Mitochondrial Gene Panel (MTRNR1 and MTTS1) Test for Nonsyndromic Hearing Loss Details
Over half of all cases of early childhood hearing loss are due to genetic causes. Mitochondrial inheritance of hearing loss has been linked to two genes: MTRNR1 (12S rRNA) and MTTS1 (tRNAser(UCN)).
Hearing loss due to pathogenic variants in the MTRNR1 (12S rRNA) and MTTS1 (tRNAser(UCN)) genes is often observed in families showing maternal inheritance, in which the mother passes a trait on to all offspring but no transmission is observed between males and their offspring. However, reduced penetrance of hearing loss associated with mitochondrial genes can make this inheritance pattern challenging to detect. For instance, additional factors such as exposure to aminoglycosides or other modifying genes may be required for the development of hearing loss, even in individuals carrying pathogenic variants. In addition, unlike autosomal diseases which require only one or two pathogenic variants to be present, mitochondrial diseases require many copies of the pathogenic variant, due to the high number of copies of the mitochondrial genome per cell. As such, variation in the percent of mutant mitochondria across individuals in a family can lead to variation in how many people with a pathogenic variant have hearing loss, as well as the severity of that hearing loss.Read More...
Hearing loss due to variants in these mitochondrial genes is sensorineural with onset ranging from birth to the 7th decade. The hearing loss can be flat, sloping or high frequency and is often progressive. The mtDNA 1555A>G pathogenic variant in the 12s rRNA gene is the most common mitochondrial variant in individuals with non-syndromic hearing loss. Affected individuals generally have bilateral and mild to profound hearing loss. Most individuals with this variant will develop hearing loss after an exposure to aminoglycoside antibiotics. However, individuals with this variant may still develop late-onset hearing loss independent of aminoglycoside exposure. Several other variants in 12s rRNA gene have been associated with hearing loss with or without an exposure to aminoglycoside antibiotic.
Individuals with certain tRNAser(UCN) variants (7472insC and 7445A>G) may manifest palmoplantar keratoderma or neurological symptoms including ataxia, myoclonic epilepsy, and cognitive impairment.Less
|MTRNR1||Ribosomal RNA, Mitochondrial, 12S||561000|
|MTTS1||Transfer RNA, Mitochondrial, Serine, 1||590080|
This test is indicated for individuals with apparent maternal inheritance of mild to profound sensorineural hearing loss with a history of exposure to aminoglycoside antibiotics. If an individual tests positive for a pathogenic variant that confers sensitivity to aminoglycoside antibiotics, it is recommended that other family members be tested to avoid the use of aminoglycoside antibiotics in positive individuals.
This test is performed by Sanger sequencing of the coding regions and splice sites of the listed genes. This test does not detect large deletions or variants in non-coding regions that could affect gene expression.
Analytical and Clinical Sensitivity
This assay is greater than 99.9% accurate in detecting variants in the sequence analyzed. The 1555A>G pathogenic variant is the most well-studied mutation and is present in variable percentages of the hearing impaired population based upon geographic and/or ethnic origin.