Usher Syndrome Type IJ and Deafness, Autosomal Recessive 48 (DFNB48) via the CIB2 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
3991 CIB2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
3991CIB281479 81479(x2) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn 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 disorder characterized by progressive retinitis pigmentosa (RP) and sensorineural hearing impairment, with or without vestibular abnormalities. Three types are recognized based on the age of onset, severity of symptoms and the vestibular involvement. Usher syndrome type 1 is the most common type. It is distinguished by congenital onset of hearing loss, RP in the first decade of life, and abnormal vestibular function (Cohen et al. 2007). Features of RP include night blindness progressing to constriction of the peripheral visual field with eventually loss of central vision, abnormal fundus with bone-spicule deposits/attenuated retinal vessels, and abnormal electroretinographic (ERG) findings (Daiger et al. 2007). The vestibular abnormality results in development delay in sitting and walking.

Hereditary or familial hearing loss (HL) and deafness can be prelingual (before language develops) or postlingual (after language develops) and may be conductive, sensorineural, or a combination of both. Causes for hereditary HL can be syndromic (associated with malformations of the external ear or other organs or with medical problems involving other organ systems) or nonsyndromic (no associated visible abnormalities of the external ear or any related medical problems). Familial forms of hearing loss must be distinguished from acquired (non-genetic) causes of hearing loss (such as environmental effects or mechanical stress) and are diagnosed by otologic, audiologic, and physical examination, family history, ancillary testing (e.g., CT examination of the temporal bone), and molecular genetic testing. Molecular genetic testing is possible for many types of syndromic and nonsyndromic deafness and plays a prominent role in diagnosis and genetic counseling (Smith et al. 2013).

Nonsyndromic hearing loss and deafness is characterized by childhood-onset, progressive, moderate-to-severe sensorineural hearing impairment. The audioprofile may vary significantly, even among family members. Affected individuals have no other associated medical findings (Smith et al. 2013).

Autosomal recessive deafness 48 (DFNA48) is a pre-lingual onset profound nonsyndromic hearing loss that affects all frequencies (Ahmad et al. 2005).

Genetics

Variants in the calcium and integrin binding family member 2 (CIB2) gene cause both autosomal recessive Usher syndrome type 1 (USH1J) and autosomal recessive nonsyndromic deafness 48 (DFNB48). A homozygous missense variant in CIB2 (c.272T>C; p.Phe91Ser) was found in 54 DFNB48 Pakistani families. A second missense variant in CIB2 (c.297C>G; p.Cys99Trp) was found in 2 different DFNB48 Pakistani families. A third missense variant in CIB2 (c.368T>C; p.Ile123Thr) was found in a Turkish DFNB48 family. A fourth missense variant in CIB2 (c.192G>C; p.Glu64Asp) was found to be homozygous in a USH1J Pakistani family (Riazuddin et al. 2012). A fifth and sixth missense and nonsense variant in CIB2 (c.196C>T; p.Arg66Trp and c. 97C>T; p.Arg33*) were found in families of Dutch origin with nonsyndromic hearing loss (Seco et al. 2015). A seventh missense variant in CIB2 (c.556C>T; p.Arg186Trp) was homozygous in two individuals with nonsyndromic hearing loss in a Caribbean Hispanic family (Patel et al. 2015).

CIB2 binds calcium and magnesium ions and interacts with integrin (Huang et al. 2012). CIB2 is expressed widely in human and mouse, including the inner ear and retina (Riazuddin et al. 2012). Transfection experiments using COS-7 cells found that five of the known CIB2 pathogenic missense variant significantly affected the ability of CIB2 to decrease ATP-induced calcium release from the cell (Riazuddin et al. 2012; Patel et al. 2015). These results suggest that CIB2 has an important role in calcium ion regulation of the mechanotransduction process in the inner ear and photoreceptor maintenance in the eye.

Clinical Sensitivity - Sequencing with CNV PGxome

In unaffected Pakistani individuals the frequency of the c.272T>C and c.297C>G CIB2 variants were reported to be 0.09% and 0.47%, respectively (Riazuddin et al. 2012). This suggests clinical sensitivity of this test in patients with Pakistan ancestry may be relatively high. Overall, clinical sensitivity is difficult to estimate because pathogenic variants have been documented only in a small number of patients outside of Pakistan. Analytical sensitivity should be high because all reported variants are detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the CIB2 gene 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 full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

All patients with symptoms of combined sensorineural hearing loss, RP and vestibular areflexia suggestive of USH1J. Patients with a family history of prelingual onset of severe to profound nonsyndromic sensorineural hearing loss with autosomal recessive inheritance suggestive of DFNB48. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in CIB2.

Gene

Official Gene Symbol OMIM ID
CIB2 605564
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Deafness, Autosomal Recessive 48 AR 609439
Usher Syndrome, Type IJ AR 614869

Citations

  • Ahmad J. et al. 2005. Human Genetics. 116: 407-12. PubMed ID: 15711797
  • Cohen M. et al. 2007. International Journal of Audiology. 46: 82-93. PubMed ID: 17365059
  • Daiger S.P. et al. 2007. Archives of Ophthalmology (chicago, Ill. : 1960). 125: 151-8. PubMed ID: 17296890
  • Huang H. et al. 2012. Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire. 90: 646-56. PubMed ID: 22779914
  • Patel K. et al. 2015. Plos One. 10: e0133082. PubMed ID: 26426422
  • Riazuddin S. et al. 2012. Nature Genetics. 44: 1265-71. PubMed ID: 23023331
  • Seco C.Z. et al. 2015. European Journal of Human Genetics : Ejhg. 0: N/A. PubMed ID: 26173970
  • Smith R.J.H. et al. 2013. Deafness and Hereditary Hearing Loss Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301607

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

loading Loading... ×

ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
×
Copy Text to Clipboard
×