Enlarged Vestibular Aqueduct Research Articles

Exonic Deletions and Deep Intronic Variants of the SLC26A4 Gene Contribute to the Genetic Diagnosis of Unsolved Patients With Enlarged Vestibular Aqueduct

Enlarged vestibular aqueduct (EVA) is a frequently occurring inner ear malformation that associates with sensorineural hearing loss (SNHL), with SLC26A4 being the responsible gene. Based on multiplex PCR enrichment and sequencing of the exonic and flanking regions of the SLC26A4 gene, we developed a panel specifically for EVA and found that up to 95% of EVA patients in our Chinese cohorts carried biallelic SLC26A4 pathogenic variants (M2). In this study, we tried to investigate the genetic etiology of 13 previously undiagnosed EVA patients with monoallelic (M1) or none (M0) SLC26A4 variant using a stepwise approach, including copy number variation (CNV) analysis of multiplex PCR enrichment and next‐generation sequencing data, single‐molecule real‐time (SMRT) sequencing of the whole SLC26A4 gene, whole exome sequencing (WES), and whole genome sequencing (WGS). CNV analysis revealed deletions in Exons 1–3, Exons 5–6, and Exons 9–10 of the SLC26A4 gene in seven patients, and SMRT sequencing identified the same heterozygous deep intronic variant (NM_000441.2:c.304+941C>T) in two patients, resulting in a final diagnosis in 9/13 patients. Notably, the variants of Exons 9–10 deletion and c.304+941C>T have not been reported previously. We further showed that the variant c.304+941C>T led to the exonization of partial AluSz6 element (126 bp) where the variant is located through sequencing of the mRNA extracted from the blood of a heterozygous variant carrier. In conclusion, our stepwise approach improved the diagnosis rate of EVA, expanded the mutational spectrum of the SLC26A4 gene, and highlighted the contribution of exonic deletions and deep intronic variants to EVA.

Study on characteristics of wideband acoustic immittance in patients with Inner Ear Malformations

ObjectiveTo compare the differences in wideband absorbance and the resonance frequency (RF) between patients with inner ear malformations and normal control, and to explore the auditory diagnostic value of wideband acoustic immittance (WAI). MethodsA total of 38 patients (59 ears) with enlarged vestibular aqueduct (EVA), 13 patients (14 ears) with incomplete partition type I (IP–I) and 13 patients (26 ears) with incomplete partition type II (IP-II) were included. 50 normal control (100 ears). All subjects underwent WAI tests to compare the absorbance configuration and resonance frequency. ResultsAll the group showed lower absorbance at ambient pressure than at peak pressure in certain frequencies under 2000Hz. Under 1000Hz, the absorbance of EVA was higher than that of other groups. The average absorbance and highest absorbance of IP-I were the lowest(P＜0.05). However, IP-II and normal group had similarity on some characteristics. The three IEM groups mainly different at low and high frequencies, but not at medium frequencies. The highest absorbance of all the groups were appeared around 3000Hz. The RF of all the groups from low to high were EVA＜IP-II＜normal control＜IP-I, and the lowest was EVA(P＜0.05). ConclusionInner ear malformations can affect energy absorbance and RF. WAI is sensitive and non-invasive to provide useful information about inner ear status and facilitate detection of ear pathology.

Characteristics of vestibular-evoked myogenic potentials in children with vestibular malformation and severe sensorineural hearing loss

BackgroundWith the increasing clinical focus on the safety of bilateral cochlear implantation (CI) and the potential risk of bilateral vestibular dysfunction, evaluating vestibular end-organ function in patients with vestibular malformations with accompanying abnormalities has been strongly recommended. ObjectivesTo identify the vestibular-evoked myogenic potential (VEMP) values among children with sensorineural hearing loss (SNHL) with vestibular malformation and assess the effectiveness of VEMP testing for inner ear malformations (IEM) diagnosis. MethodsThis study included 96 children (192 ears), including those with vestibular malformations (48 ears), large vestibular aqueduct syndrome (LVAS) (50 ears), and SNHL without IEM (94 ears; control group). All groups underwent ocular and cervical VEMP (oVEMP and cVEMP, respectively) testing. The response rates, VEMP parameters, and wave characteristics were compared. ResultsThe cVEMP response rates were 37.5 %, 64 %, and 58.51 % and the oVEMP response rates were 42.86 %, 78.95 %, and 77.27 % in the vestibular malformation, LVAS, and control groups, respectively, and significantly differed between groups (cVEMP: X2 = 18.228, P<0.001) (oVEMP: X2 = 7.528, P = 0.023). Significant inter-group differences were observed for the cVEMP and oVEMP latency and amplitude (P < 0.05). The LVAS group's waveform exhibited a prolonged latency and increased amplitude compared with that of the other groups. ConclusionPatients with SNHL were highly susceptible to otolith dysfunction, regardless of comorbid vestibular malformation presence. Measuring VEMPs is an effective and rapid evaluation technique for vestibular function and could provide a basis for vestibular rehabilitation training.

