Elsevier

The Lancet

Volume 358, Issue 9287, 29 September 2001, Pages 1082-1090
The Lancet

Seminar
Advances in hereditary deafness

https://doi.org/10.1016/S0140-6736(01)06186-4Get rights and content

Summary

Progress in the Human Genome Project, availability of cochlea-specific cDNA libraries, and development of murine models of deafness have resulted in rapid discovery of many loci and corresponding genes for deafness. Up to now, the chromosomal locations of about 70 genes for non-syndromic deafness have been mapped, and the genes of more than 20 loci have been identified and characterised. Mutations in one gene, connexin 26 (CX26GJB2), are responsible for most cases of recessive non-syndromic deafness, accounting for 30–40% of all childhood genetic deafness in some populations (eg, white people of western European descent). We summarise advances in identification of genes for deafness and provide a guide to the clinical approach to diagnosis of patients with hearing loss.

Section snippets

Classification of hearing loss

Hearing loss can be classified by the phenotype (congenital early onset or congenital late onset; high frequency or low frequency; syndromic or non-syndromic; sensorineural or conductive mixed; mild to profound; positive or negative vestibular involvement), or cause (genetic, environmental, or both) (panel). Although most genetic causes seem to be monogenic, modifications of the phenotype by other genes or environmental factors have been shown.9, 10

Syndromic hearing loss

Hearing loss has been identified as a part of the clinical range in more than 300 of several thousand genetic syndromes, the details of which can be found on the OMIM website.11 Individuals with these syndromes have other clinical features in addition to hearing impairment that allow recognition of a distinct entity. Localisation and identification of genes for syndromic deafness started in the early 1990s. Perhaps one of the most important initial achievements was the discovery in 1992 of

Non-syndromic hearing loss

Identification of genes responsible for non-syndromic hearing loss is a daunting task because of genetic heterogeneity (without distinctive clinical features that would allow grouping of families caused by mutations at the same locus), and the small size of most families. However, advances in linkage analysis, and the use of inbred population isolates to map genes has led to the mapping and cloning of genes involved in non-syndromic hearing loss. Up to now, the chromosomal locations of about 70

Genes identified in non-syndromic hearing loss

The evolving knowledge about various genes causing hearing loss has enabled us to understand the basic genetic architecture of deafness. Genes that transport ions across membranes to maintain appropriate solute concentration and pH are essential, as is seen with mutations in the various gap junction protein and potassium ion-channel genes. Genes that play a part in structural integrity are also important, as seen with mutations in the MYO7A, α-tectorin, and collagen genes. Regulatory genes,

Genes important for potassium recycling and endolymph equilibrium Connexin genes associated with deafness (DFNB1, DFNA2, DFNA3)

Connexin genes code for the subunits of gap junction proteins, which form intercellular channels in plasma membranes for transport of fluid and small molecules. Assembly of six connexin subunits forms a hemichannel called a connexon, and the docking of two connexons from adjacent cells establish the gap junction. These gap junctions are essential to recycle potassium ions needed for initiation of action potentials in hair cells. Mutations in CX26 have been identified as the most common cause of

Genes encoding cytoskeletal proteins Unconventional myosins (DFNA1, DFNB2, DFNB3)

Conventional myosin is a molecular motor protein that, with actin filaments, causes motion using energy from ATP hydrolysis. Unlike conventional myosin, unconventional myosins are present in non-muscle cells and do not form bipolar filaments. In the ear, unconventional myosins are located in the stereocilia and cuticular plate of hair cells, which contain actin and have a role in the organisation of stereocilia and the movement of tiplinks. The first implication of their role in human deafness

Genes encoding structural proteins in the organ of Corti TECTA α-tectorin gene (DFNA8, DFNA12, DFNB21)

TECTA encodes α-tectorin, which is released from the membrane of the cells where it is produced, and processed into three polypeptides. These polypeptides are crosslinked to each other and interact with β-tectorin to form the non-collagenous matrix of the tectorial membrane.6 Mutations in TECTA were recorded in different families with prelingual onset of autosomal dominant non-syndromic hearing loss (DFNA8 and DFNA12).6 Another mutation has been reported in a Lebanese family with prelingual

Genes encoding cytoskeletal proteins Unconventional myosins (DFNA1, DFNB2, DFNB3)

Conventional myosin is a molecular motor protein that, with actin filaments, causes motion using energy from ATP hydrolysis. Unlike conventional myosin, unconventional myosins are present in non-muscle cells and do not form bipolar filaments. In the ear, unconventional myosins are located in the stereocilia and cuticular plate of hair cells, which contain actin and have a role in the organisation of stereocilia and the movement of tiplinks. The first implication of their role in human deafness

Screening for hearing loss in newborn babies

Early diagnosis and intervention (before age 6 months) greatly improves communication skills of children with hearing loss, which ultimately leads to better academic success.50 Over the past several years, countries in Europe, Scandinavia, North America, and many others, have developed and implemented universal screening programmes for hearing loss in newborn babies. Two important advances in audiological screening of newborn infants have made these programmes possible, the screening auditory

Clinical approach to people with hearing loss

Implementation of screening for hearing loss in newborn babies in the USA, and rapid advances in the genetics of hearing loss leads to an urgent need to establish a rational yet simple approach for clinicians. Although a family history of hearing loss is usually an indicator of a genetic cause, many simplex cases are chance-isolated genetic cases, in which there is only one affected person in the family. In dominant forms of deafness, chance-isolated cases can arise because of new mutations,

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