Molecular Genetic Analysis Of Chinese Hearing Loss Population

Hearing loss is one of the most common sensory disorders. Profound hearing loss occurs in 1-2:1000 neonates and the cause is hereditary in about half. A distinction can be made between syndromic hearing loss (SHL), in which the hearing loss is companied by other specific abnormalities, and non-syndromic hearing loss (NSHL), in which there are no additional abnormalities (more than 70%). All types of hereditary mode can be observed in NSHL, including autosomal dominant (the associated NSHL gene loci are designated DFNA), autosomal recessive (DFNB), X-linked (DFN), Y-linked (DFNY) and maternal inheritance. NSHL is highly genetic heterogeneous. Up to July 2008, 133 NSHL gene loci have been mapped, and 45 genes have been identified. Of these GJB2 is the most common NSHL associated gene, which accounts for about 50% hereditary prelingual NSHL among Caucasian population. SLC26A4 comes next, accounts for 5%-10%, hearing loss with recessive mutations of SLC26A4 gene is usually associated with typical abnormalities of temporal bone, which is known as enlarged vestibular aqueduct (EVA). Mitochondrial DNA mutations account for about 1%. Other types of NSHL are very rare.By tracking the most updated research data of the field, two databases were set up, namely Hereditary NSHL Loci and Genes Database and Hereditary NSHL Gene Mutation Database. Meanwhile Flow Chart of NSHL Candidate Genes was also updated for easier manipulation. That significantly improved the previously established Genetic Diagnostic System for Hereditary Nonsyndromic Hearing Loss.Following polymerase chain reaction (PCR), coding sequence of GJB2 and mitochondrial genes of 12S and UCN were screened by denaturing high performance liquid chromatography (DHPLC) and restricted length fragment polymorphism (RFLP) with Alw26I and XbaI, respectively, among 407 hearing loss families collected from 1998 to 2007. Coding sequence of SLC26A4 was screened by DHPLC among 31 hearing loss families with or without EVA. All positive samples in screening were applied to direct sequencing. Mutation screening was also performed, by sequencing, to regulatory region of SLC26A4 and its regulatory gene F0XI1, in order to unveil the genotype-phenotype relationship.Among the 407 families, twenty-four probands were detected with two mutant alleles of GJB2; fifteen were with one mutant GJB2 allele. Twenty-seven probands had homogeneous mutation of A1555G of mtDNA, among which two also had homogeneous mutation of G7444A. Among those 31 families with or without EVA, seventeen patients from fifteen families were detected with two mutant alleles of SLC26A4; two were with one mutant SLC26A4 allele, none mutant alleles were detected in two EVA patients. None positive results got for the SLC26A4 regulatory components.Taking advantage of improved Genetic Diagnostic System for Hereditary Nonsyndromic Hearing Loss, with selected screening method, it could be efficient and economic for mutation screening of hereditary NSHL genes. According to published data and our own analysis, it could be concluded that 235delC of GJB2, A1555G of mtDNA, and IVS7-2A>G of SLC26A4 were hot spots of mutation among Chinese hearing loss population.