Clinical and genetic architecture of a large cohort with auditory neuropathy.

Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.

[Analysis of audiological features in infants with unilateral hearing loss].

Objective:To investigate the audiological characteristics and possible causes of unilateral hearing loss in infants and young children. Methods:105 infants from Beijing Maternal and Child Health Care Institution who failed the newborn hearing screening and were referred to the Children's Hearing Diagnosis Center of PLA General Hospital for hearing diagnosis. They were diagnosed with unilateral hearing loss and underwent clinical data collection. A full set of audiological examinations included ABR, 40 Hz auditory event related potential, ASSR, DPOAE, tympanometry. Results:①In initial diagnosis, 45 cases（42.86%） had mild hearing loss, 19 cases（18.10%） had moderate hearing loss, 14 cases（13.33%） had severe hearing loss, and 27 cases（25.71%） had severe hearing loss; Among them, 65 cases（61.90%） were conductive hearing loss or mixed hearing loss, and 40 cases（38.10%） were sensorineural hearing loss. ②83 of 105 cases had follow-up visits: 24 cases were normal, 15 cases with mild hearing loss, 4 cases with moderate hearing loss, 12 cases with severe hearing loss, and 26 cases with extremely severe hearing loss, 2 cases of hearing loss in both ears. ③From the initial diagnosis to the follow-up diagnosis, the change of mild hearing loss was the largest, followed by moderate hearing loss, severe and extremely severe hearing loss basically did not change; the number of mild and severe conductive hearing loss which recovered to normal hearing was most, the number of sensorineural hearing loss changed little. Conclusion:The infants who failed the newborn hearing screening and were diagnosed with unilateral hearing loss were mainly mild to moderate conductive hearing loss and severe to extremely severe sensorineural hearing loss. The hearing of children with hearing loss gradually improved, and severe and extremely severe sensorineural hearing loss remained unchanged.

[Application of behavioral audiometry in subjective hearing assessment of children].

Objective:To explore the value and influencing factors of behavioral audiometry in subjective hearing assessment of children. Methods:The results of behavioral audiometry（visual reinforcement audiometry or play audiometry） of 1944 children（3888 ears） in the outpatient department from January 2012 to December 2015 were retrospectively analyzed. The subjective performance（" good ", "moderate", "poor", " unfinished "） was compared according to age and hearing level. SPSS 27.0 software was used for statistical analysis. Results:The subjective performance of children was "good" in 2791 ears（71.8%）, "moderate" in 411 ears（10.6%）, "poor" in 309 ears（7.9%） and " unfinished " in 377 ears（9.7%）. In visual reinforcement audiometry, the proportion of children who subjectively performed as "good" gradually increased with age, reaching the peak at 2 years old, and decreased with age after 2 years old. In play audiometry, the proportion of children who subjectively performed as "good" gradually increased with age, peaking at 4-5 years of age. The children who did not finish the test were mainly 1-3 years old. The reasons included uncooperation for 148 ears, crying for 95 ears, refusing to wear headphones for 57 ears, fatigue for 42 ears, lack of interest for 20 ears, not understanding for 14 ears, and distraction for 1 ear. Conclusion:Behavioral audiometry was helpful to assess children's subjective hearing, and children's subjective performance was good. In clinical work, more novel and attractive test materials and methods should be adopted or developed according to the physical and mental characteristics of young children.

[The follow-up study on patients of children with auditory neuropathy].

Objective:To analyse the audiological characteristics of patients of children with auditory neuropathy（AN） for gaining a better understanding of the audiological characteristics prognosis of patients with AN. Methods:58 patients（108 ears） of children with AN were enrolled, all of whom had received further consultation within 10 years after the first consultation. Behavioral audiometry test, tympanogram test, distortion product otoacoustic emission（DPOAE）, auditory brainstem response（ABR）, cochlear microphonics（CM）, auditory steady-state response（ASSR） were performed on these patients. Results:①There were no significant changes in behavioral audiometry threshold between first and further consultation（P>0.05）；②Tympanograms were mostly of type A or As； ③The patients had worse DPOAE results in the further consultation, while the elicitation rate of other frequencies were higher except for the lower elicitation rate of 750 Hz and 1000 Hz；④There were 7 ears that had present ABR and CM in the first consultation, while three ears had present ABR and CM in the further consultation；⑤Except for 500 Hz, other frequency thresholds of ASSR in the further consultation were statistically significant compared with those in the first consultation（P<0.01）；⑥The threshold of behavioral audiometry at 4000 Hz was higher than that of ASSR, and there was no obvious correlation between the other frequencies（P>0.05）. Conclusion:There is a tendency of hearing deterioration in patients of children with AN. Patients with no DPOAE elicitation and no ABR elicitation or serious abnormalities need CM test to avoid misdiagnosis. The hearing status and speech communication ability of patients should be continuously monitored. Parents should pay attention to the changes in the behavioral ability of the children in daily life and make regular subsequent visits.

