Nonsyndromic Enlarged Vestibular Aqueduct Research Articles

A case of Landau-Kleffner syndrome with SLC26A4-related hearing impairment

BackgroundLandau-Kleffner syndrome (LKS) is an acquired aphasia and electroencephalogram (EEG) abnormalities mainly in temporoparietal areas. SLC26A4 mutations can cause hearing loss associated with enlarged vestibular aqueduct (EVA).Case presentationsWe report a case of LKS in a 5-year-old boy with non-syndromic EVA due to homozygous mutations of c.919-2A>G (IVS7-2A>G) in SLC26A4. He had normal language development before 2 years old. At the age of 2.5 years, he was admitted to the hospital due to remarkable language delay, and diagnosed with hearing loss with EVA. The seizures started at 4.4 years of age and EEG recording showed electrical status epilepticus during sleep (ESES) with a posterior-temporal predominance. He received cochlear implantation in the right ear at 4.7 years of age, which improved his hearing and language skills. The nocturnal focal motor seizures recurred at 4.9 years of age. Then a remarkable inability to respond to calls and reduction in spontaneous speech were noticed. He was treated with methylprednisolone at 5 years old, which controlled the seizures, suppressed ESES, and remarkably improved the language ability. The absence of seizures maintained until the last follow-up at 5.3 years of age, with further improvements in EEG recording and language ability.ConclusionsThe co-existence of LKS and hearing loss caused by SLC26A4 mutations increases the difficulty of LKS diagnosis, especially in the presence of hearing loss and impaired language skills. EEG discharges predominantly in temporoparietal areas, the occurrence of ESES, and language improvement after antiepileptic medications are potential indicators for LKS diagnosis.

Genetic Determinants of Non-Syndromic Enlarged Vestibular Aqueduct: A Review.

Hearing loss is the most common sensorial deficit in humans and one of the most common birth defects. In developed countries, at least 60% of cases of hearing loss are of genetic origin and may arise from pathogenic sequence alterations in one of more than 300 genes known to be involved in the hearing function. Hearing loss of genetic origin is frequently associated with inner ear malformations; of these, the most commonly detected is the enlarged vestibular aqueduct (EVA). EVA may be associated to other cochleovestibular malformations, such as cochlear incomplete partitions, and can be found in syndromic as well as non-syndromic forms of hearing loss. Genes that have been linked to non-syndromic EVA are SLC26A4, GJB2, FOXI1, KCNJ10, and POU3F4. SLC26A4 and FOXI1 are also involved in determining syndromic forms of hearing loss with EVA, which are Pendred syndrome and distal renal tubular acidosis with deafness, respectively. In Caucasian cohorts, approximately 50% of cases of non-syndromic EVA are linked to SLC26A4 and a large fraction of patients remain undiagnosed, thus providing a strong imperative to further explore the etiology of this condition.

Enlarged vestibular aqueduct and Mondini Malformation: audiological, clinical, radiologic and genetic features

PurposeWhen referring to enlarged vestibular aqueduct (EVA) we should differentiate between nonsyndromic enlarged vestibular aqueduct (NSEVA) and Pendred Syndrome (PDS), a disease continuum associated with pathogenic sequence variants of Pendrin’s Gene (SLC26A4) in about half of the cases. The study was aimed to analyse the clinical and audiological features of a monocentric cohort of Caucasian patients with NSEVA/PDS, their genetic assessment and morphological inner ear features.MethodsWe retrospectively reviewed the audiologic, genetic and anamnestic data of 66 patients with NSEVA/PDS followed by our audiology service.ResultsSLC26A4 mutations was significantly correlated with the presence of PDS rather than NSEVA (p < 0.019), with the expression of inner ear malformations (p < 0.001) and with different severity of hearing loss (p = 0.001). Furthermore, patients with PDS showed significantly worse pure tone audiometry (PTA) than patients with NSEVA (p = 0.001). Anatomically normal ears presented significantly better PTA than ears associated with Mondini Malformation or isolated EVA (p < 0.001), but no statistically significative differences have been observed in PTA between patients with Mondini Malformation and isolated EVA.ConclusionNSEVA/PDS must be investigated in all the congenital hearing loss, but also in progressive, late onset, stepwise forms. Even mixed or fluctuating hearing loss may constitute a sign of a NSEVA/PDS pathology. Our findings can confirm the important role of SLC26A4 mutations in determining the phenotype of isolated EVA/PDS, both for the type/degree of the malformation, the hearing impairment and the association with thyroid dysfunction.

