Novel OTOF gene mutations identified using a massively parallel DNA sequencing technique in DFNB9 deafness

Abstract

Objectives: This study examined the causative genes in patients with early-onset hearing loss from two Chinese families.

Method: Massively parallel sequencing, designed to screen all reported genes associated with hearing loss, was performed in a large number of Chinese individuals with hearing loss. This study enrolled patients with the same OTOF mutation and analyzed their phenotype–genotype correlations.

Results: Three novel OTOF mutations (NM_001287489) [c.1550T?>?C (p.L517P), c.5900_5902delTCA (p.I1967del), and c.4669_4677delCTGACGGTG (p.L1557-V1559del)] were found to be the cause of hearing loss in five patients. In family AH-890, the affected subject homozygous for p.L517P presented with profound hearing loss, while the affected sisters compound heterozygous for p.L517P and p.I1967del had mild-to-moderate hearing loss. The patient with hearing loss in family SD-345 was found to be compound heterozygous for p.L517P and p.L1557-V1559del.

Conclusion: Three presumably pathogenic mutations in the OTOF gene were detected for the first time, including the first pathogenic mutation detected in the TM domain. In addition to expanding the spectrum of OTOF mutations resulting in DFNB9, our findings present the diversity of its clinical presentation and indicate that MPS is an efficient approach to identify the causative genes associated with hereditary hearing loss.     

Comparative effects of unilateral and bilateral bone conduction hearing devices on functional hearing and sound localization abilities in patients with bilateral microtia-atresia

Abstract

Background: Various amplification options are available for patients with congenital bilateral conductive hearing loss. Unilateral bone conduction hearing device (BCHD) is widely used for these patients, whereas benefits of bilateral BCHDs in certain subgroups of patients require further exploration.

Objectives: To evaluate functional and directional hearing in patients with unilateral Bonebridge (MEDEL) and contralateral ADHEAR (MEDEL) devices.

Materials and methods: This study included 32 patients (20 males, 12 females), of mean age 11.8?years (range 7–27?years). Hearing thresholds, speech perception and sound localization were tested three months after activation of the Bonebridge under three conditions: unaided, unilateral BHCD (Bonebridge) and bilateral BHCDs (Bonebridge plus contralateral ADHEAR). Patient acceptance of these devices in daily life was evaluated by questionnaire.

Results: Compared with unaided, the mean hearing thresholds (0.5, 1, 2, and 4?kHz) and speech perception with unilateral BCHD and bilateral BCHDs were improved significantly (p?<?.05 each). Markers of directional hearing ability, including percentages of accurate responses, bias angles and RMS errors, were significantly better with bilateral BCHDs than unilateral BHCD (p?<?.05 each). Questionnaire revealed high patient satisfaction with both unilateral and bilateral devices.

Conclusions: Functional hearing and sound localization abilities were better with bilateral BCHDs than unilateral BCHD.     

Deafness gene mutations in newborns in Beijing

Objective To determine the incidence of congenital hearing loss (HL) in newborns by the rate of deafness-related genetic mutations. Design Clinical study of consecutive newborns in Beijing using allele-specific polymerase chain reaction-based universal array. Study sample This study tested 37 573 newborns within 3 days after birth, including nine sites in four genes: GJB2 (35 del G, 176 del 16, 235 del C, 299 del AT), SLC26A4 (IVS7-2 A?>?G, 2168 A?>?G), MTRNR1 (1555 A?>?G, 1494 C?>?T), and GJB3 (538 C?>?T). The birth condition of infants was also recorded. Results Of 37 573 newborns, 1810 carried pathogenic mutations, or 4.817%. The carrier rates of GJB2 (35 del G, 176 del 16, 235 del C, 299 del AT), GJB3 (538 C?>?T), SLC26A4 (IVS7-2 A?>?G, 2168 A?>?G), and MTRNR1 (1555 A?>?G, 1494 C?>?T) mutations were 0.005%, 0.104%, 1.924%, 0.551%, 0.295%, 0.253%, 1.387%, 0.024%, and 0.274%, respectively. Logistic regression analysis indicated no statistically significant relationship between mutations and infant sex, premature delivery, twin status, or birth weight. Conclusions The 235delC GJB2 mutation was the most frequent deafness-related mutation in the Chinese population. Genetic screening for the deafness gene will help detect more cases of newborn congenital HL than current screening practices.     