The audiological characteristics of infant auditory neuropathy patients without otoacoustic emission.

Objective: To explore the audiological characteristics of infant auditory neuropathy (AN) patients with cochlear microphonic (CM) recorded but absent otoacoustic emission (OAE), clinically reducing the rate of missed diagnosis of AN. Methods: We retrospectively analyzed the audiological characteristics of infant AN patients in our medical center between 2003 and 2020. A total of 18 infant AN patients were OAE absent group, with CM present and distortion product otoacoustic emission (DPOAE) absent in both ears. A total of 44 infant AN patients were OAE present group, with CM and DPOAE present in both ears. Results: (1) The found age in OAE absent group was 0.9 (0.02) years old, which was younger than 1.11 (1.63) years old in OAE present group (p = .041). (2) The CM threshold of OAE absent group was 80 (10) dB nHL, which was significantly higher (p < .001) than OAE present group. CM amplitude were smaller (p < .05), and CM duration were shorter (p < .05) in OAE absent group. (3) The thresholds of auditory steady-state response (ASSR) at 0.5, 1, 2, and 4 kHz were 94 (10), 94 (10), 87 (20), and 81 (10) dB HL cg, respectively in OAE absent group, which were higher than those in OAE present group (p < .01). Conclusions: Infant AN patients with CM present and OAE absent showed earlier detection and different audiological performance, which was manifested in ASSR thresholds, audiometric configurations and CM performance. CM thresholds were increased, amplitude and duration were decreased, non-linearity of I/O function was reduced. Level of Evidence: 4.

Autocollimation angle-measurement method with a large range based on spot deformation.

A novel hollow cylindrical cube-corner reflector (HCCCR) for the autocollimator (AC) is proposed. The angle measuring range of AC will be effectively increased by using the parallel propagation characteristics of the reflected light and the incident light in local area of this reflector. And the yaw and pitch angles of HCCCR will be measured through the morphological changes of the reflected beam. The experimental results show that the measuring range of the autocollimation angle measurement method is extended from ±30' to ±30°, and the dynamic measurement distance is 0.2∼5m, the measurement accuracy of pitch angle and yaw angle is better than 69" and 51", respectively.

Effect of Dynamic Preheating on the Thermal Behavior and Mechanical Properties of Laser-Welded Joints.

The high cooling rate and temperature gradient caused by the rapid heating and cooling characteristics of laser welding (LW) leads to excessive thermal stress and even cracks in welded joints. In order to solve these problems, a dynamic preheating method that uses hybrid laser arc welding to add an auxiliary heat source (arc) to LW was proposed. The finite element model was deployed to investigate the effect of dynamic preheating on the thermal behavior of LW. The accuracy of the heat transfer model was verified experimentally. Hardness and tensile testing of the welded joint were conducted. The results show that using the appropriate current leads to a significantly reduced cooling rate and temperature gradient, which are conducive to improving the hardness and mechanical properties of welded joints. The yield strength of welded joints with a 20 A current for dynamic preheating is increased from 477.0 to 564.3 MPa compared with that of LW. Therefore, the use of dynamic preheating to reduce the temperature gradient is helpful in reducing thermal stress and improving the tensile properties of the joint. These results can provide new ideas for welding processes.

Effect of Preheating Temperature on Geometry and Mechanical Properties of Laser Cladding-Based Stellite 6/WC Coating.