Enlarged vestibular aqueduct syndrome-dehiscence syndromes-honeycomb mastoid : Pathophysiology and evidence for clinical differentiation

Differential diagnosis of dizziness with hearing loss requires standardized procedures for detection and classification of rare congenital and acquired malformations of the petrous part of the temporal bone. The aim of this study was to present the physiology and pathophysiology of endolymphatic and perilymphatic pressure regulation, diagnostic guidelines, and aspects of prognosis and treatment. Relevant publications and guidelines were evaluated and own cases are reported. Enlarged vestibular aqueduct (EVA) is the most frequently observed malformation of the inner ear, which leads to increased internal hydrostatic pressure and cochleovestibular dysfunction. Non-syndromic and syndromic forms, e.g., Pendred syndrome, are known. Other pressure-relevant malformations are semicircular canal dehiscence syndrome (SCDS) and enlargement of the cochlear aqueduct. There are currently no treatment options for EVAS and enlarged cochlear aqueduct. Pendred syndrome generally requires treatment with cochlea implants (CI) in early childhood. Dizziness and autophony in patients with SCDS syndrome can be effectively treated by semicircular canal occlusion and coverage. Complaints in non-syndromic EVA and SCD syndrome are mainly caused by exposure of the inner ear to provoked and spontaneous pressure increases. Deafness and vestibular dysfunction in syndromic EVA (i.e.,Pendred syndrome, branchiootorenal syndrome) are caused by malformation of the cochlea, genetic maldevelopment of the hair cells, and pressure effects.

Receptive language acquisition in a pediatric population with Pendred syndrome and non-syndromic enlarged vestibular aqueduct

Background: Children with Pendred syndrome (PS) and non-syndromic enlarged vestibular aqueduct (NSEVA) represent a group of pre-lingual hearing-impaired individuals with rehabilitation challenges.Objective: To evaluate receptive language capabilities in a pediatric cohort with PS and NSEVA.Materials and methods: Twenty-four (24) children diagnosed with either PS or NSEVA, were examined using the Peabody Picture Vocabulary Test (PPVT) and compared to a cohort of 55 Danish children with normal hearing, as well as to a mixed group of 29 children with hearing impairment of congenital and hereditary non-syndromal type. In addition, test results were compared to normative data (PPVT-4 US standard scores).Results: PS/NSEVA children’s PPVT-4 test scores fall within the normative data for the PPVT-4 (US) but proved to be significantly lower statistically, when compared to Danish children with normal hearing (p<.0001) or to children with mixed non-syndromic hereditary hearing impairment (p=.006). Implantation age was significantly later for the PS/NSEVA group (median = 43 months), compared to the mixed non-syndromic hereditary congenial hearing impairment group (median = 11 months).Conclusions and significance: Children with PS/NSEVA perform below age equivalent for receptive vocabulary outcome when compared to both children with normal hearing, and children with non-syndromic mixed hereditary congenital hearing impairment who receive cochlear implants earlier.