Analysis of 59 cases of large vestibular aqueduct syndrome SLC26A4gene mutation frequency and new mutation sites

Objective:To study the frequency of SLC26A4 gene mutation sites in children with enlarged vestibular aqueduct deafness in Yunnan, report the new mutation sites of SLC26A4 gene, further clarify the mutation spectrum of SLC26A4gene, and explore the association between biallelic and monoallelic mutations of SLC26A4 gene and CT phenotype of inner ear, so as to provide basis for clinical and genetic diagnosis of deafness. Methods:Review the results of temporal bone CT examination of 390 children after cochlear implantation in the Department of Otolaryngology, Kunming Children's Hospital from August 2016 to September 2021. Sanger sequencing of SLC26A4 gene was performed in 59 children with enlarged vestibular aqueduct. According to the genetic test results, the children who underwent temporal bone CT examination were divided into two groups: SLC26A4 biallelic mutation group（homozygous mutation and compound heterozygous mutation）, monoallelic mutation group, and the association with inner ear CT phenotype was analyzed, and the new sites were summarized and analyzed. Results:The c.919-2a>g mutation was the most common mutation in children with enlarged vestibular aqueduct with SLC26A4 gene mutation. Three new variants of SLC26A4 gene were found; CT examination combined with genetic testing found that a part of children with enlarged vestibular aqueduct was associated with SLC26A4 monoallelic mutation or no SLC26A4 gene mutation was detected. Further research is needed to investigate the involvement of other pathogenic factors in the pathogenesis of EVA.

Follow-up of infants with mild-to-moderate sensorineural hearing loss over three years.

To observe and analyse the hearing outcome in infants with mild-to-moderate sensorineural hearing loss (SNHL) who failed universal newborn hearing screening (UNHS). This retrospective cohort analysis included infants with mild-to-moderate SNHL and with complete etiological diagnosis and followed up over three years. Out of 96 infants with mild-to-moderate SNHL 72 were stable (75%). Only one case was normal (1.04%), ten cases were improved (10.42%), and 13 were deteriorated (13.54%). The pathogenic mutation of GJB2 was the most common cause (50/96, 52.08%), and most of them were homozygous or complex heterozygous mutations of p.V37I (44/50, 88%). There were 11 cases (11.49%) with large vestibular aqueduct syndrome (LVAS) and nine cases (9.38%) with perinatal risk factors. Infants with GJB2 pathogenic mutation and those without certain etiology mostly had unchanged hearing levels, accounting for 84% (42/50) and 84.61% (22/26), respectively. Hearing deterioration in LVAS was associated with seven cases (63.64%). There was no difference in types of outcomes in perinatal risk factor infants, who were more likely to improve than the other groups, but there were three cases (33.3%) deteriorated to profound hearing loss. Comparison of outcomes of different etiologies showed statistically significant difference (Chi-square=28.673, p=0.000). Normal and improved hearing in infants with mild-to-moderate SNHL was rare before the age of three, unlike in many previous studies, and appropriate intervention is recommended. However, intervention should be adjusted according to the hearing outcomes because of the possibility of improvement or deterioration. The etiological diagnosis of infants with mild-to-moderate SNHL would be helpful for predicting the outcome and managing intervention.

Effect of congenital inner ear malformations (IEMs) on electrically evoked compound action potential (ECAP) responses in cochlear implant children.

