Radiological malformations of the ear in pendred syndrome

Phelps, P. D.; Coffey, Rebecca; Trembath, Richard C.; Luxon, Linda M.; Grossman, Ashley; Britton, K. E.; Kendall‐Taylor, P.; Graham, John M.; Cadge, B.C.; Stephens, S. D. G.; Pembrey, Marcus; Reardon, William

doi:10.1016/s0009-9260(98)80125-6

Cited by 238 publications

(138 citation statements)

References 17 publications

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“…This patient had an incomplete partition of the cochlea and mutations in SLC26A4. 35 We did not find other cases with an identifiable phenotype such as progressive HI with a downsloping audiogram caused by TMPRSS3 mutations, 7,36 and the stable HI with a cookie-bite audiogram configuration caused by mutations in TECTA. 7 This is most likely due to the fact that these genes are generally pretested in patients with these identifiable phenotypes.…”

Section: Discussioncontrasting

confidence: 54%

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

et al. 2016

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Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

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Section: Discussioncontrasting

confidence: 54%

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

et al. 2016

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“…5 The appearance of EVA by CT/MRI is demonstrated to be a reliable radiological marker, and has become one of the reliable diagnostic criteria for Pendred syndrome. 24 According to Phelps et al, 24 EVA was found in a majority of Pendred syndrome patients, but Mondini deformity, which Figure 1 Multiple-sequence alignment of selected proteins with significant sequence homology to human pendrin. The amino-acid sequence of human pendrin (hum-pendrin) is aligned relative to the sequences of the mouse pendrin (mse-pendrin) and rat pendrin (rat-pendrin).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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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.

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“…Deafness is associated with radiologically detectable structural malformations of the inner ear. In particular, typical malformations are both an enlarged vestibular aqueduct (EVA) and an enlarged endolymphatic duct and sac (EED and EES) (16,17). SNHL is a constant feature of PS, whereas goiter is observed in about 50% of the affected individuals and can vary from a slight enlargement to a large multinodular goiter, with the time of onset ranging from the first months of life until puberty.…”

Section: Introductionmentioning

confidence: 99%

“…The VA was considered enlarged when its diameter at the midpoint between the common crus and the external aperture was 1.5 mm or more on thin CT sections (16). High-resolution fast-spin echo (FSE) T2-weighted magnetic resonance imaging (MRI) was carried out (in axial and coronal planes) to study the membranous labyrinth and in particular the endolymphatic duct and sac (ED and ES).…”

mentioning

confidence: 99%

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

et al. 2007

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Objective: Pendred syndrome (PS) is characterized by the association of sensorineural hearing loss (SNHL) and a partial iodide organification defect at the thyroid level. It is caused by mutations in the SLC26A4 gene. The encoded transmembrane protein, called pendrin, has been found to be able to transport chloride and other anions. Design: The aim of the present study was to characterize a family with PS, which shows a strong intrafamilial phenotypic variability, including kidney atrophy in one member. The age of disease-onset was significantly different in all three affected siblings, ranging from 2 to 21 years for thyroid alterations and from 1.5 to 11 years for SNHL. Methods: Clinical and genetic studies were carried out in affected siblings. The functional activity of the novel duplication found was studied by a fluorimetric method in a human renal cell line (HEK293 Phoenix) in which the protein was overexpressed. Results: All three siblings were found to be compound heterozygotes for the missense mutation (1226GOA, R409H) and for a novel 11 bp duplication (1561_1571CTTGGAATGGC, S523fsX548). The latter mutation creates a frameshift leading to the loss of the entire carboxy-terminus domain. Functional studies of this mutant demonstrated impaired transport of chloride and iodide when expressed in HEK 293 Phoenix cells, when compared with wild type pendrin. Conclusions: A novel 11 bp duplication was found in a family with Pendred syndrome, showing a high intrafamilial phenotypic variability. An impaired transmembrane anionic transport of the mutated SLC26A4 protein was demonstrated in functional studies using a heterologous cell system.

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Radiological malformations of the ear in pendred syndrome

Cited by 238 publications

References 17 publications

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

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

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

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