Clinical analysis of 54 patients with non-syndromic enlarged vestibular aqueduct

Objective:To further recognize the clinical characteristics of non-syndromic enlarged vestibular aqueduct through the retrospective analysis of cases, with the purpose of providing references for clinical diagnosis and treatment. Method:Collect 54 cases of non-syndromic enlarged vestibular aqueduct, and analyze their clinical characteristics after history taking, physical examination, audiometry and imaging examination. Measure the biggest width of midpoint between internal and external of vestibular aqueduct on temporal bone thin-section CT, and analyze the relationship between the pipe width and sides of ear, types of hearing loss and degree of hearing loss through t test. Result:All 54 patients with non-syndromic enlarged vestibular aqueduct had bilateral ear involvement. There were 42 cases with prelingual deafness, 12 cases with postlingual deafness, and there were 38 ears with severe deafness, 70 ears with profound deafness. Ninety-six ears of hearing loss showed sensorineural deafness, and 12 ears manifested mixed deafness. The biggest width of midpoint between internal and external of vestibular aqueduct spread over 1.60-3.90 mm, and the average was 2.60 mm. There were no significant differences in data between left and right sides, degree of hearing loss and type of hearing loss. Conclusion:Non-syndromic enlarged vestibular aqueduct mainly manifests serious sensorineural deafness, and the diagnosis depends on imaging examination. There is no difference in the degree of expanding between left and right ear, and the extent of enlargement is not related to the type and the severity of hearing loss.

The Natural History of Hearing Loss in Pendred Syndrome and Non-Syndromic Enlarged Vestibular Aqueduct.

The aim was to investigate the progress of hearing loss over time in a cohort of pendred syndrome and non-syndromic enlarged vestibular aqueduct (PS/NSEVA) with one or two confirmed pathogenic variations in SLC26A4. Retrospective cohort study. At our tertiary referral center, a retrospective search of all patients with enlarged vestibular aqueduct, hearing loss and SLC26A4 mutations yielded 103 individuals by March 2017, 96 of whom had records of hearing levels; both an early audiometry and the latest between 3 and 668 months follow-up. Pure-tone average (PTA; average of thresholds at 0.5, 1, 2 and 4 kHz) was calculated for both ears at time 1 and time 2. Neonatal screening results were retrieved. Eighty-seven (87) individuals had biallelic (M2) and 16 had monoallelic alterations (M1) in their SLC26A4. On average, the PTA progressed to 80 dB HL by the age of 6 years for the entire cohort, and 3.2 years for the biallelic (M2) affected individuals. 25% of the cohort was screened in the neonatal screening program; of these 42% had "passed" at least monaurally. Audiometric profiles related to age show faster deterioration in high frequencies than in low frequencies. In patients with PS/NSEVA and SLC26A4 mutations, the average hearing loss progresses to 80 dB HL by the age of 6 years. For biallelic (M2) affected individuals it was 3.2 years. Although hearing levels reached severe to profound during childhood, almost 1/2 had passed neonatal hearing screening, at least monaurally, emphasizing the need for close follow-up.

A novel compound heterozygous mutation of SLC26A4 in two Chinese families with nonsyndromic hearing loss and enlarged vestibular aqueducts.

Enlarged vestibular aqueduct (EVA)‑associated hearing loss is frequently detected in individuals carrying the SLC26A4 mutation in the Chinese population. The present study aimed to identify the causative SLC26A4 coding mutations in a patient group with nonsyndromic hearing loss (NSHL) and EVA. Genomic DNA was extracted from blood samples obtained from 52 NSHL patients with EVA and from 60 normal controls. The mutation analysis for 20 coding exons of SLC26A4 was performed by direct sequencing. The results of the mutational analysis showed that there were two probands from two separate families suffering from bilateral sensorineural hearing loss with EVA, carrying the same novel compound heterozygous mutation of SLC26A4 (c.1644_1645insA and c.2168A>G). Other members of the two families had heterozygous mono‑allelic mutations with normal hearing. However, neither of these mutations were detected in the 60 normal controls. These results are the first, to the best of our knowledge, to link the compound heterozygote mutation, c.1644_1645insA and c.2168A>G, in the SLC26A4 gene to NSHL patients with EVA. The two mutations identified in the present study were located in the anti‑sigma factor antagonist domain, the core region for plasma membrane targeting of anion transporters, which suggested that the reduced or complete loss of SLC26A4 function was the direct cause of hearing loss in the two patients. These results provide a foundation for further elucidating the genetic factors responsible for EVA‑associated NSHL.