The effect of 60Si2Mn substrate preheating on the forming quality and mechanical properties of cobalt-based tungsten carbide composite coating was investigated. Substrate preheating was divided into four classes (room temperature, 150 °C, 250 °C, and 350 °C). The morphology, microstructure, and distribution of elements of the coating were analyzed using a two-color laser handheld 3D scanner, a scanning electron microscope (SEM), and an energy dispersive X-ray spectrometer (EDX), respectively. The hardness and wear properties of the cladding layer were characterized through a microhardness tester and a friction wear experiment. The research results show that the substrate preheating temperature is directly proportional to the height of the composite coating. The solidification characteristics of the Stellite 6/WC cladding layer structure are not obviously changed at substrate preheating temperatures of room temperature, 150 °C, and 250 °C. The solidified structure is even more complex at a substrate preheating temperature of 350 °C. At this moment, the microstructure of the cladding layer is mainly various blocky, petaloid, and flower-like precipitates. The hardness and wear properties of the cladding layer are optimal at a substrate preheating temperature of 350 °C in terms of mechanical properties.

Roll angle autocollimator measurement method based on a cylindrical cube-corner reflector with a high resolution and large range.

A novel high-resolution and large-range autocollimator measurement system for roll angle is proposed. The system retains the basic internal structure of the traditional autocollimator (AC), which only uses a novel non-standard cylindrical cube-corner reflector (CCCR) instead of the planar reflector. In the article, the mathematical relationship between the structure of this special reflector and the spatial coordinate vector change of the reflected beam is deduced, and the measurement formula of the roll angle autocollimator (RAC) measurement system is established based on this mathematical relationship. The effectiveness of the measurement system and method is verified by experiments. Experimental results show that this method can effectively enhance the range to ±20°, and the whole measurement accuracy is 6.1", the measuring resolution is 1".

Auditory Neuropathy as the Initial Phenotype for Patients With ATP1A3 c.2452 G > A: Genotype-Phenotype Study and CI Management.

Objective: The objective of this study is to analyze the genotype-phenotype correlation of patients with auditory neuropathy (AN), which is a clinical condition featuring normal cochlear responses and abnormal neural responses, and ATP1A3 c.2452 G > A (p.E818K), which has been generally recognized as a genetic cause of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. Methods: Four patients diagnosed as AN by clinical evaluation and otoacoustic emission and auditory brainstem responses were recruited and analyzed by next-generation sequencing to identify candidate disease-causing variants. Sanger sequencing was performed on the patients and their parents to verify the results, and short tandem repeat-based testing was conducted to confirm the biological relationship between the parents and the patients. Furthermore, cochlear implantation (CI) was performed in one AN patient to reconstruct hearing. Results: Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene. Except for the AN phenotype, patients 1 and 2 exhibited varying degrees of neurological symptoms, implying that they can be diagnosed as CAPOS syndrome. During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA). Patient 2 underwent CI on his left ear, and the result was poor. The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms. Conclusion: ATP1A3 p.E818K has rarely been documented in the Chinese AN population. Our study confirms that p.E818K in the ATP1A3 gene is a multiethnic cause of AN in Chinese individuals. Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome and offers a more accurate genetic counseling about the specific de novo mutation.

Genetic Susceptibility Study of Chinese Sudden Sensorineural Hearing Loss Patients with Vertigo.

OBJECTIVE: To investigate the genetic causes of sudden sensorineural hearing loss (SSNHL) patients in China. This study focused on analyzing variations of coding sequence of common genes related to deafness, revealing the molecular pathogenesis of sudden deafness from a genomics perspective, discovering molecular markers associated with the onset of deafness, and then supplying prevention to high-risk populations, classifying disease according to accurate etiology, and choosing a much more precision therapy. METHODS: We retrospectively analyzed the clinical characteristics of 51 patients diagnosed as SSNHL with vertigo treated in the Chinese PLA General Hospital. In this study, mutation screening of 307 nuclear genes and mitochondrial genome responsible for human or mouse deafness was performed on the 51 cases of unilateral sudden deafness patients with vertigo. RESULTS: We identified 51 cases of unilateral sudden deafness, including 2 cases of low-mid frequency hearing impairment, 18 cases of mid-high frequency hearing loss, 11 cases of flat-type hearing loss, and 20 cases of all frequency hearing loss. Among the 51 cases, 8 (15.69%) cases of GJB2 heterozygous variations, 1 (1.96%) case of GJB3 heterozygous variations, 5 (9.8%) cases of SLC26A4 heterozygous variations, 2 (3.92%) cases of COCH heterozygous variations, 14 (27.45%) cases of CDH23 heterozygous variations, 14 (27.45%) cases of OTOF heterozygous variations, 1 (1.96%) case of SLC17A8 heterozygous variations and 2 (3.92%) cases of KCNE1 heterozygous variations. No mtDNA gene variations were identified. CONCLUSION: SSNHL has some relationship with hereditary in Chinese population, but its complex genetic pathogenic mechanisms need further study.

