Ashkenazi Jewish Panel for Hearing Loss and Usher (35delG & 167delT in GJB2, GJB6-D13S1830 deletion, Arg245X in PCDH15, Asn48Lys in CLRN1) Test Details
Over half of all cases of early childhood hearing loss are due to genetic causes and approximately 7% of individuals of Ashkenazi Jewish decent are carriers of a hearing loss or Usher syndrome pathogenic variant. This tests detects the four pathogenic variants that are common in the Ashkenazi Jewish population, which are the 35delG and 167delT variants in the GJB2 (Connexin 26) gene, the GJB6-D13S1830 (Connexin 30) deletion, the Arg245X variant in the PCDH15 (USH1F) gene and the Asn48Lys CLRN1 (USH3A).Read More...
Of the genetic causes for childhood hearing loss pathogenic variants in the GJB2 gene, encoding the connexin 26 protein, represent the largest proportion. There are two pathogenic variants in the GJB2 gene that are common in the Ashkenazi Jewish population, 35delG and 167delT. Approximately 0.4% of individuals of Ashkenazi Jewish decent are carriers of the 35delG variant and approximately 4% are carriers of the 167delT variant (Morell 1998, Sobe 1999, Lerer 2000, Dong 2001, Bors 2004). A large deletion of 342,000 bases on chromosome 13 has been found to cause hearing loss. This deletion removes most of the GJB6 gene that encodes the connexin 30 protein (connexin 30) and likely impacts the neighboring GJB2 (connexin 26) gene. The carrier frequency for this pathogenic variant in the Ashkenazi Jewish population with hearing loss is approximately 3.7% (Lerer 2001).
Usher Syndrome represents the most common type of autosomal recessive syndromic hearing loss and is the most common genetic cause of combined deafness and blindness. This syndrome is subdivided into three clinical types depending on the severity and onset of hearing impairment, retinitis pigmentosa (RP), as well as the presence of a vestibular dysfunction. Usher Syndrome Type 1 is characterized by congenital, profound sensorineural hearing loss, vestibular dysfunction usually manifested as delayed walking (>18 months), and the onset of RP by the age of ten (Kimberling 2004). Usher Syndrome Type I is further subdivided into 6 types. Usher Syndrome Type 1F is due to pathogenic variants in the PCDH15 gene. An Ashkenazi Jewish founder pathogenic variant has been identified in this gene, Arg245X, which has a carrier frequency of approximately 1% in this population. Usher Syndrome Type 3 is characterized by later onset hearing loss, variable vestibular dysfunction and RP that can present between the second and fourth decade of life. To date, only pathogenic variants in the CLRN1 (USH3A) gene are known to be causative for this type of Usher Syndrome. An Ashkenazi Jewish founder mutation has been identified in this gene, Asn48Lys, which has a carrier frequency of approximately 0.7% in this population.
These variants are all associated with autosomal recessive inheritance, meaning that an individual would need to inherit two pathogenic variants in order to have the hearing loss. Two carriers have a 25% (or 1 in 4) chance of each passing on a pathogenic variant and having a child with hearing loss.Less
|GJB2||Gap Junction Protein, Beta-2||121011||13q11-q12||c.35delG, c.167delT|
|GJB6||Gap Junction Protein, Beta-6||604418||13q12||GJB6-D13S1830 (GJB6 deletion)|
Individuals of Ashkenazi Jewish descent who were born with hearing loss, of any severity, are candidates for the Ashkenazi Jewish Hearing Loss Panel. This is true even if there is no family history of hearing loss, as this is the most common presentation. The Ashkenazi Jewish Hearing Loss Panel can also be used for carrier screening and family planning. However, this test is variant specific and cannot rule out causes or risks of hearing loss due to other variants within these genes or other genes not covered by this test.
This test is performed by Sanger sequencing of the relevant exons and splice sites of the GJB2 (exon 2), PCDH15 (exon 8) and CLRN1 (USH3A) (exon1) genes. This test does not detect large deletions or variants in regions and genes not covered by this test. PCR (polymerase chain reaction) is performed to detect the presence or absence of the GJB6-D13S1830 deletion. This test does not detect point variants in the GJB6 gene.
Analytical and Clinical Sensitivity
This test is greater than 99.9% accurate in detecting variants in the sequence analyzed. Carrier frequency for each of the variants on this test varies. Variant specific carrier rates are listed below.Read More...
|Pathogenic Variant||Gene||Ashkenazi Jewish Carrier Rate||References|
|35delG||GJB2||~0.4% (0.2-1.1%)||Morell 1998; Sobe 1999; Lerer 2000; Sobe 2000; Dong 2001|
|167delT||GJB2||~4% (2.4-7.46%)||Morell 1998; Sobe 1999; Lerer 2000; Dong 2001; Bors 2004|
|GJB6-D13S1830||GJB6||~3.7% (in the AJ deaf population)||Lerer 2001|
|Arg245X||PCDH15 (USH1F)||~1% (0.79-2.48%)||Ben-Yosef 2003; Bownstein 2004|
|Asn48Lys||CLRN1 (USH3A)||~0.7%||Ness 2003|