Results of molecular genetic testing in Russian patients with Pendred syndrome and allelic disorders

Pendred syndrome is an autosomal recessive inherited disorder characterized by a combination of sensorineural hearing impairment and euthyroid goiter; its clinical manifestation in children is hardly distinguishable from nonsyndromic hearing loss. Pendred syndrome is one of the most frequent types of syndromic hearing loss. Hearing impairment is accompanied by abnormal development of the bony labyrinth—enlarged vestibular aqueduct (EVA) and occasionally combined with Mondini dysplasia. Mutations in the SLC26A4 gene, which encodes the pendrin protein, are responsible for both Pendred syndrome and for allelic disorder (nonsyndromic enlarged vestibular aqueduct). The present study for the first time conducted molecular genetic analysis in 20 Russian patients with Pendred syndrome, EVA and/or Mondini dysplasia. As a result, six pathogenic mutations in the SLC26A4 gene were revealed in four patients. The mutation c.222G>T (p.Trp74Cys) was detected for the first time. Mutations were found in patients with Pendred syndrome and nonsyndromic EVA with or without Mondini dysplasia. Mutations were not detected in patients with isolated Mondini dysplasia. One proband with clinical diagnosis Pendred syndrome was homozygous for the c.35delG mutation in the GJB2 gene. The absence of frequent mutations, including well-known ones or “hot” exons in the SLC26A4 gene, was reported. Therefore, the optimal method to search for mutations in the SLC26A4 gene in Russian patients is Sanger sequencing of all exons and exon-intron boundaries in the SLC26A4 gene.

Cochlear implantation in Pendred syndrome and non-syndromic enlarged vestibular aqueduct – clinical challenges, surgical results, and complications

Objective: To explore specific clinical issues, surgical results, and complications of 80 cochlear implantations (CI) in 55 patients with Pendred syndrome (PS) or non-syndromic enlarged vestibular aqueduct (NSEVA).Background: Previous studies have focused either on unselected case series or on populations with mixed cochlear malformations. PS/NSEVA accounts for up to 10% of congenital SNHL, rendering this a large group of cochlear implant candidates. The abnormal inner ear anatomy of these patients may be associated with a lower surgical success rate and a higher rate of complications.Study design: Retrospective review of patients’ medical records and CT/MRI.Setting: Tertiary referral center.Materials and methods: The medical records and CT/MRI images of 55 PS/NSEVA patients receiving 80 cochlear implantations from 1982–2014 were reviewed. Demographic data, surgical results, intra-operative incidents, and post-operative complications were retrieved.Results: Complications occurred in 36% of implantations; 5% hereof major complications. Gushing/oozing from the cochleostoma occurred in 10% of implantations and was related to transient, but not prolonged post-operative vertigo.Conclusion: Intra-operative risks of gushing/oozing and post-operative vertigo are the primary clinical issues in PS/NSEVA patients regarding CI. Nonetheless, the surgical success rate is high and the major complication rate is low; similar to studies of unselected series of CI recipients.

Diagnostic Value of SLC26A4 Mutation Status in Hereditary Hearing Loss With EVA: A PRISMA-Compliant Meta-Analysis.

