Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Hearing Loss, autosomal recessive, non-syndromic [H91.9]

OMIM numbers: 220290, 121011 (GJB2)604418 (GJB6)

Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh

Scientific Background

The literature mentions congenital sensorineural deafness with an incidence of 1-4 in 1,000. The proportion of genetic, sensorineural deafness is 50%. Approximately 70% of all cases of genetic deafness are non-syndromic and 30% syndromic. About 80% of all non-syndromic cases follow an autosomal recessive pattern of inheritance. Mutations in GJB2 are causing up to 50% of all autosomal recessive and up to 35% of all sporadic cases of deafness. The gene product, connexin 26, is an essential component of the gap junctions and therefore involved in the cell-cell junctions. The most common mutation in GJB2, the deletion of a guanine (35delG), causes functional loss of an allele. It can be detected in approx. 60-80% of the mutated alleles and occurs with an allele frequency of approx. 1% in the general population.

By now, several mutations are known and enough clinical and genetic data is available to establish a genotype-phenotype correlation. A deletion in GJB6 (gap junction protein connexin 30), del(GJB6-D13S1830) may also be the cause for autosomal recessive, non-syndromic deafness, especially in combination with heterozygous GJB2 mutations. Apart from that, mutations in over 40 other genes that are less frequently affected are known as possible causes of autosomal recessive or autosomal dominant, non-syndromic deafness. Furthermore, over 100 genetic syndromes are  known to be associated with deafness.

One of the non-syndromic forms of deafness is the irreversible hearing loss, a severe complication of treatment with aminoglycoside antibiotics such as streptomycin, gentamicin and kanamycin. Here, variants in the maternally inherited mitochondrial genes play an important role. A base exchange in the positions 1494 (C>T) and 1555 (A>G) of the mitochondrial 12S rRNA gene has been associated with a risk of aminoglycoside-induced deafness. The mechanism of action of aminoglycoside is based on irreversible binding to the 30S subunit of bacterial ribosomes, which leads to a defect of the protein biosynthesis. Mutations of the mitochondrial cytochrome c oxidase subunit (MTCO1 gene) have been associated with an elevated risk of aminoglycoside-induced deafness as well as with non-syndromic, sensorineural hearing loss. A combined predisposition of 12s rRNA A1555G and MTCO1 G7444A mutation seems to hold the highest risk for developing a hearing loss. In addition, less common mutations in the mitochondrial tRNA(Ser(UCN)) gene have recently been identified in association with aminoglycoside-induced deafness.