Detecting novel mutations and combined Klinefelter syndrome in Usher syndrome cases

Background: Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, vision loss, and occasionally vestibular dysfunction. Klinefelter syndrome (KS) is an X chromosome polyploidy characterized by one or more additional X chromosomes in males. To date, there has been no report of USH combined with KS.

Objectives: This study examined the causative genes in three Chinese probands with congenital hearing loss.

Material and methods: Targeted next-generation sequencing (NGS) was performed to identify mutations in three probands with hearing loss. Low-coverage whole-genome sequencing (WGS) analysis of aneuploidy was used to verify the chromosome aneuploidy.

Results: Four novel MYO7A mutations were identified in two USH1 probands who were initially diagnosed with nonsyndromic hearing loss until the onset of vision loss. Another case was initially diagnosed with nonsyndromic hearing loss and USH2 and KS were discovered incidentally after the genetic analysis.

Conclusions: Our findings expand the mutation spectrum of MYO7A. This is also the first report of concomitant USH and KS. Genetic testing can help with clinical management, particularly if an unrecognized syndromic disorder is identified before the onset of additional symptoms. A clinical genetic evaluation is recommended as part of the diagnostic work-up in congenital hearing loss.     

The auditory phenotype of children harboring mutations in the prestin gene

Conclusion Auditory phenotypes of two children harboring prestin gene mutations were congenital or pre-lingual onset, moderate to profound, slowly progressive or non-progressive, and audiograms with either flat configuration or prominently elevated thresholds at middle and high frequencies. Objectives Despite the essential role of the prestin gene in hearing, only one mutation in two families and a missense variant in a family had been reported previously before our study reporting another family. The purpose of this study was to characterize auditory phenotypes in children recently found to harbor novel mutations in the prestin gene. Methods The subjects were two sisters with bilateral sensorineural hearing loss who were compound heterozygotes for c.209G?>?A (p.W70X) and c.390A?>?C (p.R130S) mutations in the prestin gene. Clinical history and auditory test results were collected and analyzed. Results Hearing loss was present from birth in the younger sister and occurred before 6 years of age in the elder sister. The degree of hearing loss was profound in the elder sister with little progression, and moderate in the younger sister with no progression. The audiogram of the elder sister showed prominently elevated thresholds at middle and high frequencies, while that of the younger sister demonstrated a flat configuration.     

Analysis between phenotypes and genotypes of inner ear malformation

Background: The clinical characteristics of LVAS have attracted more and more attention, its audiology and imaging features have also been deeply studied.

Objective: To analyze phenotypes, genotypes of EVA, and find out the relationship between them.

Methods: Sixty EVA patients were tested by audiometry, temporal bone high-resolution CT and inner ear MRI. SNPscan technology were carried out after the patients signed informed consent. SPSS19.0 software was used.

Result: 1. Three types malformations include EVA, EVA with Mondini and Mondini were found. They accounted for 48.20%, 40.10%, and 11.70%. 2. The SLC26A4 gene mutation frequency was (47/53) 88.68% in EVA patients. The most common genotype was c.919-2A?>?G/c.919-2A?>?G, accounting for 28.30%. The most common mutation type was c.9I9-2A?>?G. 3. GJB2 and SLC26A4 gene mutation frequencies were significantly different (χ2＝65.185, p<.001).

Conclusions: 1. EVA patients with severe sensorineural hearing loss were always diagnosed in childhood and Cochlear implantation was feasible for these patients with the bilateral hearing loss. 2. SLC26A4 gene was closely related to EVA. 3. GJB2 and mtDNA genes were not responsible for EVA.

Significance: The relationship between genotype and clinical phenotype provides a theoretical basis for future gene diagnosis and prevention and treatment of LVAS.     