The study was designed to assess the electrically evoked compound action potential (ECAP) responses in children with inner ear malformations compared to children with normal inner ear anatomy. The study included 235 prelingual deaf children who were implanted in cochlear implant unit in King Fahad University hospital-Imam Abdulrahman Bin Faisel University. Subjects were using either Cochlear Nucleus or Medel cochlear implant devices. We had 171 (64.5%) subjects with normal inner ear anatomy and 94 (35.5%) subjects with inner ear malformations (IEMs) and they were classified into 6 groups according to inner ear anatomy. Fourteen subjects (14.9%) subjects had enlarged vestibular aqueduct (EVA), 30 (32%) subjects had Mondini deformity, 25 (26.6%) subjects had incomplete partition type two (IPII), 9 (9.6%) subjects had incomplete partition type one (IPI) and 16 (17%) subjects had hypoplastic cochlea type III or IV. Intraoperative electrically evoked compound action potential (ECAP) responses were analyzed and compared in all subjects. Measurable ECAP responses can be elicited in patients with IEMs in most of the channels. Severe malformations can affect the prevalence of measuring ECAP and getting identifiable waveform morphology. Additionally, increased thresholds and lower slope of AGF was observed in IEMs specially in more severe malformations (e.g. IPI). IPI patients with better word recognition scores tended to show more identifiable ECAP measurements. This could suggest the presence of some correlation between ECAP responses and patients' performance after cochlear implantation.

The correlation between deafness progression and SLC26A4 mutations in enlarged vestibular aqueduct patients.

The relationship between the hearing phenotype and the SLC26A4 mutation in enlarged vestibular aqueduct cases has not been fully elucidated. To detect SLC26A4 mutation in a group of cases with enlarged vestibular aqueduct who received cochlear implantation and to analyze the correlation between the SLC26A4 genotype and the progression of deafness. Twenty-nine enlarged vestibular aqueduct patients were selected. Using the Sanger sequence to analyze SLC26A4 gene mutations. The 29 cases were divided into group A (carrying the c.919-2A > G mutation) and group B (not carrying the c.919-2A > G mutation). The difference in the duration of deafness was analyzed between the two groups. The detection rate of the c.1174A > T mutation in the postlingual deafness group was 37.5%, higher than that in the prelingual deafness group (0%). The difference in the duration of deafness between groups A and B was not statistically significant by the Mann-Whitney U test (p > 0.05). The correlation between the SLC26A4 genotype and the duration of deafness in cases with enlarged vestibular aqueduct is not yet clear. However, the c.1174A > T mutation may be linked to delayed hearing loss and the progression of deafness may be relatively slow in some cases of c.919-2A > G mutation.

A Large Vestibular Aqueduct With Conductive Hearing Loss as the Only Manifestation.

Conductive hearing loss is a common clinical condition caused by disorders of the middle and external ear. Here, we report a case of conductive hearing loss with complete tympanic membranes. Clinical examinations revealed no external and middle ear lesions, but high-resolution temporal bone computed tomography revealed enlarged vestibular aqueducts. Detailed audiological tests and follow-up results indicate that the exclusive air-bone gap is the outcome of inner ear malformation but not middle ear lesions, preventing the need for tympanic assessment.

전정수도관 확장 증후군 환자에서 발견된 내림프낭 종양 1예

An endolymphatic sac tumor (ELST) is a tumor of neuroectodermal origin. Although several cases have been reported in Korea, it is known to be very rare. Clinically, it grows slowly but shows an aggressive pattern accompanied by bone destruction pathologically. As the tumor grows, it shows symptoms due to endolymphatic hydrops such as hearing loss, tinnitus, and dizziness. In this paper, we report a case in which an ELST was found in a patient suffering from profound sensorineural hearing loss, tinnitus, and dizziness, who turned out to be an enlarged vestibular aqueduct syn-drome.

Characteristics of large vestibular aqueduct syndrome in wideband acoustic immittance.