Clinical characteristics of patients with unilateral auditory neuropathy.

OBJECTIVE: To analyze the clinical characteristics of patients with unilateral auditory neuropathy (UAN), and to provide guidance for future clinical diagnosis and research. METHODS: Patients who were clinically diagnosed with UAN from 2004 to 2019 were included. Clinical characteristics, audiological features, imaging findings, genetic test results and management effect were summarized and followed. RESULTS: A total of 44 patients [mean age, 4.35 ± 4.39 years; 22 (50.00%) males and 22 (50.00%) females] were enrolled for analyses. Among the 38 patients who were tested by pure-tone or behavioral audiometry, the degree of hearing loss of the affected ear was characterized as mild in 2 ears (5.26%), moderate in 5 (13.16%), severe in 9 (23.68%) and profound in 22 (57.89%). For the 44 contralateral ears, 33 (75.00%) showed normal hearing and 11 (25.00%) presented with sensorineural hearing loss. Auditory brainstem responses were absent or abnormal in all 44 affected ears, while otoacoustic emissions and/or cochlear microphonics were present. Among the 18 patients who underwent magnetic resonance imaging (MRI), 7 (38.89%) presented cochlear nerve deficiency (CND). Nineteen candidate variants were found in 12 patients among the 15 UAN patients who were conducted targeted gene capture and next generation sequencing. Thirty patients were followed up by telephone to investigate their management effect. CONCLUSIONS: Our study demonstrates comprehensive audiological features of patients with UAN to improve the clinical understanding and diagnosis. Some patients with UAN could show ipsilateral CND and MRI is essential to evaluate if the nerve is deficient. No pathogenic variants that directly related to the pathogenesis of UAN have been found in this study currently.

Phenotypic Heterogeneity of Post-lingual and/or Milder Hearing Loss for the Patients With the GJB2 c.235delC Homozygous Mutation.

OBJECTIVE: To report the phenotypic heterogeneity of GJB2 c.235delC homozygotes associated with post-lingual and/or milder hearing loss, and explore the possible mechanism of these unconditional phenotypes. METHODS: Mutation screening of GJB2 was performed on all ascertained members from Family 1006983 and three sporadic patients by polymerase chain reaction (PCR) amplification and Sanger sequencing. Next generation sequencing (NGS) was successively performed on some of the affected members and normal controls from Family 1006983 to explore additional possible genetic codes. Reverse transcriptase-quantitative PCR was conducted to test the expression of Connexin30. RESULTS: We identified a Chinese autosomal recessive hearing loss family with the GJB2 c.235delC homozygous mutation, affected members from which had post-lingual moderate to profound hearing impairment, and three sporadic patients with post-lingual moderate hearing impairment, instead of congenital profound hearing loss. NGS showed no other particular variants. Overexpression of Connexin30 in some of these cases was verified. CONCLUSION: Post-lingual and/or moderate hearing impairment phenotypes of GJB2 c.235delC homozygotes are not the most common phenotype, revealing the heterogeneity of GJB2 pathogenic mutations. To determine the possible mechanism that rescues part of the hearing or postpones onset age of these cases, more cases are required to confirm both Connexin30 overexpression and the existence of modifier genes.

[Identification of a novel mutation of CEACAM16 gene in a Chinese family with autosomal dominant nonsyndromic hearing loss].

