Deafness, nonsyndromic

Congenital sensorineural deafness is estimated in the literature to have an incidence of 1-4 in 1000. The proportion of genetic sensorineural deafness is 50%. 70% of genetic deafness is non-syndromic and 30% syndromic. 80% of non-syndromic cases are inherited in an autosomal recessive manner. Pathogenic variants in the GJB2 gene are causative in up to 50% of all autosomal recessive and up to 35% of sporadic cases of deafness. The gene product, connexin26, is an essential component of the gap junctions and is therefore involved in the formation of the cell-cell junction. The most common pathogenic variant in the GJB2 gene, the deletion of a guanine (35delG), leads to the functional loss of an allele. It is detectable in approx. 60-80% of mutant alleles and occurs in the total population with an allele frequency of approx. 1%.

Many pathogenic variants of the GJB2 gene are now known, and sufficient clinical and genetic data are available to establish a genotype-phenotype correlation. A deletion in the GJB6 gene (gap junction protein connexin 30), del(GJB6-D13S1830) may also be causative for autosomal recessive non-syndromic deafness, especially in combination with heterozygous GJB2 alterations. Apart from this, changes in more than 150 other genes are known that can lead to autosomal recessive or autosomal dominant non-syndromic deafness.

Pathogenic mitochondrial variants can be detected in <1% of patients with prelingual sensorineural hearing loss and 2-27% of postlingual forms. Irreversible hearing loss is a serious complication of treatment with aminoglycoside antibiotics such as streptomycin, gentamycin and kanamycin. The base pair substitutions at positions 1555, 7444, 7445, 7510 and 7511 of the mitochondrial genome are associated with non-syndromic sensorineural hearing loss and an increased risk of aminoglycoside-induced deafness. In contrast to classical Mendelian inheritance, mitochondrial genes are inherited maternally. In addition, other variants of the mitochondrial genome have been described that lead to syndromic or non-syndromic forms of hearing loss.

References

Del Castillo et Del Castillo 2017, Front Mol Neurosci 10:428 / Chan et Chang 2014, Laryngos 124:E34 / Mani et al. 2009, Europ J of Hum Genet 17:502 / Petersen et al. 2006, Clin Genet 69:371 / Snoeckx et al. 2005, Am J Hum Genet 77:945 / Cryns et al. 2004, J Med Genet 41:147 / Pallares-Ruiz et al. 2002, Eur J Hum Genet 10:72 / Rabionet et al. 2000, Hum Genet 106:40 / Murgia et al. 1999, J Med Genet 36:829  / Lench et al. 1998, Lancet 351:415