Use of<i>SLC26A4</i>Mutation Testing for Unilateral Enlargement of the Vestibular Aqueduct

Chattaraj, Parna; Reimold, Fabian R.; Muskett, Julie; Shmukler, Boris E.; Madeo, Anne C.; Pryor, Shannon; Zalewski, Christopher; Butman, John A.; Brewer, Carmen C.; Kenna, Margaret A.; Alper, Seth L.; Griffith, Andrew J.

doi:10.1001/jamaoto.2013.4185

Cited by 28 publications

(26 citation statements)

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“…We previously reported two unilateral EVA subjects in the NIH cohort with two mutant alleles of SLC26A4 , leading us to propose an expansion of the indications for SLC26A4 testing to include unilateral EVA 8. In our current study, two (18%) of 11 NIH M1 subjects carrying the CEVA haplotype had unilateral hearing loss and EVA (table 3).…”

Section: Discussionsupporting

confidence: 51%

A commonSLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

et al. 2017

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Background Enlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and one-half have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype. Methods We performed genotype–haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families. Results We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten ’mutation-negative’ chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042). Conclusions T he CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.

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Section: Discussionsupporting

confidence: 51%

A commonSLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

et al. 2017

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“…This could imply that monoallelic SLC26A4 mutations may play a role in hearing impairment but are not the only cause of hearing loss in the IEVA individuals. A study on unilateral EVA subjects supports this because only 8.3% had two mutant alleles, 16.7% had one mutant allele, and 75% had no mutant alleles in the SLC26A4 gene …”

Section: Discussionmentioning

confidence: 91%

Association of SLC26A4 mutations, morphology, and hearing in pendred syndrome and NSEVA

Mey¹,

Muhamad

Tranebjærg

et al. 2019

The Laryngoscope

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Objective: To investigate the relations of monoallelic (M1), biallelic (M2), or the absence of mutations (M0) in SLC26A4 to inner ear morphology and hearing levels in individuals with Pendred syndrome (PS) or nonsyndromic enlarged vestibular aqueduct (NSEVA) associated with hearing loss.Methods: In a cohort of 139 PS/NSEVA individuals, 115 persons from 95 unrelated families had full genetic sequencing of SLC26A4, and 113 had retrievable images for re-assessment of inner ear morphology. The association between the number of mutant alleles in SLC26A4, inner ear morphology (including endolymphatic sac size and protein content on magnetic resonance imaging), and hearing level (pure tone average) was explored.Results: Biallelic SLC26A4 mutations (M2) occurred in three-quarters of the cohort and was invariably associated with poor hearing; in 87%, it was associated with incomplete partition type II of the cochlea as well as enlarged endolymphatic sac and vestibular aqueduct. M1 or M0 individuals exhibited a greater variability in inner ear morphology. Endolymphatic sac size and presence of "high-protein" sac contents were significantly higher in M2 individuals compared to M1 and M0 individuals.Conclusion: The number of SLC26A4 mutations is associated with severity and variability of inner ear morphology and hearing level in individuals with PS or NSEVA. M2 individuals have poorer hearing and present largely incomplete partition type II of the cochleas with enlarged endolymphatic sacs, whereas individuals with M1 and no detectable SLC26A4 mutations have less severe hearing loss and more diverse inner ear morphology.

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“…Subjects, methods, and their description are essentially as reported . Our study was approved by the Combined Neuroscience Institutional Review Board, National Institutes of Health (NIH), Bethesda, Maryland.…”

Section: Methodsmentioning

confidence: 99%

“…Subjects were evaluated at the NIH Clinical Center as previously described . We relied upon records from outside healthcare providers for subjects who did not come to the NIH Clinical Center.…”

Section: Methodsmentioning

confidence: 99%

Atypical patterns of segregation of familial enlargement of the vestibular aqueduct

et al. 2015

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Objective Hearing loss and enlargement of the vestibular aqueduct (EVA) can be inherited as an autosomal recessive trait caused by mutant alleles of the SLC26A4 gene. In some other families, EVA does not segregate in a typical autosomal recessive pattern. The goal of this study was to characterize the SLC26A4 genotypes and phenotypes of extended families with atypical segregation of EVA. Study Design Prospective study of cohort of families ascertained between 1998 and 2014 at the National Institutes of Health Clinical Center. Methods Study subjects were members of eight families segregating EVA in at least two members who were not related as siblings. Evaluations included pure-tone audiometry, temporal bone imaging, SLC26A4 nucleotide sequence analysis, SLC26A4-linked marker genotype and haplotype analysis, and pedigree analysis. Results One family had members with EVA caused by different etiologies, and two families had pseudo-dominant inheritance of recessive mutations of SLC26A4. In five families, the etiology remained unknown and could include inheritance of mutant alleles at another genetic locus, non-genetic influences, or a combination of these factors. Conclusions Familial EVA can demonstrate a variety of atypical segregation patterns. Pseudo-dominant inheritance of SLC26A4 mutations or recessive alleles of other hearing loss genes may be more likely to occur in families in which deaf individuals have intermarried. The etiologic basis of atypical segregation of EVA without detectable SLC26A4 mutations remains unknown. Future studies of these families may reveal novel genes for EVA.

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Use ofSLC26A4Mutation Testing for Unilateral Enlargement of the Vestibular Aqueduct

Abstract: Unilateral EVA can be associated with all possible SLC26A4 genotype results. The distinct combination of prognoses and recurrence probability associated with each genotype supports the clinical use of testing for SLC26A4 mutations in subjects with unilateral EVA.

Cited by 28 publications

References 20 publications

A commonSLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

A commonSLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

Association of SLC26A4 mutations, morphology, and hearing in pendred syndrome and NSEVA

Atypical patterns of segregation of familial enlargement of the vestibular aqueduct

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