SickKids

Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
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Hearing Loss: Non-Syndromic (Connexin 26 & 30)

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
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Background

Non-syndromic sensorineural hearing loss (NSHL) is a common disability affecting approximately 1 in 1000 newborns. In approximately 50% of children with congenital deafness the hearing loss is due to inherited causes. The most common form of inherited hearing loss is autosomal recessive non-syndromic hearing loss (AR-NSHL), which affects approximately 1 in every 2500 children.

Many different genes have been shown to play a role in NSHL.Mutations in the in the GJB2 gene have been implicated in 50 to 80% of AR-NSHL cases, making this the most common cause of AR-NSHL. The GJB2 gene encodes a gap junction protein called connexin 26, which is important in the development of the inner ear. A second gap junction protein, connexin 30 encoded by the GJB6 gene, can also cause AR-NSHL. In particular a recurrent deletion in the GJB6 gene (delGJB6-D13S1830) has been reported to cause AR-NSHL in approximately 20% of patients who also have one GJB2 gene mutation.

The strategy used for testing for non-syndromic hearing loss is complete sequencing of the coding region and flanking exon/intron boundaries of the GJB2 gene, and direct mutation testing for the recurrent deletion mutation (delGJB6-D13S1830) in the GJB6 gene.

Who should be tested

  • individuals clinically suspected of being affected with non-syndromic hearing loss
  • relatives of probands with identified GJB2 or GJB6 mutations

Testing Methodology

Direct Mutation Analysis: Mutations in the GJB2 gene are identified through direct sequencing; the recurrent deletion mutation delGJB6-D13S1830 in the GJB6 gene is identified by a direct PCR mutation assay.

Test Sensitivity: Mutations in the GJB2 gene are responsible for 50-80% of all AR-SNHL cases. Most alterations to this gene will be detected by this test. Approximately 20% of patients with one GJB2 mutation will also carry the GJB6 recurrent deletion mutation (delGJB6-D13S1830). 20-50% of AR-NSHL cases and other forms of sensorineural hearing loss are not caused by mutations in the GJB2 or GJB6 genes. These cases cannot be detected by the methodologies in place in the Molecular Diagnostics Laboratory.

Potential Outcomes & Interpretation of Test Results

Reason for
referral

GJB Gene
Mutations
allele 1 / allele 2

Explanation

carrier testing

none detected/
none detected

  • This individual is unlikely to be a carrier of a mutation in the GJB2 gene or a carrier of the recurrent deletion in the GJB6 gene (delGJB6-D13S1830)

carrier testing

mutation detected/
none detected

  • This individual is a carrier of non-syndromic hearing loss, and may transmit a mutation to offspring.

diagnosis

none detected/
none detected

  • This result does not support a diagnosis of non-syndromic hearing loss.

diagnosis

mutation detected/
none detected

  • This result is unable to confirm a diagnosis of non-syndromic hearing loss.

diagnosis

mutation detected / mutation detected

  • This result confirms a diagnosis of non-syndromic hearing loss.

Cautions

  • Current molecular testing will not detect all possible mutations causing non-syndromic hearing loss. A negative result does not rule out the possibility that the individual has a mutation not included in the assay and is affected with non-syndromic hearing loss.
  • Test results should be interpreted in the context of clinical findings, family history and other laboratory data.
  • These tests were developed and the performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. They have not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. These tests are used for clinical purposes.

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