Familial nonsyndromic hearing loss with incomplete partition type II caused by novel DSPP gene mutations

Background: Familial nonsyndromic hearing loss (NSHL) with incomplete partition type II (IP-II) is a very rare condition.

Aims/Objectives: To determine the audiological feature, inheritance patterns and genetic etiology of familial NSHL with IP-II in a Chinese family with eight family members.

Material and methods: Clinical data were collected from all eight family members, selected deafness genes were sequenced in proband and whole genome sequencing of seven family members was performed.

Results: The proband were a pair of male nonidentical twins (III:1, III:2). Three patients in this family, including the twins and their father (II:1), were diagnosed with bilateral NSHL with IP-II, and no mutation was found in the genes of SLC26A4, GJB2, GJB3, mitochondrial 12S rRNA, and MITF. Whole genome sequencing data indicated de novo mutations of the gene DSPP, c.3085A?>?G and c.3087C?>?T, which resulted in p.N1029D and co-segregated with deafness phenotype, were the underlying genetic etiology.

Conclusion and significance: Familial NSHL with IP-II is extremely rare. In this family, de novo DSPP gene mutations, were considered to be the most probable genetic etiology. And this is the first report to reveal DSPP gene mutations leading to familial NSHL with IP-II.     

Acute sensorineural hearing loss in hemodialysis patients

Abstract

Background: Approximately, 30–40% of patients experienced hearing loss under regular hemodialysis.

Objective: This study reviewed our experience on treating acute hearing loss in patients under regular hemodialysis over the past two decades.

Methods: Twenty-six patients having acute hearing loss under hemodialysis were divided into two groups based on their etiologies. Sixteen patients (16 ears) with sudden sensorineural hearing loss (SSHL) were assigned to Group A and 10 patients (13 ears) with endolymphatic hydrops (EH) were assigned to Group B.

Results: No significant difference was noted between Groups A and B, regardless of hemodialysis duration, clinical manifestation, underlying systemic diseases, blood examination, and vestibular test battery. In contrast, serum osmolality was significantly lower in Group B (292?±?11 mOsm/kg) than in Group A (310?±?11 mOsm/kg). Furthermore, Group B (40?±?14?dB) had better mean hearing level than Group A (87?±?21?dB) in the initial audiogram, and a higher hearing improvement rate (69%) than Group A (19%).

Conclusions and significance: Both SSHL and EH are major causes for precipitating acute hearing loss in hemodialysis patients. Compared to SSHL, the less deteriorated MHL and lower serum osmolality in EH provide two clues for differentiating acute hearing loss in hemodialysis patients.     

Efficacy of combination therapy in adolescent and adult patients with total-deafness sudden sensorineural hearing loss

Background: Combination therapy is the first-line option for total-deafness sudden sensorineural hearing loss (SSNHL). Age may act as a crucial prognostic factor.

Objective: The aim of this study was to compare efficacy of combination therapy between adolescent and adult patients with total-deafness SSNHL.

Materials and methods: Twenty-five adolescent patients (adolescent group) and 106 adult patients (adult group) with total-deafness SSNHL were recruited. All the recruited patients underwent initial treatment with batroxobin, methylprednisolone, and gastrodin. After 10-day treatment, hearing outcomes were determined by pure-tone average measured by audiometry. Moreover, the total effective rates in the hearing recovery and improvement of tinnitus were calculated.

Results: There existed no significant difference between two groups in the total effective rate of the hearing recovery (p?=?.110). However, a significant difference was found in the total effective rate of improvement of tinnitus between two groups (p?=?.016). Both adolescent and adult patients could receive the optimal hearing gains at 500?Hz (20.2?±?13.3 and 23.1?±?13.9dB, respectively), followed by those at 1000?Hz (18.8?±?12.5 and 22.7?±?14.8dB, respectively). Yet, adult patients could get better hearing gains only at 500?Hz than adolescent patients (p?=?.02).

Conclusion: Compared with adult patients, adolescent patients with total-deafness SSNHL undergoing combination therapy may be less likely to have hearing recovery and the improvement of tinnitus.     

