Hereditary non-syndromic sensorineural hearing loss: transforming silence to sound

Abstract

Tremendous progress has been made in our understanding of the molecular basis of hearing and hearing loss. Through recent advances, we have begun to understand the fascinating biology of the auditory system and unveiled new molecular mechanisms of hearing impairment. Changes in the diagnostic impact of genetic testing have occurred, as well as exciting developments in therapeutic options. Molecular diagnosis, which is already a reality for several hearing-associated genes, will doubtlessly continue to increase in the near future, both in terms of the number of mutations tested and the spectrum of genes. Genetic analysis for hearing loss is mostly used for diagnosis and treatment, and relatively rarely for reproductive decisions, in contrast to other inherited disorders. Inherited hearing loss, however, is characterized by impressive genetic heterogeneity. An abundance of genes carry a large number of mutations, but specific mutations in a single gene may lead to syndromic or non-syndromic hearing loss. Some mutations predominate in individual ethnic groups. For clinical and laboratory diagnosticians, it is challenging to keep abreast of the unfolding discoveries. This review aims to provide the framework pertinent to diagnosticians and a practical approach to mutation analysis in the hearing impaired.

Figure 1

A subdivision of hearing impairment by cause (column 1), presence or absence of associated features in cases of genetic etiology (column 2), and mode of inheritance in the non-syndromic group (column 3). The smallest boxes in column 3 represent X-linked hearing loss, which accounts for ∼1% of non-syndromic hearing loss, and mitochondrial hearing loss, which accounts for at least 1%. AD, autosomal dominant; AR, autosomal recessive.

Figure 2

Schematic representation of the long arm of chromosome 13, band 12 (not to scale). The GJB2 and GJB6 genes, which encode connexin 26 and connexin 30, respectively, are adjacent. Δ, a 309-kb deletion, which eliminates part of the GJB6 gene and is associated with recessive hearing loss in homozygous form, or in the heterozygous state in combination with a mutation in GJB2. This deletion was formerly thought to span 342 kb.

Figure 3

Six connexin proteins (cxi) group to form a hemichannel in the cell membrane. This channel is called a connexon (cxo). Connexons can be made of six identical connexins (homomeric) or of different types (heteromeric). Two neighboring connexons, which create a functional communication channel, can be identical (homotypic, as shown under A) or of different composition (heterotypic, as shown under B).