**1. Introduction**

246 Hearing Loss

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Nonsyndromic deafness in humans involves hearing loss as the only presenting feature in contrast to syndromes in which hearing loss is accompanied by other abnormalities. The majority of nonsyndromic deafness is recessively inherited which involves mutations of both alleles of a gene.

Deafness is a sensory impairment which results in a partial or total loss in reception of sound. The intensity of sound can be measured in decibels (dB). It is usual to assess hearing thresholds at frequencies of 0.25, 0.5, 1, 2, 4 and 8 KHz. Sounds of each frequency are presented at different intensities to a subject and the response is recorded graphically as an audiogram. A loss in hearing is indicated if the threshold for perception of sound for any frequency is elevated by 10 dB or greater as compared to the defined standard value for each frequency. Like visual foveae, organisms also have acoustic foveae, in which a certain frequency occupies greater space and is resolved more than other frequencies. In humans, the frequencies of 2 to 4 KHz are finely resolved. The frequencies of 0.5-2 KHz are the most important for hearing conversations. Therefore, individuals can have usable hearing if deafness does not impair these frequencies to a profound degree. A hearing loss of >91 dB constitutes profound deafness while those between 41 to 90 dB are defined as moderate (41-55 dB), moderate to severe (56-70 dB) or severe hearing loss (71-90 dB), respectively. Progressive deafness involves a gradual loss in the ability to hear over time.

The genetics and biology of moderate to severe and progressive hearing loss in humans has been understudied. More than 65 loci have been mapped for nonsyndromic recessively inherited deafness. Notably, mutations of only some of these genes are associated with stable moderate to severe hearing loss (Chishti et al., 2009; Naz et al., 2003; Villamar et al., 1999; Zwaenepoel et al., 2002). The past few years have revealed mutations in more than 10 genes and loci which can cause variable degrees of hearing loss or progressive deafness in humans. Additionally, the observation of intra- and inter- familial variability in the degree of deafness associated with identical mutations in a few genes has also implicated

Genetics of Nonsyndromic Recessively Inherited

Moderate to Severe and Progressive Deafness in Humans 249

**LOCUS GENE PHENOTYPE REFERENCE** 

extension domain cause less severe

mutations cause less severe degree of HL which may be progressive

*DFNB7 TMC1* Progressive HL in one family (de Heer et al., 2011)

may cause progressive HL

audiograms provided)

audiogram provided)

progressive inferred

shaped audiograms)

audiogram provided)

*DFNB25 GRXCR1* Progressive HL (Schraders et al.,

genotype-phenotype correlation

*DFNB33* Unknown Severe HL (No audiograms provided) (Belguith et al., 2009;

*DFNB42 ILDR1* Moderate to profound HL (Aslam et al., 2005;

*DFNB59 PJVK* Progressive HL in two families (Ebermann et al.,

No genotype-phenotype correlation

*DFNB30 MYO3A* Progressive HL (Walsh et al., 2002) *DFNB32* Unknown Severe HL (No audiograms provided) (Masmoudi et al.,

(Snoeckx et al., 2005)

(Hildebrand et al.,

(Cengiz et al., 2010; Nal et al., 2007)

(Kitamura et al., 2000; Lopez-Bigas et al., 1999; Luxon et al.,

(Hutchin et al., 2005; Scott et al., 2001; Veske et al., 1996; Weegerink

(Astuto et al., 2002)

(Masmoudi et al., 2004; Mustapha et al., 1998)

(Villamar et al., 1999)

(Moynihan et al., 1999)

(Meyer et al., 2007; Naz et al., 2003)

(Zwaenepoel et al.,

(Bashir et al., 2010b)

Medlej-Hashim et al.,

Borck et al., 2011b)

(Riazuddin et al., 2006)

2002)

2010a)

2003)

2002)

2007b)

2010)

2003)

et al., 2011)

phenotype correlation

less severe degree of HL

*DFNB1 GJB2* Mild to profound HL, No genotype-

*DFNB2\* MYO7A* A missense mutations may cause a

degree of HL

progressive HL

*DFNB12 CDH23* Compound heterozygous mutations

*DFNB13* Unknown Progressive or Severe HL (No

*DFNB16 STRC* Moderate to severe HL (One

*DFNB20* Unknown Moderate to profound HL,

*DFNB22 OTOA* Moderate to severe HL (No

*DFNB29 CLDN14* Moderate to profound HL, No

*DFNB49 TRIC* Moderately severe to profound HL,

*DFNB21 TECTA* Moderate to severe HL (Flat or U-

*DFNB3 MYO15A* Mutations affecting N-terminal

*DFNB4 SLC26A4* Splice site and some missesnse

*DFNB8 TMPRSS3* Hypomorphic alleles cause

a role for specific additional epistatic interactions which can modify the hearing loss in some instances.
