retinitis pigmentosa. Archives of ophthalmology 125: 151-158. PubMed ID: 17296890
  • García-García G, Besnard T, Baux D, Vaché C, Aller E, Malcolm S, Claustres M, Millan JM, Roux AF. 2013. The contribution of GPR98 and DFNB31 genes to a Spanish Usher syndrome type 2 cohort. Molecular Vision 19: 367-373. PubMed ID: 23441107
  • Kimberling WJ, Hildebrand MS, Shearer AE, Jensen ML, Halder JA, Trzupek K, Cohn ES, Weleber RG, Stone EM, Smith RJ. 2010. Frequency of Usher syndrome in two pediatric populations: Implications for genetic screening of deaf and hard of hearing children. Genetics in Medicine 12(8): 512-516. PubMed ID: 20613545
  • Krawitz PM, Schiska D, Krüger U, Appelt S, Heinrich V, Parkhomchuk D, Timmermann B, Millan JM, Robinson PN, Mundlos S, Hecht J, Gross M. 2014. Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome. Molecular Genetics and Genomic Medicine 2(5): 393-401. PubMed ID: 25333064
  • Ogun O, Zallocchi M. 2014. Clarin-1 acts as a modulator of mechanotransduction activity and presynaptic ribbon assembly. Journal of Cell Biology 207(3): 375-391. PubMed ID: 25365995
  • Riazuddin S, Belyantseva IA, Giese AP, Lee K, Indzhykulian AA, Nandamuri SP, Yousaf R, Sinha GP, Lee S, Terrell D, Hegde RS, Ali RA, Anwar S, Andrade-Elizondo PB, Sirmaci A, Parise LV, Basit S, Wali A, Ayub M, Ansar M, Ahmad W, Khan SN, Akram J, Tekin M, Riazuddin S, Cook T, Buschbeck EK, Frolenkov GI, Leal SM, Friedman TB, Ahmed ZM. 2012. Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nature Genetics 44(11): 1265-1271. PubMed ID: 23023331
  • Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, Abeysinghe S, Krawczak M, Cooper DN. 2003. Human Gene Mutation Database (HGMD): 2003 update. Human Mutation 21(6): 577-581. PubMed ID: 12754702
  • Weil D, Blanchard S, Kaplan J, Guilford P, Gibson F, Walsh J, Mburu P, Varela A, Levilliers J, Weston MD. 1995. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374: 60-61. PubMed ID: 7870171
  • Yang J, Liu X, Zhao Y, Adamian M, Pawlyk B, Sun X, McMillan DR, Liberman MC, Li T. 2010. Ablation of whirlin long isoform disrupts the USH2 protein complex and causes vision and hearing loss. PLoS Genetics 6(5): e1000955. PubMed ID: 20502675
  • Zou J. et al. 2014. Human Molecular Genetics. 23: 2374-90. PubMed ID: 24334608

Ordering/Specimens

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