Mutation spectrum and hotspots of the common deafness genes in 314 patients with nonsyndromic hearing loss in Heze area,China

Background: Although, half of the childhood deafness is genetically related, the molecular etiology of hearing impairment has not been demonstrated explicitly. In addition, the mutation spectrums of deafness genes vary among different areas and ethnics.

Objectives: To know more about the mutation spectrums of deafness genes in China, we tested the mutations of three common deafness genes (GJB2, SLC26A4, and mtDNA12SrRNA) in a particular deafness population from Heze area.

Materials and methods: SNPscan technology was utilized to perform mutation screening for these three common deafness genes in 314 nonsyndromic deaf patients from Heze area.

Results: 38.21% (120/314) of these 314 patients with nonsyndromic hearing loss from Heze area were related to the genetic defects in these three deafness genes, including 20.06% (63/314) for GJB2, 15.29% (48/314) for SLC26A4, and 2.87% (9/314) for mtDNA12SrRNA. Furthermore, the mutation hotspots in three deaf genes were GJB2 235delC, SLC26A4 c.919-2A?>?G, and mtDNA12SrRNA 1555A?>?G, respectively, distinct from hotspots reported in other regions worldwide.

Conclusion: Our results disclosed a special and unique mutation spectrum of these three common deaf genes in Heze deaf population.     

Microdrill stapedotomy for otosclerosis with small and large preoperative air-bone gap: a retrospective comparison of results

Abstract

Background: In otosclerosis mixed hearing loss is the most frequent symptom and arises when the focus involves the stapes footplate. Surgeons usually prefer to wait a minimum air-bone gap of 25 – 35?dB before surgery.

Objectives: To evaluate the outcome of microdrill stapedotomy for otosclerosis in patients with a preoperative air-bone gap (ABG) <25?dB versus patients with a preoperative gap ≥ 25?dB.

Material and methods: For this retrospective study, the outcomes and complications after microdrill stapedotomy were compared between adult patients with a preoperative small ABG (n?=?127, ABG <25?dB) and those with a large ABG (n?=?254, ABG ≥25?dB).

Results: The postoperative ABG was significantly smaller than the preoperative ABG (p?<?.05) in both groups; there were no differences in complications rates (severe sensorineural hearing loss, footplate fracture or early postoperative vertigo) between the two groups.

Conclusions: Our findings show that microdrill stapedotomy is safe and can be performed even in patients with a preoperative small ABG without increasing the risk of sensorineural hearing loss due to inner ear damage.     

Threshold monitoring of intraoperative auditory steady-state responses for ossiculoplasty surgery

Objective: The objective of this study is to establish a reliable intraoperative auditory threshold monitoring system for ossiculoplasty surgery.

Design: The chirp signal of self-designed sound field earphone (SFE) was calibrated physically and psychophysically. The interaural attenuation of the SFE was tested in patients with unilateral complete deafness and contralateral normal hearing (10 patients). Self-designed SFEs were used to measure the chirp-evoked auditory steady-state responses (Chirp-ASSR) threshold of patients (14 cases and 15 ears) with conductive hearing loss after anesthesia but before surgery.

Results: The response threshold of Chirp-ASSR under anesthesia displayed a strong correlation with the hearing threshold for pure tones: the Pearson coefficients at various frequencies (1, 2, and 4?kHz) were 0.56 (p?=?.03), 0.82 (p?p?p?=?0.02), 0.90 (p?p?Conclusions: By combining Chirp-ASSR with self-designed SFE, we obtained objective multi-frequency intraoperative auditory thresholds that correlate well with the pure tone audiometry threshold. This reliable system can be applied to future intraoperative auditory threshold monitoring for ossiculoplasty surgery.     

