Deafness, Autosomal Dominant 3B (DFNA3B) and Deafness, Autosomal Recessive 1B (DFNB1B) via the GJB6 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
7679 GJB6 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7679GJB681479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

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

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).

Nonsyndromic hearing loss and deafness due to pathogenic variants in the GJB6 gene are associated with prelingual, progressive, mild-to-severe high-frequency sensorineural hearing impairment. Audioprofiles may vary significantly, even within a family. No vestibular or temporal bone abnormalities are typically found (Smith et al. 1993).

Genetics

The GJB6 gene encodes the gap junction protein beta 6, more commonly known as connexin 30. Connexins form gap junctions that facilitate metabolite and ion transport between adjacent cells. The role of connexin 30 in proper auditory function remains unclear, although it appears to be necessary for normal repair following sensory cell loss in the inner ear (Jagger and Forge 2015).

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 GJB6 gene is located adjacent to the GJB2 gene in chromosomal region 13q12. GJB2 and GJB6 are both associated with nonsyndromic hearing loss inherited in both an autosomal dominant (DFNA3) and autosomal recessive (DFNB1) manner.

DFNA3 is caused by missense variants in either GJB2 (>90%) or GJB6 (<10%). DFNA3 has been further defined as DFNA3A (GJB2) and DFNA3B (GJB6). Both are characterized by prelingual, progressive, mild-to-severe high-frequency sensorineural hearing impairment, although DFNA3A is also reported to cause postlingual hearing loss (Smith et al. 1993). However, the association of GJB6 missense variants with DFNA3B remains uncertain due to limited evidence of dominant inheritance across multigenerational families (Grifa et al. 1999; Yang et al. 2007).

DFNB1 is caused by missense, nonsense, splicing and regulatory variants in GJB2 (~98%) or large deletions of GJB2 and/or upstream regions including GJB6 (~2%). DFNB1 has been further defined as DFNB1A (GJB2) and DFNB1B (GJB6). DFNB1 is characterized by congenital, non-progressive, mild to profound sensorineural hearing impairment. All DFNB1 documented pathogenic variants involving GJB6 are large deletions. Missense or nonsense variants in GJB6 have not been associated with DFNB1 (Smith et al. 1993).

Previous reports of individuals with hearing loss that were heterozygous for a variant in GJB2 and also heterozygous for a large deletion encompassing sequences upstream of GJB2 including all or part of GJB6 were thought to indicate digenic inheritance of DFNB1. However, subsequent experiments have shown that the mechanism of action of the deletions encompassing GJB6 is through altered GJB2 expression via loss of cis-regulatory elements in proximity to GJB6 (Rodriguez-Paris and Schrijver 2009; Rodriguez-Paris et al. 2011).

Aside from nonsyndromic hearing loss, pathogenic variants in the GJB6 gene can also cause Clouston syndrome or hidrotic ectodermal dysplasia, which is an autosomal dominant inherited skin disorder characterized by marked thickening of the palms and soles (palmoplantar hyperkeratosis), patchy or total hair loss (alopecia), thinning or thickening of nails (nail hypoplasia), as well as other nail deformities (Essenfelder et al. 2004).

Clinical Sensitivity - Sequencing with CNV PG-Select

The sensitivity of our sequencing and CNV detection assay for this gene is currently unknown. In total, only 18 GJB6 variants have been documented as pathogenic for hearing loss. Only missense variants have been described in association with DFNA3, while only large deletions have been described in association with DFNB1. For both DFNA3 and DFNB1, variants in the related gene GJB2 represent the vast majority of documented causative variants.

Testing Strategy

This test provides full coverage of the single coding exon of the GJB6 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Nonsyndromic hearing loss and deafness due to variants in GJB6 is suspected in individuals with the following: pre- or postlingual, mild to profound, progressive 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 recessive or more rarely, autosomal dominant inheritance. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in GJB6.

Gene

Official Gene Symbol OMIM ID
GJB6 604418
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
  • Essenfelder G.M. et al. 2004. Human Molecular Genetics. 13: 1703-14. PubMed ID: 15213106
  • Grifa A. et al. 1999. Nature Genetics. 23: 16-8. PubMed ID: 10471490
  • Hilgert N. et al. 2009. Mutation Research. 681: 189-96. PubMed ID: 18804553
  • Jagger D.J., Forge A. 2015. Cell and Tissue Research. 360: 633-44. PubMed ID: 25381570
  • Rodriguez-Paris J. et al. 2011. Plos One. 6: e21665. PubMed ID: 21738759
  • Rodriguez-Paris J., Schrijver I. 2009. Biochemical and Biophysical Research Communications. 389: 354-9. PubMed ID: 19723508
  • Smith et al. 1993. Nonsyndromic Hearing Loss and Deafness, DFNA3. 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: 20301708
  • Van Camp G. et al. 1997. American Journal of Human Genetics. 60: 758-64. PubMed ID: 9106521
  • Yang J.J. et al. 2007. Audiology & Neuro-otology. 12: 198-208. PubMed ID: 17259707

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.

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

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