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Recessive mutations of the SLC26A4 (PDS) gene on chromosome 7q31 can cause sensorineural deafness with goiter (Pendred syndrome, OMIM 274600) or NSRD with goiter (at the DFNB4 locus, OMIM 600791). H723R (2168A>G) is the most commonly reported SLC26A4 mutations in Korean and Japanese and known as founder mutation. We recently experienced one patient with enlarged vestibular aqueduct syndrome. The genetic study showed H723R homozygous in the proband and H723R heterozygous mutation in his family members. The identification of a disease-causing mutation can be used to establish a genotypic diagnosis and provide important information to both families and their physicians.

Tight junctions (TJs) are essential components of eukaryotic cells, and serve as paracellular barriers and zippers between adjacent tissues. TJs are critical for normal functioning of the organ of Corti, a part of the inner ear that causes loss of sensorineural hearing when damaged. To investigate the relation between genes involved in TJ function and hereditary loss of sensorineural hearing in the Korean population, we selected the TJP2 and CLDN14 genes as candidates for gene screening of 135 Korean individuals. The TJP2 gene, mutation of which causes autosomal dominant non-syndromic hearing loss (ADNSHL), lies at the DFNA51 locus on chromosome 9. The CLDN14 gene, mutation of which causes autosomal recessive non-syndromic hearing loss (ARNSHL), lies at the DFNB29 locus on chromosome 21. In the present study, we conducted genetic analyses of the TJP2 and CLDN14 genes in 87 unrelated patients with ADNSHL and 48 unrelated patients with either ARNSHL or potentially sporadic hearing loss. We identified two pathogenic variations, c.334G>A (p.A112T) and c.3562A>G (p.T1188A), and ten single nucleotide polymorphisms (SNPs) in the TJP2 gene. We found eight non-pathogenic variations in the CLDN14 gene. These findings indicate that, whereas mutation of the TJP2 gene might cause ADNSHL, CLDN14 is not a major causative gene for ARNSHL in the Korean population studied. Our findings may improve the understanding of the genetic cause of non-syndromic hearing loss in the Korean population.

Hearing loss (HL) is a congenital disease with a high prevalence, and patients with hearing loss need early diagnosis for treatment and prevention. The GJB2, MT-RNR1, and SLC26A4 genes have been reported as common causative genes of hearing loss in the Korean population and some mutations of these genes are the most common mutations associated with hearing loss. Accordingly, we developed a method for the simultaneous detection of seven mutations (c.235delC of GJB2, c.439A>G, c.919-2A>G, c.1149+3A>G, c.1229C>T, c.2168A>G of SLC26A4, and m.1555A>G of the MT-RNR1 gene) using multiplex SNaPshot minisequencing to enable rapid diagnosis of hereditary hearing loss. This method was confirmed in patients with hearing loss and used for genetic diagnosis of controls with normal hearing and neonates. We found that 4.06% of individuals with normal hearing and 4.32% of neonates were heterozygous carriers. In addition, we detected that an individual is heterozygous for two different mutations of GJB2 and SLC26A4 gene, respectively and one normal hearing showing the heteroplasmy of m.1555A>G. These genotypes corresponded to those determined by direct sequencing. Overall, we successfully developed a robust and cost-effective diagnosis method that detects common causative mutations of hearing loss in the Korean population. This method will be possible to detect up to 40% causative mutations associated with prelingual HL in the Korean population and serve as a useful genetic technique for diagnosis of hearing loss for patients, carriers, neonates, and fetuses.

Hearing loss, which is genetically heterogeneous, can be caused by mutations in the mitochondrial DNA (mtDNA). The A1555G mutation of the 12S ribosomal RNA (rRNA) gene in the mtDNA has been associated with both aminoglycoside-induced and non-syndromic hearing loss in many ethnic populations. Here, we report for the first time the clinical and genetic characterization of nine Korean pedigrees with aminoglycoside-induced and non-syndromic hearing loss. These Korean families carry in the A1555G mutation of 12S rRNA gene and exhibit variable penetrance and expressivity of hearing loss. Specifically, the penetrance of hearing loss in these families ranged between 28.6% and 75%, with an average of 60.8%. These results were higher than the 29.8% penetrance that was previously reported in a Chinese population but similar to the 65.4% and 54.1% penetrance observed in a large Arab-Israeli population and nineteen Spanish pedigrees, respectively. The mutational analysis of the complete mtDNA genome in these families showed that the haplogroups of the Korean population, which belongs to the eastern Asian population, were similar to those of the Chinese population but different from the Spanish population, which belongs to the European-Caucasian population. The mtDNA variants that may act as modifier factors were also found to be similar to the Chinese population. Although the mtDNA haplogroups and variants were similar to the eastern Asian population, we did find some differing phenotypes, although some subjects had the same variants. This result suggests that both the ethnic background and environmental factors lead to a variable phenotype of the A1555G mutation.