To describe the characteristics of large vestibular aqueduct syndrome (LVAS) in wideband acoustic immittance (WAI) and to explore whether inner ear deformity has an impact on WAI results. Subjects with typical LVAS (LVAS group) and control subjects with a normal anatomical structure of the inner ear (control group) were screened from pediatric patients with cochlear implants using thin-slice computed tomography (CT) images of the temporal bone. With inflammation of the auditory canal and middle ear excluded by routine ear examination and 226 Hz acoustic immittance, WAI data were acquired. Then, the maximum absorbance as the major observation indicator on the mean tympanogram was compared between the LVAS group and control group, and a descriptive comparison of the mean tympanogram and frequency-absorbance curve at peak pressure was performed between the two groups. The LVAS group included 21 cases (38 ears), and the control group included 27 cases (45 ears). All LVAS subjects met the Valvassori criteria, and the VA at the horizontal semicircular canal displayed flared expansion. On the mean tympanogram, the maximum absorbance in the LVAS group (0.542 ± 0.087) was significantly higher than that in the control group (0.455 ± 0.087) (p < 0.001). The tympanogram in the LVAS group showed an overall elevation, and the absorbance at all pressure sampling points was significantly higher than that in the control group (p < 0.001). The frequency-absorbance curve at peak pressure first increased and then decreased in both groups, and the LVAS group showed higher absorbance than the control group in the frequency range below 2,828 Hz. The absorbance at 343-1,124 Hz was significantly different between the two groups (p < 0.001), and 343-1,124 Hz was the major frequency range at which the maximum absorbance on the mean tympanogram increased in the LVAS group. Large vestibular aqueduct syndrome (LVAS) shows increased absorbance in low and medium frequency ranges in WAI. The maximum absorbance on the mean tympanogram can serve as a reliable evaluation indicator. Inner ear factors must be considered when middle ear lesions are analyzed by WAI.

Fluid-solid coupling model and biological features of large vestibular aqueduct syndrome.

Objective: Computed tomography (CT) images of the temporal bone of large vestibular aqueduct syndrome (LVAS) patients were used to establish 3D numerical models based on the structure of the inner ear, which are, in turn, used to construct inner ear fluid-solid coupling models. The physiological features and pathophysiology of LVAS were analyzed from a biomechanical perspective using finite element analysis. Methods: CT images of the temporal bone were collected from five children attending the Second Hospital of Dalian Medical University in 2022. The CT images were used to build 3D models of the inner ear containing the vestibular aqueduct (VA) by Mimics and Geomagic software, and round window membrane models and fluid-solid coupling models were built by ANSYS software to perform fluid-solid coupling analysis. Results: By applying different pressure loads, the deformation of the round window membranes occurred, and their trend was basically the same as that of the load. The deformation and stress of the round window membranes increased with the increase in load. Under the same load, the deformation and stress of the round window membranes increased with the expansion of the midpoint width of the VA. Conclusion: CT images of the temporal bone used clinically could establish a complete 3D numerical model of the inner ear containing VA. Fluctuations in cerebrospinal fluid pressure could affect inner ear pressure, and VA had a limiting effect on the pressure from cerebrospinal fluid. The larger the VA, the smaller the limiting effect on the pressure.

Hearing Loss Related to Gene Mutations in Distal Renal Tubular Acidosis

Introduction: Distal renal tubular acidosis (dRTA) is a disease that may develop either primarily or secondarily, resulting from urinary acidification defects in distal tubules. Hearing loss may accompany primary forms of dRTA. This study aims to determine the characteristics of hearing loss due to different gene mutations in patients with dRTA. Methods: Behavioral and electrophysiological audiological evaluations were performed after otolaryngology examination in 21 patients with clinically diagnosed dRTA. Radiological imaging of the inner ear (n = 9) was conducted and results of genetic analyses using next-generation sequencing method (n = 16) were included. Results: Twenty-one patients with dRTA from 20 unrelated families, aged between 8 months and 33 years (median = 12, interquartile range = 20), participated. All patients with ATP6V1B1 mutations (n = 9) had different degrees of hearing loss. There was one patient with hearing loss in patients with ATP6V0A4 mutations (n = 6). One patient with the WDR72 mutation had normal hearing. Large vestibular aqueduct syndrome (LVAS) was detected in 6 (67%) of 9 patients whose radiological evaluation results were available. Conclusions: LVAS is common in patients with dRTA and may influence the type and severity of hearing loss in these patients. The possibility of both congenital and late-onset and progressive hearing loss should be considered in dRTA patients. A regular audiological follow-up is essential for the early detection of a possible late-onset or progressive hearing loss in these patients.

