Introduction

Recent advances in the molecular biology of hearing and deafness are being transferred from the research laboratory to the clinical arena. This transfer of knowledge is enhancing patient care by facilitating the diagnosis of hereditary deafness. Traditionally, hereditary deafness has been distinguished from nongenetic causes of deafness by otologic, audiologic, and physical examinations, complemented by a family history and ancillary tests such as temporal bone computed tomography, urinalysis, thyroid function studies, ophthalmoscopy, and electrocardiography. Even using this test battery, an unequivocal distinction between genetic and nongenetic causes of deafness often is difficult. If comorbid conditions are identified,the deafness may fall into one of more than 400 recognized types of syndromic hearing loss, but if hearing loss segregates as the only abnormality, diagnosing the deafness as nonsyn-dromic and inherited is challenging.1

The relative contributions of syndromic and nonsyn-dromic deafness to the total deafness genetic load vary with age of ascertainment. Because syndromes are generally straightforward to recognize, most are noted at birth. In aggregate, syndromes account for about 30% of prelin-gual deafness. The majority of congenital hereditary deafness, however, is nonsyndromic, and this relative contribution increases with age, reflecting the greater occurrence and diagnosis of postlingual nonsyndromic as compared to postlingual syndromic deafness in late childhood and adulthood.

In many cases, the diagnosis of autosomal recessive non-syndromic deafness (ARNSD) is a diagnosis of exclusion. Current data suggest that even with a thorough history and physical examination, in simplex families (only one affected child) errors in diagnosis are made one third of the time; that is, a child is diagnosed with ARNSD when the correct diagnosis is congenital acquired deafness.2 This type of error precludes appropriate genetic counseling and can be a source of concern and anxiety for the family.

Molecular genetic testing offers a potential means to unequivocally diagnose inherited deafness. Allele variants of many genes are known to cause hereditary deafness;3 however, extreme heterogeneity and the relatively small contribution each gene makes to the total deafness genetic load make it impractical to offer complete mutation screening of all genes known to cause inherited deafness. Currently, clinical mutation screening is offered for three genes that cause nonsyndromic hearing loss and deafness (DFNB), GJB2, SLC26A4, and WFS1, and one gene that causes syndromic deafness, EYA1. The clinical utility of screening GJB2 and SLC26A4 is based on three facts. First, both genes cause types of deafness that are difficult to diagnose without genetic testing (GJB2 for DFNB1; SLC26A4 for DFNB4 and Pendred syndrome); second, the relative contribution of these two genes to the total genetic deafness mutation load is high; and third, both genes are relatively easy to screen by molecular methods. Mutation screening of WFS1 (nonsyndromic autosomal dominant deafness, DFNA6/14) is offered because the audioprofile of affected persons is unique, and in the case of EYA1, the occasional association of branchio-oto-renal syndrome with prenatal lethality has been the impetus to develop molecular genetic testing. In this chapter, genetic testing of these four genes is reviewed.

DFNB1(GJB2)

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