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.
EYA1 mutations cause branchio-oto-renal (BOR) syndrome. These mutations include single nucleotide transitions and transversions, small duplications and deletions, and complex genomic rearrangements. The last cannot be detected by coding sequence analysis of EYA1. We sought to refine the clinical diagnosis of BOR syndrome by analyzing phenotypic data from families segregating EYA1 disease-causing mutations. Based on genotype-phenotype analyses, we propose new criteria for the clinical diagnosis of BOR syndrome. We found that in approximately 40% of persons meeting our criteria, EYA1 mutations were identified. Of these mutations, 80% were coding sequence variants identified by SSCP, and 20% were complex genomic rearrangements identified by a semiquantitative PCR-based screen. We conclude that genetic testing of EYA1 should include analysis of the coding sequence and a screen for complex rearrangements.
Fifty to eighty percent of autosomal recessive congenital severe to profound hearing impairment result from mutations in a single gene, GJB2, that encodes the protein connexin 26. One mutation of this gene, the 35delG allele, is particularly common in white populations. We report evidence that the high frequency of this allelic variant is the result of a founder eVect rather than a mutational hot spot in GJB2, which was the prevailing hypothesis. Patients homozygous for the 35delG mutation and normal hearing controls originating from Belgium, the UK, and the USA were genotyped for diVerent single nucleotide polymorphisms (SNPs). Four SNPs mapped in the immediate vicinity of GJB2, while two were positioned up to 76 kb from it. Significant diVerences between the genotypes of patients and controls for the five SNPs closest to GJB2 were found, with nearly complete association of one SNP allele with the 35delG mutation. For the most remote SNP, we could not detect any association. We conclude that the 35delG mutation is derived from a common, albeit ancient founder. (J Med Genet 2001;38:515-518)
GJB2 encodes the protein Connexin 26, one of the building blocks of gap junctions. Each Connexin 26 molecule can oligomerize with five other connexins to form a connexon; two connexons, in turn, can form a gap junction. Because mutations in GJB2 are the most common cause of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss, the effect of the Connexin 26 allele variants on this dynamic 'construction' process and the function of any gap junctions that do form is particularly germane. One of the more controversial allele variants, M34T, has been hypothesized to cause autosomal dominant nonsyndromic hearing loss. In this paper, we present clinical and genotypic data that refutes this hypothesis and suggests that the effect of the M34T allele variant may be dependent on the mutations segregating in the opposing allele.
Mutations in SLC26A4 cause Pendred syndrome, an autosomal-recessive disorder characterized by sensorineural deafness and goiter, and DFNB4, a type of autosomal recessive nonsyndromic deafness in which, by definition, affected persons do not have thyromegaly. The clinical diagnosis of these two conditions is difficult, making mutation screening of SLC26A4 a valuable test. Although screening can be accomplished in a variety of ways, all techniques are not equally accurate, timely or cost effective. We found single-strand conformational polymorphism analysis (SSCP) to be 63% effective in detecting mutations a panel of different SLC26A4 allele variants when compared to data from direct sequencing. Because direct sequencing can be time consuming and expensive, especially for a gene with 21 exons, we studied DHPLC as an alternative screening method. We found DHPLC as accurate and reliable as direct sequencing but to be more rapid and cost effective. In addition, we report 11 novel disease-causing allele variants of SLC26A4.
Hereditary hearing loss (HHL) is an extremely common disorder. About 70% of HHL is non-syndromic, with autosomal recessive forms accounting for approximately 85% of the genetic load. Although very heterogeneous, the most common cause of HHL in many different world populations is mutations of GJB2, a gene that encodes the gap junction protein connexin 26 (Cx26). This study investigates the contribution of GJB2 to the autosomal recessive non-syndromic deafness (ARNSD) load in the Iranian population. One hundred sixty eight persons from 83 families were studied. GJB2-related deafness was diagnosed in 9 families (4, 35delG homozygotes; 3, 35delG compound heterozygotes; 1, W24X homozygote; 1, non-35delG compound heterozygote). The carrier frequency of the 35delG allele in this population was approximately 1% (1/83). Because the relative frequency of Cx26 mutations is much less than in the other populations, it is possible that mutations in other genes play a major role in ARNSD in Iran.
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