Evidence of vestibular dysfunction in children with enlarged vestibular aqueduct

ObjectiveTo investigate the occurrence and characteristics of balance and vestibular deficits in pediatric patients with enlarged vestibular aqueduct (EVA). Materials and methodsRetrospective review of 53 children with EVA who underwent a comprehensive vestibular evaluation in our pediatric balance and vestibular program. Laboratory testing included videonystagmography (VNG), rotary chair, video head impulse testing (vHIT), vestibular evoked myogenic potential (VEMP), subjective visual vertical (SVV) and Sensory Organization Test (SOT) in posturography. ResultsThe mean age of these children, 31 girls and 22 boys, was 7.1 years (SD = 4.8). Among these 53 children, 16 had unilateral EVA (7 on the left side and 9 on the right side) and 37 had bilateral EVA, in which genetic testing confirmed 5 cases of Pendred syndrome. Abnormal testing results were found in 58% (11/19) on SOT, 67% (32/48) on rotary chair, 55% (48/88 of ears) on VEMP, 30% (8/27) on vHIT, 39% (7/18) on SVV, and 8% (4/53) on VNG. ConclusionsVestibular dysfunction may be a common finding in children with EVA. Clinicians who provide medical care for children with EVA need to be familiar with signs of potential balance and vestibular impairments. Although performing vestibular evaluation on young children with EVA can be difficult, objective testing is important in order to identify any potential vestibular deficit in these pediatric patients so that proper vestibular rehabilitation and balance retraining can be provided.

Molecular Genetic Etiology and Revisiting the Middle Ear Surgery Outcomes of Branchio-Oto-Renal Syndrome: Experience in a Tertiary Referral Center.

To explore the phenotypes and genotypes of patients with branchio-oto-renal (BOR) and branchio-otic (BO) syndrome, and to analyze the middle ear surgery outcomes qualitatively and quantitatively, proposing a factor usefully prognostic of surgical outcomes. Retrospective cohort study. Tertiary referral center. Eighteen patients with BOR/BO syndrome in 12 unrelated Korean families. Middle ear surgery, including either stapes surgery or ossicular reconstruction. Clinical phenotypes, genotypes, and middle ear surgery outcomes. Eight probands (66.7%) were confirmed genetically; the condition segregated as a dominant or de novo trait. Six EYA1 heterozygous variants were identified by exome sequencing and multiplex ligation-dependent probe amplification. All variants were pathogenic or likely pathogenic based on the ACMG/AMP guidelines. Two novel EYA1 frameshift variants (p.His373Phefs*4 and p.Gln543Asnfs*90) truncating a highly conserved C-terminal Eya domain were identified, expanding the genotypic spectrum of EYA1 in BOR/BO syndrome. Remarkably, middle ear surgery was individualized to ensure optimal audiological outcomes and afforded significant audiological improvements, especially in BOR/BO patients without enlarged vestibular aqueducts (EVAs). A significant difference in air-bone gap closure after middle ear surgery was noted between the two groups even after adjusting for confounders: -20.5 dB in ears without EVAs (improvement) but 0.8 dB in ears with EVAs (no change or deterioration). Furthermore, the success rate was significantly associated with the absence of EVA. The results of this study were against the notion that middle ear surgery is always contraindicated in patients with BOR/BO syndrome, and an EVA could be a negative prognostic indicator of middle ear surgery in BOR/BO patients. This may aid to determine the strategy of audiological rehabilitation in patients with BOR/BO syndrome.

Advances in the study of fluctuating sensorineural hearing loss

Fluctuating sensorineural hearing loss（FSNHL） is a special type of sensorineural hearing loss, which can be manifested in many clinical diseases. In this paper, some clinical diseases associated with FSNHL are summarized, such as Meniere's disease, large vestibular aqueduct syndrome, acute low frequency sensorineural hearing loss, delayed endolymphatic hydrops, autoimmune inner ear disease and syndromes leading to FSNHL. The pathogenesis, diagnosis and treatment of FSNHL were summarized in order to improve clinicians' understanding of FSNHL, reduce the probability of misdiagnosis of related diseases and improve the prognosis of patients.

Single-cell whole-genome sequencing, haplotype analysis in prenatal diagnosis of monogenic diseases.

Monogenic inherited diseases are common causes of congenital disabilities, leading to severe economic and mental burdens on affected families. In our previous study, we demonstrated the validity of cell-based noninvasive prenatal testing (cbNIPT) in prenatal diagnosis by single-cell targeted sequencing. The present research further explored the feasibility of single-cell whole-genome sequencing (WGS) and haplotype analysis of various monogenic diseases with cbNIPT. Four families were recruited: one with inherited deafness, one with hemophilia, one with large vestibular aqueduct syndrome (LVAS), and one with no disease. Circulating trophoblast cells (cTBs) were obtained from maternal blood and analyzed by single-cell 15X WGS. Haplotype analysis showed that CFC178 (deafness family), CFC616 (hemophilia family), and CFC111 (LVAS family) inherited haplotypes from paternal and/or maternal pathogenic loci. Amniotic fluid or fetal villi samples from the deafness and hemophilia families confirmed these results. WGS performed better than targeted sequencing in genome coverage, allele dropout (ADO), and false-positive (FP) ratios. Our findings suggest that cbNIPT by WGS and haplotype analysis have great potential for use in prenatally diagnosing various monogenic diseases.