Many SLC26A4 mutations have been identified in patients with nonsyndromic enlarged vestibular aqueduct (EVA). However, the roles of SLC26A4 genotypes and phenotypes in hereditary deafness remain unexplained. This study aims to perform a meta-analysis based on the PRISMA statement to evaluate the diagnostic value of SLC26A4 mutant alleles and their correlations with multiethnic hearing phenotypes in EVA patients. The systematic literature search of the PubMed, Wiley Online Library, EMBASE, Web of Science, and Science Direct databases was conducted in English for articles published before July 15, 2015. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by discussion and a third investigator. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale. Data were synthesized using random-effect or fixed-effect models. The effect sizes were estimated by measuring odds ratios (ORs) with 95% confidence interval (CI). Twenty-five eligible studies involved 2294 cases with EVA data. A total of 272 SLC26A4 variations were found in deafness with EVA and 26 mutations of SCL26A4 had higher frequency. The overall OR was 646.71 (95% CI: 383.30-1091.15, P = 0.000). A total of 22 mutants were considered statistically significant in all ethnicities (ORs >1, P < 0.05). In particular, 8 mutants were specificity of EVA phenotypes in mutations of SLC26A4 for Asia deafness populations (ORs >1, P < 0.05), 4 mutants for Europe and North America (ORs >1, P < 0.05), and the IVS7-2A>G mutations in SLC26A4 were found to have the highest frequency in deafness individuals with EVA phenotype (62.42%). Moreover, subgroups for studies limited to cases with EVA phenotype, 11 mutants relevant risks (RRs) were P < 0.05, especially for IVS7-2A>G bi-allelic mutants assayed in a deafness population (RR = 0.880, P = 0.000). Diagnostic accuracy of SLC26A4 mutation results also identified the significant association of IVS7-2A>G (AUC = 0.99, 95% CI: 0.97-0.99) and p.H723R (AUC = 0.99, 95% CI: 0.98-1.00) detecting deafness with EVA. To conclude, the IVS7-2A>G and H723R in SLC26A4 present a significant predicting value and discriminatory ability for clinical use on diagnosis of EVA within a deafness population.

A 7666-bp genomic deletion is frequent in Chinese Han deaf patients with non-syndromic enlarged vestibular aqueduct but without bi-allelic SLC26A4 mutations

ObjectivesTo investigate the genetic cause of the patients with non-syndromic enlarged vestibular aqueduct (EVA) but without bi-allelic SLC26A4 mutations. MethodsPresence of a homozygous genomic deletion was detected in a Chinese Han deaf patient (D1467-1) who failed to amplify the first three exons of SLC26A4. The breakpoints of the deletion were fine-mapped and revealed by PCR amplification and sequencing. This deletion was subsequently screened in 22 Chinese Han EVA probands with mono-allelic SLC26A4 mutations. The possible founder effect of the newly identified genomic deletion was evaluated by haplotype analysis. ResultsA homozygous c.-2071_307+3801del7666 deletion of SLC26A4 was identified in patient D1467-1. This novel genomic deletion was subsequently identified in 18% (4/22) of the Chinese Han EVA probands with mono-allelic SLC26A4 mutations. Haplotype analysis showed that this genomic deletion is likely a founder mutation in Chinese Hans. ConclusionOur results suggested that the cryptic c.-2071_307+3801del7666 deletion of SLC26A4 is relatively frequent in Chinese Han non-syndromic EVA patients without bi-allelic SLC26A4 mutations. Screening of this genomic deletion should be incorporated into the routine DNA testing of SLC26A4 in Chinese Hans.

Mono-allelic mutations of SLC26A4 is over-presented in deaf patients with non-syndromic enlarged vestibular aqueduct

ObjectivesRecessive mutations of SLC26A4 are the major cause of hearing impairment associated with enlarged vestibular aqueduct (EVA). In a significant percentage of non-syndromic EVA patients, however, only mono-allelic mutations of SLC26A4 can be identified. In this study, we aimed to evaluate whether presence of mono-allelic mutations of SLC26A4 in those patients was coincidental or etiologically associated with the disorder. MethodsThe exons and flanking splicing sites of SLC26A4 were sequenced in 150 Chinese Han deaf probands with non-syndromic EVA. c.919-2A >G and p.H723R, two frequent mutations of SLC26A4 in Chinese Hans, were screened by an allele-specific PCR-based array in 3056 ethnically-matched normal hearing controls. The frequency of mono-allelic c.919-2A >G and p.H723R mutations was determined in each group. The statistical significance of the difference was analyzed by Fisher′s exact test. ResultsBi-allelic, mono-allelic and no mutation of SLC26A4 were detected in 98 (65.3%), 18 (12%) and 34 (22.67%) deaf probands with non-syndromic EVA, respectively. The frequency of mono-allelic c.919-2A >G and p.H723R mutations were significantly higher in the 150 deaf probands with non-syndromic EVA (8.67%) than in the 3056 normal hearing controls (1.4%, P=1.8×10−6). ConclusionPresence of mono-allelic mutations of SLC26A4 in non-syndromic EVA patients is etiologically associated with this disorder. Additional genetic or environmental causes may be present in those patients and demand further investigation and consideration during the genetic diagnosis and counseling.

