Distinctive audiometric profile associated with DFNB21 alleles of TECTA.

Genetic factors are thought to account for approximately one half of cases of childhood hearing loss, the majority of which is non-syndromic and not associated with other abnormalities. Seventy-seven percent of hereditary, non-syndromic, prelingual deafness is autosomal recessive, 22% is autosomal dominant, and 1% is transmitted as a matrilineal or X linked trait. So far, more than 30 distinct genetic loci (known as DFNB loci) have been mapped for nonsyndromic recessive deafness (NSRD). In the absence of syndromic associations to guide genetic diagnosis, the auditory and vestibular features provide the only phenotypic clues to direct molecular diagnostic testing. Unfortunately, the phenotype of NSRD is usually non-specific; prelingual, nonprogressive, and severe-profound impairment is associated with mutations in a majority of DFNB loci. In contrast, inherited dominant hearing loss is more phenotypically heterogeneous; it is usually postlingual, progressive, and can be associated with a variety of different audiometric configurations. Mutations in the gene encoding α-tectorin (TECTA) are associated with both dominant and recessive modes of inherited hearing loss, DFNA8/A12 (MIM 601543 and MIM 601842) and DFNB21 (MIM 603629), respectively, and provide a robust model of genotype-phenotype correlation. Missense substitutions in TECTA result in dominant hearing loss (table 1). Three of these missense dominant alleles result in substitution of cysteine residues and are associated with progressive hearing loss. All other dominant missense alleles of TECTA are associated with stable, non-progressive hearing loss. 7 The only known recessive allele of TECTA is a splice site mutation that causes prelingual, severe-profound deafness linked to DFNB21. α-tectorin is one of the major glycoproteins of the tectorial membrane, the acellular matrix overlying the cochlear neuroepithelium. 10 α-tectorin has predicted structural domains with similarity to protein modules important for cross linking with other proteins. 10 One such region is similar to a sperm protein, zonadhesin, while another predicted domain resembles proteins found in the zona pellucida, an extracellular matrix surrounding the oocyte. Missense substitutions in the zona pellucida domain of TECTA cause a moderate degree of hearing loss with greater involvement of mid frequencies. 11 In contrast, missense substitutions in the zonadhesin domain of TECTA cause mild to moderate hearing loss primarily affecting high frequencies. 4 Here we report two novel mutations of TECTA, predicted to be functional null alleles, which cosegregate with recessive, moderate to severe hearing loss in large consanguineous families. The distinctive phenotype associated with DFNB21 deafness provides a useful clinical marker to facilitate its genetic diagnosis.