Newborn Hearing Screening Results in Patients with Enlarged Vestibular Aqueduct.

Enlarged vestibular aqueduct (EVA) is the most common anatomic abnormality contributing to permanent hearing loss (HL) in children. Although the association between EVA and HL is well-documented, the pass rate for the newborn hearing screening (NBHS) for patients with EVA-related HL is not. Our objective was to investigate the association between NBHS results and audiologic and clinical outcomes in a large cohort of pediatric patients with EVA. This was a retrospective chart review of patients seen in the Boston Children's Hospital (BCH) Department of Otolaryngology and Communication Enhancement with confirmed HL, known NBHS results, and confirmed EVA. Demographic, clinical, audiologic, and imaging data were collected from the medical record. Frequency-specific data points from pure-tone audiograms and/or automated auditory brainstem response tests were recorded, and four-frequency pure tone average was calculated using air conduction thresholds at 500, 1000, 2000, and 4000 Hz. Of the 183 patients included in the study, 84 (45.9%) passed their NBHS, whereas 99 (54.1%) did not pass. Compared with patients who did not pass, patients who passed were more likely to have unilateral EVA and unilateral HL, whereas they were less likely to undergo cochlear implantation and to have causative SLC26A4 variants. EVA-associated HL may be identified at birth or during childhood, with nearly half the patients in this cohort passing their NBHS. Our results provide prognostic information for patients with EVA who pass their NBHS and highlight the importance of regular hearing monitoring for children not initially suspected of having HL. 4 Laryngoscope, 133:2786-2791, 2023.

Vestibular Loss in Children Affected by LVAS and IP2 Malformation and Operated with Cochlear Implant.

This is a single center cohort study regarding the prevalence of vestibular loss in hearing impaired children affected by large vestibular aqueduct syndrome (LVAS) with incomplete cochlear partition malformation type II (IP2), fitted with cochlear implant (CI). Twenty-seven children received CI operations at 0.4-13 years on one or both ears and tested for vestibular loss with head impulse test, video head impulse test, mini ice-water test and cervical VEMP. Vestibular loss was found in 19% of operated ears and in 13.9% of non-operated ears. The difference was not statistically significant and was not significantly modified by age at implantation, age at testing, sex, presence of SLC26A4 gene mutation or bilaterality. However, the presence of anatomic anomalies at the level of the vestibulum or semicircular canals was significantly associated with a higher incidence of vestibular loss in CI operated children but not in those non-operated. No other factors, such as the surgical access, the electrode type, the presence of Gusher perioperatively, or post-operative vertigo modified significantly the prevalence of vestibular loss. In conclusion, LVAS/IP2 appears to be the major determinant of vestibular loss in these children, with a less obvious impact of CI, excluding the cases with vestibulum/canal anomalies: this group might have a higher risk for vestibular loss after CI surgery.

Analysis of genotypes on 850 newborns with SLC26A4 single-allele mutation and the phenotypes of those with second variant

