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

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.     

Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity

Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.     

Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment

Pendred syndrome is an autosomal‐recessive disorder characterized by congenital sensorineural hearing loss combined with goiter. This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS/SLC26A4) has been mapped to chromosome 7q22‐q31 and encodes a chloride‐iodide transport protein. Mutations in this gene are also a cause of non‐syndromic autosomal recessive hearing impairment (DFNB4). We have analyzed the PDS/SLC26A4 gene in Spanish and Italian families and we have detected five new mutations (X871M, T132I, IVS1‐2A>G, Y556H and 406del5). © 2001 Wiley‐Liss, Inc.     

Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations

Mutations in PDS (SLC26A4) cause both Pendred syndrome and DFNB4, two autosomal recessive disorders that share hearing loss as a common feature. The hearing loss is associated with temporal bone abnormalities, ranging from isolated enlargement of the vestibular aqueduct (dilated vestibular aqueduct, DVA) to Mondini dysplasia, a complex malformation in which the normal cochlear spiral of 2(1/2) turns is replaced by a hypoplastic coil of 1(1/2) turns. In Pendred syndrome, thyromegaly also develops, although affected persons usually remain euthyroid. We identified PDS mutations in the proband of 14 of 47 simplex families (30%) and nine of 11 multiplex families (82%) (P=0.0023). In all cases, mutations segregated with the disease state in multiplex families. Included in the 15 different PDS allele variants we found were eight novel mutations. The two most common mutations, T416P and IVS8+1G>A, were present in 22% and 30% of families, respectively. The finding of PDS mutations in five of six multiplex families with DVA (83%) and four of five multiplex families with Mondini dysplasia (80%) implies that mutations in this gene are the major genetic cause of these temporal anomalies. Comparative analysis of phenotypic and genotypic data supports the hypothesis that the type of temporal bone anomaly may depend on the specific PDS allele variant present.     

一个中国耳聋家系的SLC26A4基因分析

目的 确定一个非综合征型耳聋家系的致病基因。方法 应用聚合酶链反应-直接测序方法，对溶质转运蛋白家族26，成员4（solute carrier family 26，member 4；SLC26A4）基因的所有外显子及其与内含子交界处进行测序寻找突变。结果 在该家系先证者发现SLC26A4基因的N392Y、S448X复合杂合突变，其父亲为S448X的杂合突变，其母亲为N392Y的杂合突变。结论 SLC26A4基因的N392Y、S448X复合杂合突变是导致该先证者耳聋发生的原因。     

Spectrum and frequencies of mutations in the GJB2 (Cx26) gene among 156 Czech patients with pre-lingual deafness

Mutations in the gene gap junction beta 2 (GJB2), the gene for the connexin 26, are the most common cause of pre-lingual deafness worldwide. The mutation 35delG within GJB2 is prevalent in Europe. To date, there are no data about GJB2 mutation spectrum and frequencies from the Czech population. We investigated and report here the spectrum and frequencies of mutations in the GJB2 gene among 156 unrelated, congenital deafness Czech patients. Allele-specific polymerase chain reaction, together with fluorescent fragment analysis, were used for the detection of the 35delG mutation. The entire coding region of the GJB2 was directly sequenced in all patients who were not homozygous for the 35delG. No pathogenic mutation was detected in 51.9% of patients. At least one pathogenic mutation was found in 48.1% of patients, and both pathogenic mutations were detected in 37.8% of patients. Single mutations in a heterozygous state were detected in 10.3% of patients. The mutation 35delG accounts for 82.8% of detected disease mutations, Trp24stop accounts for 9.7% of pathogenic alleles and was found in patients with gypsy heritage. Mutation 313del14 accounts for 3.7% of pathogenic alleles. The frequency of 35delG heterozygotes in the Czech Republic is 1 : 29.6. Testing for only the three most common mutations would detect over 96% of all pathogenic alleles in the Czech Republic.     

A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China

There is a worldwide interest in studying SLC26A4 mutations that are responsible for enlarged vestibular aqueduct (EVA) in different ethnic background and populations. The spectrum of SLC26A4 mutations in Chinese population is yet to be fully characterized. In this study, all the 21 exons of SLC26A4 were screened in 107 Chinese patients with hearing loss associated with EVA or both EVA and Mondini dysplasia (MD), taken from six multiplex and 95 simplex families. The two types of control populations consisted of 84 normal-hearing subjects and 46 sensorineural hearing loss subjects without inner ear malformations. Biallelic mutations were found in 12 patients from multiplex families and 84 patients (88.4%) from the simplex families. In addition, monoallelic variant was detected in nine patients in the remaining 11 simplex families. Overall, up to 97.9% patients were found having at least one possible pathogenic variant in SLC26A4 , with most having biallelic variants consistent with recessive inheritance of this disorder. A total of 40 mutations including 25 novel mutations were identified in the Chinese patients but were not detected in all the controls except for one normal subject. For the Chinese mutation spectrum of SLC26A4 gene, IVS7-2A>G mutation was the most common form accounting for 57.63% (102/177) of all the mutant alleles.     

Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan

Mutations in OTOF , encoding otoferlin, cause non-syndromic recessive hearing loss. The goal of our study was to define the identities and frequencies of OTOF mutations in a model population. We screened a cohort of 557 large consanguineous Pakistani families segregating recessive, severe-to-profound, prelingual-onset deafness for linkage to DFNB9 . There were 13 families segregating deafness consistent with linkage to markers for DFNB9 . We analyzed the genomic nucleotide sequence of OTOF and detected probable pathogenic sequence variants among all 13 families. These include the previously reported nonsense mutation p.R708X and 10 novel variants: 3 nonsense mutations (p.R425X, p.W536X, and p.Y1603X), 1 frameshift (c.1103_1104delinsC), 1 single amino acid deletion (p.E766del) and 5 missense substitutions of conserved residues (p.L573R, p.A1090E, p.E1733K, p.R1856Q and p.R1939W). OTOF mutations thus account for deafness in 13 (2.3%) of 557 Pakistani families. This overall prevalence is similar, but the mutation spectrum is different from those for Western populations. In addition, we demonstrate the existence of an alternative splice isoform of OTOF expressed in the human cochlea. This isoform must be required for human hearing because it encodes a unique alternative C-terminus affected by some DFNB9 mutations.     

Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population

Mutations in the connexin 26 gene (GJB2), which encodes a gap-junction protein and is expressed in the inner ear, have been shown to be responsible for a major part of nonsyndromic hereditary prelingual (early-childhood) deafness in Caucasians. We have sequenced the GJB2 gene in 39 Japanese patients with prelingual deafness (group 1), 39 Japanese patients with postlingual progressive sensorineural hearing loss (group 2), and 63 Japanese individuals with normal hearing (group 3). Three novel mutations were identified in group 1: a single nucleotide deletion (235delC), a 16-bp deletion (176-191 del (16)), and a nonsense mutation (Y136X) in five unrelated patients. The 235delC mutation was most frequently observed, accounting for seven alleles in 10 mutant alleles. Screening of 203 unrelated normal individuals for the three mutations indicated that the carrier frequency of the 235delC mutation was 2/203 in the Japanese population. No mutation was found in group-2 patients. We also identified two novel polymorphisms (E114G and I203T) as well as two previously reported polymorphisms (V27I andV37I). Genotyping with these four polymorphisms allowed normal Japanese alleles to be classified into seven haplotypes. All 235delC mutant alleles identified in four patients resided only on haplotype type 1. These findings indicate that GJB2 mutations are also responsible for prelingual deafness in Japan.     

Resistance to hypertension and high Cl− excretion in humans with SLC26A4 mutations

Pendrin is a membrane transporter encoded by solute carrier family26A4 (SLC26A4). Mutations in this gene are known to cause hearing loss, and recent data from animal studies indicate a link between pendrin expression and hypertension; although, this association in humans is unclear. To clarify this issue, we investigated the influence of pendrin on blood pressure by analyzing demographic and biochemical data – including blood pressure and urinary electrolyte excretion – in patients with bi‐allelic SLC26A4 mutations. Systolic and diastolic blood pressure and the left ventricular hypertrophy index were lower in subjects with pendrin mutations than in controls. In addition, fractional excretion of Na⁺ and Cl^? was increased and serum renin, angiotensin I and II levels were higher in subjects with pendrin mutations as compared to controls. Thus, patients with impaired pendrin function are likely to be resistant to high blood pressure due to enhanced urinary Na⁺/Cl^? excretion. These results suggest that pendrin may regulate blood pressure through increased urinary salt excretion.     

A genotype-phenotype correlation for GJB2 (connexin 26) deafness

Introduction: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test.

Objective: To assess a possible genotype-phenotype correlation for GJB2.

Design: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations.

Subjects: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations.

Results: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes.

Conclusions: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.

     

Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population

Mutations in the GJB2 gene are associated with hereditary hearing loss. Although most studies of GJB2 mutations have dealt with hearing-impaired patients, there are few reports of the frequency of these mutations in the general population. The purpose of this study is to evaluate the prevalence of GJB2 mutations causing inherited deafness in the general Korean population. Blood samples were obtained from 2,072 newborns with normal hearing. The dried blood samples were subjected to PCR to amplify the entire coding region of the GJB2 gene, which was followed by direct DNA sequencing. A total of 24 different sequence variants were identified in the coding region of GJB2, including eight pathogenic mutations (p.V37I, p.G45E, p.R143 W, c.176_191del16, c.235delC, c.292_298dup7, c.299_300delAT and c.605ins46), four polymorphisms (p.V27I, p.E114G, p.G160S and p.I203T), six unclassified variants (p.G4D, p.S85Y, p.T123 N, p.R127H, p.A171T and p.F191L) and six novel variants (p.W3T, p.I20L, p.K41E, c.147C > T, c.186C > T and c.576A > G). Pathogenic mutations causing inherited deafness were identified in 3% (62/2,072) of the newborns with normal hearing. Of the eight pathogenic mutations found, p.V37I was the most common (1.35%, 28/2,072), followed by c.235delC (1.25%, 26/2,072). These data provide information about carrier frequency for GJB2-based hearing loss and have important implications for genetic diagnostic testing for inherited deafness in the Korean population.