Deafness, Autosomal Dominant 2B (DFNA2B) via the GJB3 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
9089 GJB3 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9089GJB381479 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

  • Ben Dorshorst, PhD

Clinical Features and Genetics

Clinical Features

Nonsyndromic hearing loss is characterized by difficulty or inability to hear that is not associated with any visible defects involving the external ear, other organs, or any other medical condition. Nonsyndromic hearing loss may be associated with abnormalities involving the middle ear and/or the inner ear (Ciuman 2013; Dodson et al. 2011; Hilgert et al. 2009). At least 70% of cases involving hearing loss are nonsyndromic (Van Camp et al. 1997).

The clinical features of nonsyndromic hearing loss and deafness due to pathogenic variants in the GJB3 gene vary widely with autosomal dominant variants causing bilateral sensorineural hearing loss with a downsloping audiogram and moderate hearing loss at high frequencies (Xia et al. 1998). Autosomal recessive variants cause early-onset moderate to severe bilateral sensorineural hearing loss with flat audiograms and normal vestibular function (Liu et al. 2000).

Genetics

The GJB3 gene encodes the gap junction protein beta 3, more commonly known as connexin 31. Connexins form gap junctions that facilitate metabolite and ion transport between adjacent cells. Connexin 31 is expressed in fibrocytes of the spiral ligament and spiral limbus of the mouse chochlea and auditory and peripheral nerves, although its role in auditory function remains unclear (Xia et al. 2000; López-Bigas et al. 2001).

The different gene loci for nonsyndromic hearing loss are designated DFN (for DeaFNess) and named on the mode of inheritance; DFNA for autosomal dominant, DFNB for autosomal recessive and DFNX for X-linked inheritance, respectively. The GJB3 gene is located in chromosomal region 1p34.3 and is associated with nonsyndromic hearing loss inherited in an autosomal dominant manner (DFNA2B), with some reports of autosomal recessive and digenic inheritance.

Autosomal dominant nonsyndromic hearing loss due to pathogenic variants in GJB3 has only been reported in two small Chinese families (Xia et al. 1998). However, these variants were found in both affected and unaffected individuals. Additionally, it is unlikely that hearing loss due to the nearby and at that time undiscovered KCNQ4 gene was excluded in these families. No subsequent reports have convincingly identified variants in GJB3 as causing autosomal dominant hearing loss in other families.

Autosomal dominant nonsyndromic hearing loss with peripheral neuropathy due to pathogenic variants in GJB3 has been reported in one multi-generation Spanish family (López-Bigas et al. 2001).

Autosomal recessive nonsyndromic hearing loss due to pathogenic variants in GJB3 has only been reported in two small Chinese families in which affected individuals were compound heterozygotes for two different missense variants (Liu et al. 2000). A Turkish family with one missense variant in GJB3 was reported to have autosomal recessive nonsyndromic hearing loss, although the second pathogenic variant was not identified (Uyguner et al. 2003).

Autosomal recessive nonsyndromic hearing loss has also been reported to be caused by digenic inheritance of variants in GJB3 and GJB2 (DFNA1A) in three Chinese families (Liu et al. 2009).

The role of GJB3 in causing nonsyndromic hearing loss is currently viewed as questionable due to limited evidence (Hilgert et al. 2009; Smith and Hildebrand 2015).

Heterozygous and homozygous variants in GJB3 are also known to cause erythrokeratodermia variabilis et progressiva, a skin disorder characterized by transient erythematous hyperkeratotic plaques (Gottfried et al. 2002).

Clinical Sensitivity - Sequencing with CNV PGxome

The sensitivity of our sequencing assay for this gene is currently unknown. However, since only missense, nonsense and small deletion variants have been described for this gene in association with nonsyndromic hearing loss, we believe that our sequencing assay will be able to identify all of these variants. Overall, pathogenic variants in GJB3 are thought to play a small role in nonsyndromic hearing loss due to the limited number of families that have been identified (Hilgert et al. 2009; Smith and Hildebrand 2015).

No large deletions or duplications in GJB3 have been reported for nonsyndromic hearing loss.

Testing Strategy

This test provides full coverage of all coding exons of the GJB3 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

Nonsyndromic hearing loss and deafness due to variants in GJB3 is suspected in individuals with the following: pre- or postlingual, moderate to severe, bilateral sensorineural hearing impairment; no related systemic findings identified by medical history and physical examination; or a family history of nonsyndromic hearing loss consistent with autosomal dominant or more rarely, autosomal recessive inheritance. Variants in GJB3 causative for Erythrokeratodermia Variabilis et Progressiva have not been reported to also cause hearing loss, and vice versa. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in GJB3.

Gene

Official Gene Symbol OMIM ID
GJB3 603324
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Ciuman R.R. 2013. Medical Science Monitor. 19: 1195-210. PubMed ID: 24362017
  • Dodson K.M. et al. 2011. American Journal of Medical Genetics. Part A. 155A: 993-1000. PubMed ID: 21465647
  • Gottfried I. et al. 2002. Human Molecular Genetics. 11: 1311-6. PubMed ID: 12019212
  • Hilgert N. et al. 2009. Current Molecular Medicine. 9: 546-64. PubMed ID: 19601806
  • Hilgert N. et al. 2009. Mutation Research. 681: 189-96. PubMed ID: 18804553
  • Liu X.Z. et al. 2000. Human Molecular Genetics. 9: 63-7. PubMed ID: 10587579
  • Liu X.Z. et al. 2009. Human Genetics. 125: 53-62. PubMed ID: 19050930
  • López-Bigas N. et al. 2001. Human Molecular Genetics. 10: 947-52. PubMed ID: 11309368
  • Smith R.J.H. and Hildebrand M. 2015. DFNA2 Nonsyndromic Hearing Loss. 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: 20301388
  • Uyguner et al. 2003. Clinical Genetics. 64: 65-9. PubMed ID: 12791041
  • Van Camp G. et al. 1997. American Journal of Human Genetics. 60: 758-64. PubMed ID: 9106521
  • Xia et al. 2000. Neuroreport. 11: 2449-53. PubMed ID: 10943702
  • Xia J.H. et al. 1998. Nature Genetics. 20: 370-3. PubMed ID: 9843210

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

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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: $
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