Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in pendred syndrome/enlarged vestibular aqueducts

Landa, Priya; Differ, Ann-Marie; Rajput, Kaukab; Jenkins, Lucy; Bitner‐Glindzicz, Maria

doi:10.1186/1471-2350-14-85

Cited by 40 publications

(25 citation statements)

References 39 publications

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“…Though FOXI1 and KCNJ10 have been confirmed to be related to EVA, most research devoted to these genes has failed to find specific pathogenic variants through large sample screening studies [46,47]. Two FOXI1 gene variants were detected in our work and one KCNJ10 variant (c.812G>A) was detected in another study [48].…”

Section: Discussionmentioning

confidence: 63%

A New Genetic Diagnostic for Enlarged Vestibular Aqueduct Based on Next-Generation Sequencing

Wang

Liu³

et al. 2016

PLoS ONE

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Enlarged vestibular aqueduct (EVA) is one of the most common congenital inner ear malformations and accounts for 1–12% of sensorineural deafness in children and adolescents. Multiple genetic defects contribute to EVA; therefore, early molecular diagnosis is critical for EVA patients to ensure that the most effective treatment strategies are employed. This study explored a new genetic diagnosis method for EVA and applied it to clinic diagnoses of EVA patients. Using next-generation sequencing technology, we set up a multiple polymerase chain reaction enrichment system for target regions of EVA pathogenic genes (SLC26A4, FOXI1, and KCNJ10). Forty-six EVA samples were sequenced by this system. Variants were detected in 87.0% (40/46) of cases, including three novel variants (SLC26A4 c.923_929del, c.1002-8C>G, and FOXI1 c.519C>A). Biallelic potential pathogenic variants were detected in 27/46 patient samples, leading to a purported diagnostic rate of 59%. All results were verified by Sanger sequencing. Our target region capture system was validated to amplify and measure SLC26A4, FOXI1, and KCNJ10 in one reaction system. The result supplemented the mutation spectrum of EVA. Thus, this strategy is an economic, rapid, accurate, and reliable method with many useful applications in the clinical diagnosis of EVA patients.

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Section: Discussionmentioning

confidence: 63%

A New Genetic Diagnostic for Enlarged Vestibular Aqueduct Based on Next-Generation Sequencing

Wang

Liu³

et al. 2016

PLoS ONE

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“…Moreover, possible undetected large deletions in the SLC26A4 gene could explain the occurrence of PS not showing second allelic mutations that went undetected by Sanger sequencing; however, this factor is likely only to influence the figures minimally because such larger genomic alterations seem to be rare, as evidenced by several reports . In our study, the M1 patients underwent MLPA analysis to ensure no undetected second allelic mutation.…”

Section: Discussionmentioning

confidence: 83%

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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“…Approximately, 180 mutations have been reported (http://www.healthcare.uiowa.edu/labs/ pendredandbor/slcMutations.htm), which include missense, nonsense, splice site, and frameshift mutations, as well as partial gene deletions (4,5). Mutations in FOXI1 (6) and KCNJ10 (7) mutations have also been implicated in some cases of Pendred syndrome, although their role, if any, is likely to be minor (8,9).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of genotype–phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome

Soh

Druce

Grossman

et al. 2015

European Journal of Endocrinology

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Design: Patients with Pendred syndrome have genotypic and phenotypic variability, leading to challenges in definitive diagnosis. Deaf children with enlarged vestibular aqueducts are often subjected to repeated investigations when tests for mutations in SLC26A4 are abnormal. This study provides genotype and phenotype information from patients with suspected Pendred syndrome referred to a single clinical endocrinology unit. Methods: A retrospective analysis of 50 patients with suspected Pendred syndrome to investigate the correlation between genetic, perchlorate discharge test (PDT) and endocrine status. Results: Eight patients with monoallelic SLC26A4 mutations had normal PDT. Of the 33 patients with biallelic mutations, ten of 12 patients with O30% discharge developed hypothyroidism. In our cohort, c.626GOT and c.3-2AOG result in milder clinical presentations with lower median perchlorate discharge of 9.3% (interquartile range 4-15%) compared with 40% (interquartile range 21-60%) for the remaining mutations. Eight novel mutations were detected. All patients with PDT !30% remained euthyroid to date, although the majority are still under the age of 30. There was a significant correlation between PDT and goitre size (RZ0.61, PZ0.0009) and the age of onset of hypothyroidism (RZK0.62, PZ0.0297). In our population, the hazard of becoming hypothyroid increased by 7% per percentage point increase in PDT (P!0.001). Conclusion: There is a correlation between SLC26A4 genotype and thyroid phenotype. If results hold true for larger patient numbers and longer follow-up, then for patients with monoallelic mutations, PDT could be unnecessary. Patients with biallelic mutations and PDT discharge O30% have a high risk of developing goitre and hypothyroidism, and should have lifelong monitoring.

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Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in pendred syndrome/enlarged vestibular aqueducts

Cited by 40 publications

References 39 publications

A New Genetic Diagnostic for Enlarged Vestibular Aqueduct Based on Next-Generation Sequencing

A New Genetic Diagnostic for Enlarged Vestibular Aqueduct Based on Next-Generation Sequencing

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

Evaluation of genotype–phenotype relationships in patients referred for endocrine assessment in suspected Pendred syndrome

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