Role of genetics in deafness in the population

Many reports of clinical populations of children with permanent hearing impairment have been published, usually suggesting between a third and a half of children have a genetic etiology (e.g. Fortnum et al., 2002; Morzaria et al., 2004). However, the criteria for ascribing a genetic aetiology often are not clear: many authors assume a genetic causation in the absence of any other clear cause, while others report syndromic deafness as a separate category even when it is highly likely to be due to a single gene mutation. Other reports of the role of single gene mutations in hearing impairment use a selected clinical population as the denominator. Examples of this are the reports of the frequent involvement of mutations of the GJB2 gene in deafness (in some Mediterranean populations up to 50%): the clinical populations reported often include only those with a definitive family history suggesting autosomal recessive inheritance of severe or profound deafness, excluding the sporadic cases where only one child is affected and excluding those with mild or moderate hearing impairment. Nonetheless, all authors agree that genetics has an important role in childhood deafness.

What of age-related hearing loss? As mentioned above, hearing impairment increases with age in the population, and age of onset for an individual can be at any age (Figure 33.1). Three studies suggest that genetics plays an important role in this later-onset hearing loss. The first report looked at intraclass correlations in male twins from a Swedish register (Karlsson et al., 1997). A total of 250 monozygotic pairs and 307 dizygotic pairs aged between 36 and 80 years old were examined by audiometry. Analysis of audiograms suggested that the hearing levels of the subjects were representative of the Swedish male population as a whole, and thresholds for high frequencies (3, 4, 6 and 8 kHz) were grouped together for study. The intraclass correlations in monozygotic twins decreased from 0.716 in the youngest group to

0.516 in the oldest group, while for dizygotic twins the correlations were much smaller. This suggests that genetic effects play a very significant role in explaining the variance observed, and also that environmental effects play an increasing role with increasing age. Heritability for the younger age groups was very high, approaching one.

A second study used the Framingham, Massachusetts, cohort which has been investigated at regular intervals over many years for a number of traits (Gates et al., 1999). After excluding cases with known causes of hearing impairment such as trauma, surgery or Meniere disease, and cases with unilateral impairment or evidence of middle ear disease (air-bone gap > 15 dB), 1079 members of the original cohort remained to be analyzed together with 1232 of their offspring. Thresholds for low, middle and high frequencies were measured by audiometry and were adjusted for age and sex using the population standards. The authors asked if adjusted thresholds in related pairs were more highly correlated than in unrelated pairs. The related pairs included sibs and parent-child pairs. Strong familial aggregations of age-adjusted thresholds were found, especially for mother—daughter and sister pairs, with heritability calculated to be between 0.26 and 0.35, and high frequency thresholds showed the greatest correlation in the overall analysis. When sensorineural hearing loss was analysed separately (assessed by the sloping shape of the audiogram towards high frequencies, as illustrated in Figure 33.3) low and mid-frequencies showed the largest heritability scores, up to 0.55. A later analysis of this cohort used the largest 328 families comprising 1789 individuals to carry out linkage analysis (DeStefano et al., 2003). Six chromosomal regions showed log likelihood (LOD) scores of 1.5 or more for low or mid-frequency thresholds: 3 regions of chromosome 11, plus regions on chromosomes 10, 14 and 18. The implicated regions on 11q13.5, 11p and 14q include genes known to be involved in Usher syndrome type 1 (severe or profound childhood deafness, vestibular dysfunction and progressive retinitis pigmentosa): Usher 1B caused by MYO7A mutations; Usher 1C caused by harmonin mutations; and Usher 1A, which is not yet identified, respectively. MYO7A is also involved in non-syndromic deafness DFNB2 and DFNA11. The 11q25 location implicated in age-related hearing loss overlaps with DFNB20, another non-syndromic deafness locus for which we have not yet found the responsible gene. These genes represent good candidates for searching for mutations associated with later-onset progressive hearing loss.

A third study used self-reported hearing loss by questionnaire in twins aged 70 years and older from the Danish twin registry (Christensen et al., 2001). This analysis suggested a heritability of 0.4, which the authors considered to be an underestimate because of the limitations of self-report compared with audiometry.

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