Mutations in the Pendred Syndrome (PDS/SLC26A) Gene: An Increasingly Complex Phenotypic Spectrum From Goiter to Thyroid Hypoplasia

Pendred syndrome is an autosomal recessive disorder traditionally defined by sensorineural deafness, goiter, and a partial defect in the organification of iodide (OMIM 274600; http://www.ncbi.nlm.nih.gov/omim) (1). The syndromic association of goiter and deafness was first described by the British practitioner Vaughan Pendred in 1896 (2), and the partial iodide organification defect was recognized by Morgans and Trotter (3) in 1958 by submitting affected individuals to a perchlorate discharge test. The molecular causeunderlying thisdisorder,whichaccounts for about 10% of hereditary hearing loss and is one of most common forms of syndromic deafness, was identified in 1997 through the demonstration of biallelic mutations in the SLC26A4 (solute carrier 26A4) gene (4), which encodes the multifunctional anion exchanger pendrin. Pendrin functions as a coupled electroneutral iodide/chloride, iodide/bicarbonate, and chloride/bicarbonate exchanger with a 1:1 stoichiometry (5). In the thyroid, pendrin is expressed at the apical membrane of follicular cells and is thought to mediate iodide efflux into the follicular lumen, although this step likely involves an additional, unidentified anion transporter or exchanger (6, 7). Clinically, the hallmark of Pendred syndrome is sensorineural hearing impairment. Most patients present with severe prelingual deafness, and others develop progressive hearing impairment later in life. Radiological studies of the innerearrevealanenlargementof theendolymphaticsystem, which is most readily detected by documenting an enlarged vestibular aqueduct (EVA) (8). The thyroid enlargement is variable among affected family members, and functionally some individuals are euthyroid, whereas others have (congenital) hypothyroidism. It is thought that the variability of the thyroid phenotype is, at least in part, influenced by the nutritional iodine intake (1). In countries with a high iodine intake, goiter development and thyroid dysfunction are usually not seen in patients with biallelic mutations in the SLC26A4 gene. Without performing molecular analyses and/or a perchlorate discharge test, which is unfortunately poorly standardized and subject to other factors such as iodide intake, it is not possible to clinically distinguish Pendred syndrome from nonsyndromic familial EVA (8). The patients withfamilialEVAhaveanidenticalphenotypeatthelevelofthe innerearbutabsent thyroidabnormalities,andtheyhaveeither no mutations or monoallelic mutations in the SLC26A gene, indicating that Pendred syndrome and nonsyndromic EVA are distinct clinical and genetic entities (8). Now, thephenotypic spectrumassociatedwithmutations in the SLC26A4 gene is unfolding with further complexity. In this issue of the JCEM, Kuhnen et al (9) report on two patients from distinct families with thyroid hypoplasia and biallelic mutations in the SLC26A4 gene. A heterogeneous groupofdevelopmental abnormalities, referred toas thyroid dysgenesis, is found in approximately 85% of all patients with sporadic congenital hypothyroidism. Thyroid dysgenesis includes a spectrum of anomalies: (hemi)agenesis, ectopy, and hypoplasia. In an effort to identify novel genetic defects underlying thyroid dysgenesis, these investigators performed whole exome sequencing of the DNA obtained from a patient with thyroid hypoplasia from a consanguineousfamily.Theinvestigatorsdetected760biallelicsequence variants with the potential to alter the encoded proteins, but only 17 were predicted to have damaging consequences based on prediction programs assessing the functional consequences of these alterations. Surprisingly, this led to the

Identification of PENDRIN (SLC26A4) Mutations in Patients With Congenital Hypothyroidism and “Apparent” Thyroid Dysgenesis