Objective: To clarify the phenotypes of the newborns with SLC26A4 single-allele mutation in deafness genetic screening and second variant; to analyze the SLC26A4 genotype and hearing phenotype. Methods: 850 newborns born in Beijing from April 2015 to December 2019 were included and there were 468 males and 382 females. They received genetic deafness screening for 9 or 15 variants, with the result of SLC26A4 single-allele mutation. Firstly, three step deafness gene sequencing was adopted in this work, i.e., the first step was "SLC26A4 gene whole exons and splice sites" sequencing; the second step was "SLC26A4 gene promoter, FOXI1 gene and KCNJ10 gene whole exons" sequencing; and the third step was detection for "SLC26A4 gene copy number variation". Secondly, we collected the results of newborn hearing screening for all patients with the second mutation found in the three step test, and conducted audiological examinations, such as acoustic immittance, auditory brainstem response and auditory steady state response. Thirdly, for novel/VUS mutations, we searched the international deafness gene database or software, such as DVD, ClinVar and Mutation Taster, to predict the pathogenicity of mutations according to the ACMG guideline. Lastly, we analyzed the relationship between genotype and phenotype of newborns with SLC26A4 single allele mutation. Results: Among 850 cases, the median age of diagnosis was 4 months. In the first step, 850 cases were sequenced. A total of 32 cases (3.76%, 32/850) of a second variants were detected, including 18 cases (2.12%, 18/850) with identified pathogenic variants; 832 cases were sequenced and 8 cases of KCNJ10 gene missense variants were detected among the second step. No missense mutations in the FOXI1 gene and abnormal SLC26A4 gene promoter were detected; the third step sequencing results were all negative. Genotypes and hearing phenotypes included 18 cases combined with the second clear pathogenic variant, 16 cases (16/18) referred newborn hearing screening and 2 cases (2/18) passed in both ears; degree of hearing loss consisted of 18 profound ears (18/36), 13 severe ears (13/36) and 5 moderate ears (5/36); audiogram patterns comprised 17 high frequency drop ears (17/36), 14 flat ears (14/36), 3 undistinguished ears (3/36), and 2 U shaped ears (2/36); 11 cases underwent imaging examination, all of which were bilateral enlarged vestibular aqueduct. As for 22 cases of other genotypes, all passed neonatal hearing screening and the hearing diagnosis was normal, including 9 cases with VUS or possibly novel benign variants, 8 cases with KCNJ10 double gene heterozygous variants, and 5 cases with double heterozygous variants. Conclusions: The probability of individuals with SLC26A4 single-allele variant who merge with a second pathogenic variant is 2.12%, all of which are SNV, which can provide scientific basis for the genetic diagnosis and genetic counseling of SLC26A4 variants. Those who have merged with second pathogenic variant are all diagnosed with sensorineural hearing loss. Patients with KCNJ10 gene mutations do not manifest hearing loss during the infancy, suggesting the need for further follow-up.

Imaging Study &amp; Surgical Perspective Of Cochlear Implantees

Introduction: A cross-sectional prospective clinical study was done to evaluate the inner ear anomalies in candidates undergoing cochlear implantation. Materials and Methods: Study was carried out over a period of 07 years (Jan 2013 to Dec 2019) at Cochlear Implant Centre, Combined Military Hospital Dhaka. A total 206 deaf candidates, both pre and post lingual, were included in convenient sampling method. Result: The sample consisted of 206 candidates, of whom 117 (56.80%) were female and 89 (43.20%) were male. All candidates had severe to profound bilateral deafness. 182 (88.35%) of them were pre and 24 (11.65%) were in post lingual group. All patients diagnosed audiologically as profound deafness underwent HRCT scan of temporal bone with 3D reconstruction of cochlea and MRI of internal auditory canal &amp; brain. Radiological examination revealed that 36 (17.47%) candidates had ear anomalies. Mondini deformity 14 (06.80%), cochlear ossification 11 (5.34%), large vestibular aqueduct 04 (1.94%), high jugular bulb 04 (1.94%) and anteriorly placed sigmoid sinus 03 (1.45%) were noted. During intervention, 42 (20.39%) candidates had anomalous intra operative findings. Among them CSF gusher 19 (9.23%), ossification of basal turn 12 (5.83%), isolated rotated Cochlea 02 (0.97%), high jugular bulb 04 (1.94%), anteriorly placed sigmoid sinus 03 (1.45%), and very high facial nerve 02 (0.97%) were observed. During surgery, electrode insertion difficulty due to high CSF gusher was experienced in19 (9.23%) cases, full length of electrode insertion was not possible due to ossified basal turn 12 (5.83%), difficult to find out round window membrane due to rotated cochlea 02 (0.97%), prevented direct visualization of the round window due to high jugular bulb 04 (1.94%), difficult to approach round window due to very high facial nerve 02 (0.97%). and approach to round window membrane was compromised due to anteriorly placed sigmoid sinus 03 (1.45%). Most of these difficulties were effectively managed during surgery. Conclusions: This study highlights the importance of preoperative radiological scanning in the assessment of patients undergoing cochlear implantation. It provides vital information on cochlear status and in ruling out non cochlear causes where cochlear implantation is not feasible. Detection of anatomical abnormalities with appropriate evaluation, specially imaging should be mandatory in every patient undergoing cochlear implantation. J Dhaka Med Coll. 2021; 30(2) : 167-175