Compound heterozygous GJB2 mutations associated to a consanguineous Han family with autosomal recessive non-syndromic hearing loss

Conclusion: This study demonstrates that the gap junction protein beta-2 gene (GJB2) p.R32C and p.L79Cfs*3 variants are associated to a consanguineous family with autosomal recessive non-syndromic hearing loss (ARNSHL). The p.R32C variant is found for the first time in the NSHL patients of Han Chinese origin. The finding sheds new light on the accurate genetic diagnosis and counseling for the family. Objective: ARNSHL is a highly heterogeneous genetic disease. ARNSHL usually displays non-progressive congenital or pre-lingual deafness. In this study, the aim is to detect the disease-causing mutation(s) in a Han family with ARNSHL. Methods: A consanguineous Han family with ARNSHL was enrolled. Two hundred ethnicity-matched unrelated subjects without any hearing impairments were used as normal controls. Exome sequencing and Sanger sequencing were applied to identify the causative mutation in the ARNSHL family. Results: Compound heterozygous variants c.94C?>?T (p.R32C) and c.235delC (p.L79Cfs*3) in the GJB2 gene were identified in the two patients of the ARNSHL family, and the heterozygous GJB2 c.94C?>?T and c.235delC variants were identified in his unaffected father and mother, respectively. The two variants in the GJB2 gene were absent in the 200 unrelated controls.     

Sudden sensorineural hearing loss during pregnancy: clinical characteristics,management and outcome

Background: Sudden sensorineural hearing loss (SSNHL) may occur during pregnancy with a rare prevalence, and little is known about it.

Aims: To retrospectively analyze cases of SSNHL during pregnancy and investigate their clinical characteristics, management and outcome.

Material and methods: Records of 30 SSNHL patients during pregnancy were reviewed, including age, localization, duration from onset to treatment, gestation period, accompanying symptoms, initial hearing threshold, final hearing threshold, audiogram, treatment and outcome.

Results: Twenty-four patients (80.0%) suffered SSNHL in the second trimester or the last trimester with a high rate of tinnitus (70.0%). The initial hearing threshold was 63.4?±?25.1?dB, and most audiograms were flat and profound. The overall recovery rate was 60.0%, including complete recovery (33.3%) and partial recovery (26.7%). Further, 16 patients received adjuvant intratympanic steroid showed a better audiologic outcome (improvement 27.1?±?16.4 vs. 15.7?±?12.0?dB, p?=?.042) than those who had not.

Conclusions and significance: SSNHL during pregnancy often occurred in the second trimester or the last trimester with a severe hearing loss, the most audiogram configurations are flat and profound. Dextran-40 is a safe and beneficial therapy for SSNHL patients during pregnancy and adjuvant intratympanic steroid increase the probability of hearing recovery.     

Intratympanic steroids as a salvage therapy for severe to profound idiopathic sudden sensorineural hearing loss

Abstract

Background: Idiopathic sudden sensorineural hearing loss (ISSNHL) is defined as a decline in hearing affecting three or more frequencies by 30?dB

Objective: The aim of this study was to evaluate the results of intratympanic steroids as a salvage treatment for severe ISSNHL.

Materials and methods: A regimen of three IT steroid injections was offered to patients who failed a 7-days intravenous steroid treatment. Eighty-four patients underwent IT salvage treatment (IT group). Their outcomes were compared with those of 255 patients with severe ISSNHL who received the same intravenous steroid regimen without salvage IT steroid therapy (Control group).

Results: 56% of the patients in the IT group had a hearing improvement of >15?dB after one month. The average hearing improvements were 26.5?±?28?dB and 27.9?±?24?dB in the IT group and the Control group, respectively (p?=?.67). However, patients with a type E audiogram pattern (total deafness), displayed a substantial hearing gain.

Conclusion: Intratympanic steroids failed to show a global auditory benefit as a salvage treatment in patients with severe ISSNHL.

Significance: Our data suggest that a salvage treatment with intratympanic dexamethasone may be offered to patients with total deafness for whom the first systemic treatment has failed.     