Congenital hypothyroidism, the most frequent endocrine congenital disease, can occur either based on a thyroid hormone biosynthesis defect or can predominantly be due to thyroid dysgenesis. However, a genetic cause could so far only be identified in less than 10% of patients with a thyroid dysgenesis. Exome sequencing was used for the first time to find additional genetic defects in thyroid dysgenesis. In a consanguineous family with thyroid dysgenesis, exome sequencing was applied, and findings were further validated by Sanger sequencing in a cohort of 94 patients with thyroid dysgenesis. By exome sequencing we identified a homozygous missense mutation (p.Leu597Ser) in the SLC26A4 gene of a patient with hypoplastic thyroid tissue, who was otherwise healthy. In the cohort of patients with thyroid dysgenesis, we observed a second case with a homozygous missense mutation (p.Gln413Arg) in the SLC26A4 gene, who was additionally affected by severe hearing problems. Both mutations were previously described as loss-of-function mutations in patients with Pendred syndrome and nonsyndromic enlarged vestibular aqueduct. We unexpectedly identified SLC26A4 mutations that were hitherto diagnosed in thyroid dyshormonogenesis patients, now for the first time in patients with structural thyroid defects. This result resembles the historic description of thyroid atrophy in patients with the so-called myxedematous form of cretinism after severe iodine deficiency. Most likely the thyroid defect of the two homozygous SLC26A4 gene mutation carriers represents a kind of secondary thyroid atrophy, rather than a primary defect of thyroid development in the sense of thyroid agenesis. Our study extends the variable clinical spectrum of patients with SLC26A4 mutations and points out the necessity to analyze the SLC26A4 gene in patients with apparent thyroid dysgenesis in addition to the known candidate genes TSHR, PAX8, NKX2.1, NKX2.5, and FOXE1.

Molecular etiology of hearing impairment associated with nonsyndromic enlarged vestibular aqueduct in East China

Recessive mutations in SLC26A4 and in rarer cases double heterozygous mutations of FOXI1/SLC26A4 and KCNJ10/SLC26A4 lead to hearing impairment associated with enlarged vestibular aqueduct (EVA), the most common inner ear malformation. In our large cohort study, we addressed several important questions to the molecular etiology of this disorder. The overall prevalence of SLC26A4 mutations in nonsyndromic childhood sensorineural hearing loss (11.2%, 37/330) were determined by sequencing of SLC26A4 in 330 hearing impaired children who did not undergo inner ear radiologic imaging prior to their genetic test. The penetrance of EVA in bi-allelic SLC26A4 mutation carriers (100%, 37/37) was determined by follow-up computed tomography scanning. Combined with the study of 140 additional probands diagnosed with nonsyndromic EVA, we characterized the mutation spectrum of SLC26A4 in East China, which consisted of 19 novel SLC26A4 mutations and differed from those reported in other regions of China.

Molecular analysis of SLC26A4 gene in patients with nonsyndromic hearing loss and EVA: Identification of two novel mutations in Brazilian patients

The SLC26A4 gene has been described as the second gene involved in most cases of sensorineural non-syndromic hearing loss, since the first is the GJB2 gene. Recessive mutations in the SLC26A4 gene encoding pendrin, an anion transporter, are responsible for non-syndromic hearing loss associated with an enlarged vestibular aqueduct (EVA) and Pendred syndrome, which causes early hearing loss and affects the thyroid gland. Typically, the hearing loss is profound and prelingual. However, in some individuals, hearing impairment may develop later in childhood and then progress. Over 200 different SLC26A4 mutations have been reported, with each ethnic population having its own distinctive mutant allele series including a few prevalent founder mutations. ObjectivePerform the screening of the 20 coding exons of SLC26A4 gene in Brazilian deaf individuals with EVA. Patients and methodsAmong the 23 unrelated non-syndromic hearing loss Brazilian patients with EVA, in whom no deafness-causing mutations of the GJB2 gene, the direct sequencing was performed to screen the 20 exons and their flanking regions of the SLC26A4 gene. ResultsThe sequencing results revealed 9 cases (39%) carrying 13 different SLC26A4 mutations, including 11 known mutations (279delT, V138F, T193I, IVS8+1G>A, T410M, Q413R, R409H, L445W, IVS15+5G>A, V609G, and R776C) and 2 novel mutation (G149R and P142L). ConclusionThe SLC26A4 mutations have a high carrying rate in non-syndromic hearing loss Brazilian patients. The identification of a disease-causing mutation can be used to establish a genotypic diagnosis and provide important information to the patients and their families.

