Autosomal recessive non-syndromic hearing loss/deafness (DFNB1) is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment. No other associated medical findings are present. DFNA3 is a rare form of autosomal dominant non-syndromic hearing loss that is characterized by childhood-onset, progressive, moderate-to-severe high-frequency sensorineural hearing impairment.

The genetic underpinnings of hearing loss are diverse and complicated. Fifty percent (50%) of pre-lingual deafness in children is thought to be genetic. Of this, 70% is non-syndromic (i.e. auditory dysfunction is the only abnormality) and may be autosomal-recessive (75 – 85%), autosomal dominant (15 – 24%), or X-linked (1 – 2%).

Of autosomal recessive non-syndromic hearing loss, DFNB1 is the cause in half. The vast majority of patients with DFNB1 (98%) have 2 identifiable mutations in the GJB2 gene. An additional 2% have one mutation in the GJB2 and a large deletion that includes a portion of the GJB6 gene.

DFNA3 as a cause of autosomal dominant non-syndromic hearing loss is extremely rare. To date, 11 mutations in either GJB2 or GJB6 have been reported to segregate in individuals with DFNA3.

1. Confirmation of diagnosis:
   1. In patients with non-syndromic deafness and a family history suggestive of either autosomal recessive (DFNB1) or autosomal dominant (DFNA3) inheritance
2. Carrier testing:
   1. In adults at risk to be carriers of a GJB2 or GJB6 mutation due to a family history of confirmed GJB2/6-related deafness.
3. Prenatal testing (technically feasible but not routinely performed – contact MGL to discuss):
   1. Pregnancies at risk of non-syndromic deafness due to (a) known mutation(s) in GJB2/GJB6.

Bidirectional Sanger sequencing of the entire coding region and flanking intronic sequences, as well as the exon 1 / intron 1 splice site of the GJB2 gene. If the patient is found to be heterozygous for a GJB2 mutation, gap-PCR is performed to assess for presence of the ΔGJB6-D13S1830 deletion mutation.

GJB2: NM_004004.5 The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

GJB6: NM_006783.4 The ‘A’ within the initiation codon, ATG, is designated as nucleotide number 1.

Blood: 4 mL EDTA is optimal (Minimum: 1 mL EDTA)
DNA: 100 μL at 200 ng/μL is optimal (Minimum: 30 μL at 200 ng/μL)

Label each sample with three patient identifiers; preferably patient name, PHN, and date of birth and ship to the address below. Samples should be shipped at room temperature with a completed MGL Requisition to arrive Monday to Friday (not on Canadian statutory holidays). 

Testing is only available to residents of Canada, except in very specific circumstances where testing is urgent or emergent.  Payment is not required when requests are made for individuals who are insured by Health Insurance BC (administered through the BC Medical Services Plan (MSP)) AND eligible for testing according to the test utilization guidelines / policy. If the individual undergoing testing is not insured by these providers or does not meet utilization guidelines or policy, please complete a billing form; testing will only commence after receipt of billing informationTest prices can be found here.

Molecular genetic testing is limited by the current understanding of the genome and the genetics of a particular disease, as well as by the method of detection used. This method will not detect all mutations (e.g., large genomic deletions/duplications, promoter mutations, regulatory element mutations).

For carrier/predictive testing due to a family history, it is generally important to first document the gene mutation in an affected or carrier family member. This information should be provided to the laboratory for assessment of whether the assay is appropriate for detection of the familial mutation, and to aid in the interpretation of data.

In some cases, DNA alterations of undetermined or unclear clinical significance may be identified.

Rare single nucleotide variants or polymorphisms could lead to false-negative results. If results obtained do not match the clinical findings, consult the on-service Molecular Geneticist.

A previous bone marrow transplant from an allogenic donor will result in molecular data that reflects the donor genotype rather than the recipient (patient) genotype. Consult the on-service Molecular Geneticist for approach to testing in such individuals.

Transfusions performed with packed red blood cells will generally not affect the outcome of molecular genetic testing. However, if there is no clinical urgency, the cautious approach is to wait one week post packed red cell transfusion before collecting a sample for genetic testing. Consult the on-service Molecular Geneticist as needed.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.