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Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
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Hearing Loss: Mitochondrial Deafness

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

Background

Non-syndromic mitochondrial hearing loss is characterized by moderate-to-profound hearing loss, a lack of other systemic clinical findings, and a mutation in either the MTRNR1or MTTS1. The MTRNR1 gene encodes the 12S ribosomal RNA and the MTTS1 gene encodes transfer RNA for serine, both of which are important in mitochondrial protein synthesis. Several recurrent mutations have been reported to cause nonsyndromic mitochondrial hearing loss, including recurrent mutations in the MTRNR1 gene (m.C1494T, m.A1555G, m.961delT+Cn) and MTTS1 gene (m.A7443G, m.G7444A, m.A7445C, m.T7510C, m.T7511C).

Individuals with an MTRNR1 mutation may have a predisposition to aminoglycoside ototoxicity causing deafness and/or late onset sensorineural hearing loss. In these individuals, hearing loss associated with aminoglycoside ototoxicity is bilateral and severe to profound and occurs within a few days to weeks after administration of any amount of aminoglycoside antibiotic. Individuals with an MTTS1 mutation generally have an onset of sensorineural hearing loss during childhood. Variability in clinical findings may be due to the presence of variable numbers of mitochondria containing mutations in different tissues of the body (heteroplasmy).

Since non-syndromic mitochondrial sensorineural hearing loss is due to mutations in mitochondrial DNA (mtDNA) it is transmitted by maternal inheritance. In most cases, the mother of a proband has a disease-causing mtDNA mutation, and may or may not have hearing loss. All offspring of females with a mtDNA mutation are at risk of inheriting the mutation. Offspring of males with a mtDNA mutation are not at risk of inheriting the mutation.

The strategy used for testing for mutations causing non-syndromic mitochondrial hearing loss is direct mtDNA sequencing to identify recurrent mutations in the MTRNR1 and MTTS1 genes.

Who should be tested

  • individuals clinically suspected of being affected with non-syndromic mitochondrial hearing loss
  • relatives of probands with identified MTRNR1 or MTTS1 mutations

Testing Methodology

Direct Mutation Analysis: Patient samples are analyzed by direct mtDNA sequencing. For the MTRNR1 gene, the region sequenced encompasses nucleotides 860–1226 and 1313–1601 of the mitochondrial genome. For the MTTS1 gene, the entire gene is sequenced including the exon/intron boundaries.

Test Sensitivity: Of individuals affected with mitochondrial non-syndromic hearing loss, three mutations in the MTRNR1 gene (m.C1494T, m.A1555G, m.961delT+Cn) account for ~70 per cent of mutations, while five mutations in the MTTS1 gene (m.A7443G, m.G7444A, m.A7445C, m.T7510C, m.T7511C) account for a further ~14 per cent of mutations. A negative result does not rule out the possibility that the individual has a different MTRNR1 or MTTS1 mutation, or a mutation in another gene, not detected in the assay and is affected with non-syndromic mitochondrial hearing loss. In addition, sequencing analysis will not detect low levels of heteroplasmic mutant mitochondria.

Potential Outcomes & Interpretation of Test Results

Reason for
referral

MTRNR1/MTTS1
Gene
Mutations

Explanation

diagnosis

none detected

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

diagnosis

mutation detected

  • This result supports a diagnosis of non-syndromic mitochondrial 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.
  • Low levels of heteroplasmic mutant mitochondia may not be detected by this testing.
  • 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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