Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese

Abstract

Molecular diagnosis makes a substantial contribution to precise diagnosis, subclassification, prognosis, and selection of therapy. Mutations in the PDS (SLC26A4) gene are known to be responsible for both Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct, and the molecular confirmation of the PDS gene has become important in the diagnosis of these conditions. In the present study, PDS mutation analysis confirmed that PDS mutations were present and significantly responsible in 90% of Pendred families, and in 78.1% of families with nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Furthermore, variable phenotypic expression by the same combination of mutations indicated that these two conditions are part of a continuous category of disease. Interestingly, the PDS mutation spectrum in Japanese, including the seven novel mutations revealed by this study, is very different from that found in Caucasians. Of the novel mutations detected, 53% were the H723R mutation, suggesting a possible founder effect. Ethnic background is therefore presumably important and should be noted when genetic testing is being performed. The PDS gene mutation spectrum in Japanese may be representative of those in Eastern Asian populations and its elucidation is expected to facilitate the molecular diagnosis of a variety of diseases.

Estimation of carrier frequencies of six autosomal-recessive Mendelian disorders in the Korean population

“…7,15 As shown in Table 3, this is slightly lower than the carrier frequencies reported for Korea's neighboring countries, Japan and China; these differences might be because of the small number of subjects tested in those countries. [22][23][24][25] The frequency of carriers with mutations in the SLC26A4 was 1 in 75, similar to the carrier frequencies reported previously in the Korean population 8 and Japanese population 21 (Table 4). Given that the one mutation that we investigated represents 45.5% of the genetic variation in Korean hearing-loss patients with the SLC26A4 mutations, 8 we presume that the carrier frequency of the SLC26A4-related mutations in the Korean population is 1 in 34.…”

“…18 Genetic deafness is highly heterogeneous, with more than 100 genes predicted to cause this disorder. 19 In spite of this large heterogeneity, mutations in the GJB2 and SLC26A4 account for up to 50% 20 and 10% of hereditary HL in diverse populations, 21 respectively. In the study, the total frequency of carriers with mutations in the GJB2 was 1 in 41, similar to that previously reported in the Korean population.…”

Association of SLC26A4 muations with clinical features and thyroid function in deaf infants with enlarged vestibular aqueduct

“…Compound heterozygous missense and splice site mutations were found in four of six patients. The mutations, H723R, IVS7-2A>G, IVS8+1G>A, and 322delC, were previously reported in Japanese families with either Pendred syndrome or NSRD with EVA (Tsukamoto et al 2003). R581S, 919-2A>G, and IVS15+5G>A were novel SLC26A4 mutations.…”

“…The distributions of mutant SLC26A4 alleles differ significantly between various ethnic populations. The mutation H723R accounts for 53% of SLC26A4 mutation in Japanese patients, suggesting a possible founder effect (Tsukamoto et al 2003). In Caucasoid populations, the mutations IVS8+1G>A, L236P, and T416P account for nearly half of all SLC26A4 mutation alleles (Campbell et al 2001).…”

“…The gene has 21 exons that encode a 780 amino acid protein called pendrin, a 73 kDa glycoprotein with 11 or 12 transmembrane domains. More than 60 different SLC26A4 mutations have been identified in individuals with Pendred syndrome or NSRD with EVA (Park et al 2003), suggesting that some of the variability in clinical expression of these syndrome is correlated with mutation genotype (Tsukamoto et al 2003). The majority of the mutations are missense substitutions that often result in the formation of a truncated protein, but intronic mutations affecting splice sites also seem to be a frequent cause of Pendred syndrome and NSRD with EVA (Massa et al 2003;Yang et al 2005).…”