Objective:To explore the genetic cause of a Chinese autosomal dominant nonsyndromic hearing loss family and investigate the clinical features and molecular genetic characteristics of this family. Method:Detailed medical history and systematic audiology tests were carried out in the family members, and they were subjected to comprehensive genetic analyses using massively parallel sequencing, which targeted 139 known deafness genes and 6 mitochondrial DNA mutations associated with hearing loss. Result:This family's hearing loss was consistent with autosomal dominant nonsyndromic hearing loss. The affected family members appeared to have developed a high-frequency hearing loss with the onset of twenties. We identified a heterozygous missense mutation, c.418A>G/p. Thr140Ala in the CEACAM16 gene, segregating with the deafness in this family. Conclusion:In this study, we identified a new mutation of CEACAM16 gene, which was the second mutation identified in Chinese hearing loss population. It has enriched the mutation spectrum of this gene.

High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population.

To decipher the genotype-phenotype correlation of auditory neuropathy (AN) caused by AIFM1 variations, as well as the phenotype progression of these patients, exploring the potential molecular pathogenic mechanism of AN. A total of 36 families of individuals with AN (50 cases) with AIFM1 variations were recruited and identified by Sanger sequencing or next-generation sequencing; the participants included 30 patients from 16 reported families and 20 new cases. We found that AIFM1-positive cases accounted for 18.6% of late-onset AN cases. Of the 50 AN patients with AIFM1 variants, 45 were male and 5 were female. The hotspot variation of this gene was p.Leu344Phe, accounting for 36.1%. A total of 19 AIFM1 variants were reported in this study, including 7 novel ones. A follow-up study was performed on 30 previously reported AIFM1-positive subjects, 16 follow-up cases (53.3%) were included in this study, and follow-up periods were recorded from 1 to 23 years with average 9.75 ± 9.89 years. There was no hearing threshold increase during the short-term follow-up period (1-10 years), but the low-frequency and high-frequency hearing thresholds showed a significant increase with the prolongation of follow-up time. The speech discrimination score progressed gradually and significantly along with the course of the disease and showed a more serious decline, which was disproportionately worse than the pure tone threshold. In addition to the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is also observed in AIFM1-related AN and affects females. In conclusion, we confirmed that AIFM1 is the primary related gene among late-onset AN cases, and the most common recurrent variant is p.Leu344Phe. Except for the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is another probability of AIFM1-related AN, with females affected. Phenotypical features of AIFM1-related AN suggested that auditory dyssynchrony progressively worsened over time.

Serum Bilirubin Level as a Potential Marker for the Hearing Outcome in Severe-Profound Bilateral Sudden Deafness.

OBJECTIVE: To investigate the association of serum bilirubin level with hearing outcomes in bilateral sudden sensorineural hearing loss (BSSHL) patients. PARTICIPANTS: One hundred thirteen in-patient BSSHL patients were consecutively enrolled between July 2008 and December 2015 in a tertiary center. MAIN OUTCOME MEASURES: Multivariable linear regression, generalized estimating equations (GEE), and stratified analyses were applied to examine the association between serum bilirubin level and hearing outcome measures such as final hearing threshold and absolute and relative hearing gains in BSSHL. RESULTS: After full adjustment for potential confounders, total bilirubin levels (TBIL) were observed to be positively and independently associated with hearing outcomes as measured by final hearing (ß [95% confidence interval {CI}]: -1.5 [-2.7, -0.2] dB HL per 1 µmol/L increase in TBIL) and absolute and relative hearing gains (ß [95% CI]: 1.4 [0.2, 2.7] dB and 1.6 [0.2, 3.1] dB, respectively) in the severe to profound hearing loss subpopulation. CONCLUSIONS: Higher TBIL levels, within the normal or mildly elevated ranges, were independently and significantly associated with better hearing outcome in BSSHL patients with severe to profound hearing loss. Given bilirubin elevation treatments exist, our finding suggests a novel pharmacological strategy for this specific subpopulation.

Further evidence for "gain-of-function" mechanism of DFNA5 related hearing loss.

