Connexin (GJB2 Sequencing and GJB6-D13S1830 Deletion) Test Details
Over half of isolated childhood hearing loss has a genetic etiology, with many genes involved. The most common genetic causes of autosomal recessive, non-syndromic hearing loss are pathogenic changes in the GJB2 and GJB6 genes. Changes in these genes cause hearing at an incidence of approximately 1 in 2500 to 5000 individuals with both males and females equally affected. There are several ethnic groups with higher carrier frequencies of pathogenic variants in these genes. These include 35delG in the Caucasian population, 167delT in the Ashkenazi Jewish population, 235delC in the Asian population and the GJB6-D13S1830 deletion in individuals of Spanish, French and Ashkenazi Jewish descent.Read More...
Connexin-related hearing loss is caused by either two pathogenic variants in the GJB2 gene, homozygous deletions in both copies of the GJB6 gene, or compound heterozygous variants including one deletion of the GJB6 gene and one pathogenic variant in the GJB2 gene. The hearing loss is nonsyndromic, sensorineural, and typically congenital but can present in early childhood. The severity can range from mild to profound and over time about 50% of those with a connexin related hearing loss will progress in severity. This hearing loss is most commonly inherited in an autosomal recessive pattern meaning that each parent is unaffected but is a carrier of a single variant in the GJB2 gene. Two carriers have a 25% (or 1 in 4) risk for having an affected child.Less
|GJB2||Gap Junction protein, beta 2 (Connexin 26)||121011||13q12|
|GJB6||Gap Junction protein, beta 6 (Connexin 30)||604418||13q12|
Given the large contribution of the connexin 26 and connexin 30 genes to genetic causes of hearing loss, the testing of these two genes is often the first line strategy in a diagnostic work up. Genetic testing for these two genes would be recommended in a child born with hearing loss of any severity. This is true even if there is no family history of hearing loss, as this is the most common presentation. The Connexin Test alone gives parents the highest likelihood of obtaining a cause for their child's hearing loss. Furthermore, a positive test result can alleviate concerns that other medical problems may arise in their child due to the association of hearing loss with many other syndromes (e.g. Usher syndrome in which blindness can develop at a later age). If the results are negative then additional tests, including more comprehensive panels, such as the OtoGenome™ can be pursued.
In addition, this test can be offered to someone whose partner is a known carrier of a pathogenic variant in the connexin 26 gene or the common connexin 30 deletion. In this situation, the test can identify or rule out carrier status in a hearing individual and determine the risk for connexin-related hearing loss in future children.
This test is performed by Sanger sequencing of exon 1 and exon 2 of the GJB2 gene, PCR (polymerase chain reaction) is performed to detect the presence or absence of the GJB6-D13S1830 deletion. This test does not detect large deletions or variants in non-coding regions of GJB2 that could affect gene expression. Furthermore, this test does not detect point mutations or other deletions in the GJB6 gene.
Analytical and Clinical Sensitivity
This assay is more than 99.9% accurate in detecting variants in the GJB2 sequence analyzed. Two GJB2 variants are detected in approximately 20% of individuals with nonsyndromic sensorineural hearing loss. However, a negative result does not rule out a diagnosis of GJB2-related hearing loss because there may be other variants within the GJB2 gene (for example, within the promoter or other non-coding or regulatory regions) that are not detected by this test. The GJB6-D13S1830 deletion may be present in 2-67% of persons with a single GJB2 variant, the exact percentage depending on ethnicity. The presence of two copies of the deletion is rare.