Molecular Epidemiology and Functional Assessment of Novel Allelic Variants of SLC26A4 in Non-Syndromic Hearing Loss Patients with Enlarged Vestibular Aqueduct in China

BackgroundMutations in SLC26A4, which encodes pendrin, are a common cause of deafness. SLC26A4 mutations are responsible for Pendred syndrome and non-syndromic enlarged vestibular aqueduct (EVA). The mutation spectrum of SLC26A4 varies widely among ethnic groups. To investigate the incidence of EVA in Chinese population and to provide appropriate genetic testing and counseling to patients with SLC26A4 variants, we conducted a large-scale molecular epidemiological survey of SLC26A4.MethodsA total of 2352 unrelated non-syndromic hearing loss patients from 27 different regions of China were included. Hot spot regions of SLC26A4, exons 8, 10 and 19 were sequenced. For patients with one allelic variant in the hot spot regions, the other exons were sequenced one by one until two mutant alleles had been identified. Patients with SLC26A4 variants were then examined by temporal bone computed tomography scan for radiological diagnosis of EVA. Ten SLC26A4 variants were cloned for functional study. Confocal microscopy and radioisotope techniques were used to examine the membrane expression of pendrin and transporter function.ResultsOf the 86 types of variants found, 47 have never been reported. The ratio of EVA in the Chinese deaf population was at least 11%, and that in patients of Han ethnicity reached at least 13%. The mutational spectrum and mutation detection rate of SLC26A4 are distinct among both ethnicities and regions of Mainland China. Most of the variants caused retention of pendrin in the intracellular region. All the mutant pendrins showed significantly reduced transport capability.ConclusionAn overall description of the molecular epidemiological findings of SLC26A4 in China is provided. The functional assessment procedure can be applied to identification of pathogenicity of variants. These findings are valuable for genetic diagnosis, genetic counseling, prenatal testing and pre-implantation diagnosis in EVA families.

251 Molecular Etiology of Childhood Hearing Impairment Associated with Non-Syndromic Enlarged Vestibular Aqueduct in Southeastern China

BackgroundMutations in SLC26A4, and in rarer cases double heterozygous mutations of FOXI1/SLC26A4 or KCNJ10/SLC26A4, lead to childhood hearing impairment associated with non-syndromic enlarged vestibular aqueduct (EVA), the most common inner...

SLC26A4 gene copy number variations in Chinese patients with non-syndromic enlarged vestibular aqueduct

BackgroundMany patients with enlarged vestibular aqueduct (EVA) have either only one allelic mutant of the SLC26A4 gene or lack any detectable mutation. In this study, multiplex ligation-dependent probe amplification (MLPA) was used to screen for copy number variations (CNVs) of SLC26A4 and to reveal the pathogenic mechanisms of non-syndromic EVA (NSEVA).MethodsBetween January 2003 and March 2010, 923 Chinese patients (481 males, 442 females) with NSEVA were recruited. Among these, 68 patients (7.4%) were found to carry only one mutant allele of SLC26A4 and 39 patients (4.2%) lacked any detectable mutation in SLC26A4; these 107 patients without double mutant alleles were assigned to the patient group. Possible copy number variations in SLC26A4 were detected by SALSA MLPA.ResultsUsing GeneMapper, no significant difference was observed between the groups, as compared with the standard probe provided in the assay. The results of the capillary electrophoresis showed no significant difference between the patients and controls.ConclusionOur results suggest that CNVs and the exon deletion in SLC26A4 are not important factors in NSEVA. However, it would be premature to conclude that CNVs have no role in EVA. Genome-wide studies to explore CNVs within non-coding regions of the SLC26A4 gene and neighboring regions are warranted, to elucidate their roles in NSEVA etiology.