To report two DFNA5 pathogenic splice-site variations and a novel benign frameshift variation to further support the gain-of-function mechanism of DFNA5 related hearing impairment, targeted genes capture and next generation sequencing were performed on selected members from Family 1007208, 1007081 and a sporadic case with sensorineural hearing loss. Reverse transcriptase polymerase chain reaction was conducted on the proband from Family 1007208 to test how the splice-site variation affects the transcription in RNA level. A novel heterozygous splice-site variation c.991-3 C > A in DFNA5 was found in Family 1007208; a known hotspot heterozygous splice-site variation c.991-15_991_13delTTC was identified in Family 1007081. Both the splice-site variations were segregated with the late onset hearing loss phenotype, leading to the skipping of exon 8 at RNA level. In addition, a novel DFNA5 frameshift variation c.116_119delAAAA was found in the sporadic case, but was not segregated with the hearing impairment phenotype. In conclusion, we identified one novel and one known pathogenic DFNA5 splice-site variation in two Chinese Families, as well as a novel DFNA5 frameshift variation c.116_119delAAAA in a sporadic case, which does not the cause for the hearing loss case. Both the two pathogenic splice-site variations and the nonpathogenic frameshift variation provide further support for the specific gain-of-function mechanism of DFNA5 related hearing loss.

Identification of four TMC1 variations in different Chinese families with hereditary hearing loss.

BACKGROUND: Variants in TMC1 (transmembrane channel-like 1) can cause both autosomal dominant and recessive hearing loss in human population. Mice with Tmc1 variants have been shown to be ideal animal models for gene therapy. In this article, we report four TMC1 variants in four different Chinese families and the follow-up auditory phenotype of a previously reported family. METHODS: Four families with TMC1 variants, as well as a previously described family with TMC1 variant orthologous to the Beethoven mouse, were recruited in this study. A comprehensive auditory evaluation was performed on all ascertained family members. High-throughput sequencing was conducted using genomic DNA from the probands and other family members to identify probable deafness genes. RESULTS: We identified four TMC1 (NM_138691.2) variations, including two pathogenic variants, c.1714G>A, and c.1253T>A, one likely pathogenic variant, c.[797T>C];[797T>C], and one single nucleotide polymorphism (SNP), c.2276G>A. Among these variants, c.[797T>C];[797T>C] is a novel likely pathogenic variant, and c.1714G>A and c.1253T>A are known pathogenic variants at the DFNB7/11 (DFNA36) locus. Phenotype-genotype correlation analysis of TMC1 variants showed that the TMC1 dominant variation-related phenotype was late-onset, progressive, high frequency to all frequency sensorineural hearing loss, while the TMC1 recessive variant was related to congenital all frequency sensorineural hearing impairment. CONCLUSIONS: Two pathogenic, one likely pathogenic variants and one SNP of TMC1 were identified in four Chinese families with hereditary hearing loss, indicating that TMC1 may be a more frequent cause of hearing loss than expected. TMC1 variants related to hearing loss result in specific phenotypes. The TMC1 c.1253T>A (p.M418K) variation, homologous to the Tmc1 c. 1235 T> A (p.M412K) variant in Beethoven mice, was the second report of this variant in human patients with hearing loss, suggesting the possibility to translational gene therapy from Beethoven mice to human patients.

Novel recessive PDZD7 biallelic mutations in two Chinese families with non-syndromic hearing loss.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic condition. PDZD7 has emerged as a new genetic etiology of ARNSHL. Biallelic mutations in the PDZD7 gene have been reported in two German families, four Iranian families, and a Pakistani family with ARNSHL. The effect of PDZD7 on ARNSHL in other population has yet to be elucidated. Two Chinese ARNSHL families, each of which had two affected siblings, were included in this study. The families underwent target region capture and high-throughput sequencing to analyze the exonic, splice-site, and intronic sequences of 128 genes. Furthermore, 1751 normal Chinese individuals served as controls, and 122 Chinese families segregating with apparent ARNSHL, who had been previously excluded for variants in the common deafness genes GJB2 and SLC26A4, were subjected to screening for candidate mutations. We identified a novel homozygous missense mutation (p.Arg66Leu) and novel compound heterozygous frameshift mutations (p.Arg56fsTer24 and p.His403fsTer36) in Chinese families with ARNSHL. This is the first report to identify PDZD7 as an ARNSHL-associated gene in the Chinese population. Our finding could expand the pathogenic spectrum and strengthens the clinical diagnostic role of the PDZD7 gene in ARNSHL patients.