Identification of two recurrent mutations of COL1A1 gene in Chinese Van der Hoeve syndrome patients

Conclusion: The two discovered mutations in COL1A1 gene, although first reported in China, are recurrent ones that have also been found elsewhere in type I osteogenesis imperfecta patients, suggesting their role in pathogenesis of Van der Hoeve syndrome. Objectives: The aim of this study is to find mutational patterns of COL1A1 gene that may account for the putative Van der Hoeve syndrome in the patients carrying symptoms of osteogenesis imperfecta, blue sclera, and conductive deafness. Method: Genomic DNA was extracted from the blood of each patient and exons of COL1A1 gene were amplified using PCR and sequenced. Results: Sequencing in some of the two family members revealed point mutations in exon 26 (c.1792C?>?T) and exon 43 (c.3076C?>?T) of COL1A1 gene, respectively.     

Dosimetric parameters associated with conductive or sensorineural hearing loss 5 years after intensity-modulated radiation therapy in nasopharyngeal carcinoma

Background: Most previous studies are separate dosimetric analyses of conductive or sensorineural hearing loss, and they are not conducive to a comprehensive assessment of auditory radiation damage.

Aims/objectives: Our study aimed to evaluate the long-term incidence of sensorineural hearing loss (SNHL) or conductive hearing loss (CHL) in patients with nasopharyngeal carcinoma (NPC) after intensity-modulated radiation therapy (IMRT), and to investigate the relationship between SNHL or CHL and patient factors, treatment-related factors, and radiation dose parameters.

Material and methods: Seventy patients (117 ears) with NPC, who were also treated with IMRT in our hospital from 2006 to 2014, were retrospectively analyzed. Radiation doses to the Eustachian tube (ET), middle ear (ME), cochlear (Co), and internal auditory canal (IAC) were assessed. Pure tone audiometry and impedance audiometry were performed before and during the follow-up period. The relationships between low-frequencies (0.5–2?kHz) or high-frequency (4?kHz) SNHL/CHL and radiotherapy dose parameters were analyzed.

Results: Of the 117 ears studied, 7.69% had low-frequency SNHL, 35.9% had high-frequency SNHL, 23.93% had low-frequency CHL, and 18.80% had high-frequency CHL. The incidence of high-frequency CHL was higher in the T4 group than in the T (1–3) group (p?<?.05). When IAC D_max?>?42.13?Gy or IAC D_mean?>?32.71?Gy, the risk of high-frequency SNHL increased in NPC patients. When ME D_max?>?44.27?Gy, ME D_mean?>?29.28?Gy, or ET D_max?>?57.23?Gy, the risk of high-frequency CHL in NPC patients increased.

Conclusions and significance: SNHL and CHL remain common ear complications after IMRT for NPC. IAC D_max, IAC D_mean, ME D_max, ME D_mean, and ET D_max all need to be carefully considered during the IMRT treatment protocol.     

Effect of esterified hyaluronic acid as middle ear packing in tympanoplasty for adhesive otitis media

Objectives: The goal of this study was to evaluate the effects of middle ear packing agents (MEPA) on post-operative hearing improvement and complications after tympanoplasty in patients with adhesive otitis media (OM).

Materials and methods: Patients with adhesive OM who underwent tympanoplasty surgery were enrolled in the study between January 2012 and January 2015. A total of 205 patients who received canal wall-down tympanoplasty with ossicular chain reconstruction were randomized into one of the three groups with different MEPA. Group 1 (n?=?72) received MeroGel as the MEPA, Group 2 (n?=?64) cartilage, and Group 3 (n?=?69) both. Air conduction (AC) and bone conduction (BC) thresholds at 0.5, 1, 2, and 4?kHz were measured, and air-bone gaps (ABG) were analyzed before and after the surgery for each patient.

Results: Mean pre- and post-operative ABG was 30.9?dB and 17.6?dB in Group 1, 31.4?dB and 21.9?dB in Group 2, and 32.2?dB and 19.1?dB in Group 3. The ABG closure was 13.3?±?7.5 in Group 1, 9.5?±?5.9 in Group 2, and 13.1?±?9.3 in Group 3. The improvement of ABG after surgery was statistically significant in all three groups (p?p?Conclusions: Tympanoplasty using esterified hyaluronic acid (i.e. MeroGel) or cartilage as the MEPA resulted in improved hearing for patients with conductive hearing loss due to adhesive OM. Using MeroGel as the MEPA appeared to achieve a better post-operative outcome than using cartilage.