Genetic Causes Of Hearing Loss Research Articles

HEARRING group genetic marker study: genetic background of CI patients

Background While cochlear implantation (CI) and electric acoustic stimulation (EAS) have a positive outcome in most cases, their effectiveness varies depending on the etiology of the hearing loss. Among the various etiologies, genetic factors are the leading cause of hearing loss and may impact CI and EAS outcomes. Aims/Objectives To reveal the genetic background of the hearing loss in CI/EAS patients in each ethnic population, we undertook a multi-center study involving the genetic testing of hearing loss in CI/EAS patients from 10 centers. Material and Methods Saliva samples and clinical information for the patients and their family members were obtained and next-generation sequencing analysis using a panel carrying 63 deafness genes was then performed. Results Genetic testing successfully identified the causative gene variants in 54.5% (48/88) of patients with pre-lingual onset hearing loss (onset under 6 years) and in 12% (12/95) of those with late-onset hearing loss (onset at 6 years or more). Conclusions and Significance We clearly indicated that genetic factors are the most common cause of hearing loss regardless of ethnic background. Saliva-based genetic testing is a useful tool for multi-center studies seeking to clarify the genetic causes of hearing loss in CI or EAS patients between countries separated by distance.

In silico and in vivo analyses of a novel variant in MYO6 identified in a family with postlingual non-syndromic hearing loss from Argentina.

Hereditary hearing loss stands as the most prevalent sensory disorder, with over 124 non-syndromic genes and approximately 400 syndromic forms of deafness identified in humans. The clinical presentation of these conditions spans a spectrum, ranging from mild to profound hearing loss. The aim of this study was to identify the genetic cause of hearing loss in a family and functionally validate a novel variant identified in the MYO6 gene. After Whole Exome Sequencing analysis, the variant c.2775G>C p.Arg925Ser in MYO6 was detected in a family with postlingual non-syndromic hearing loss. By protein modeling a change in the electrostatic charge of the single alpha helix domain surface was revealed. Through a knockdown phenotype rescue assay in zebrafish, the detrimental effects of the identified variant on the auditory system was determined. These findings underscore the significance of a comprehensive approach, integrating both in silico and in vivo strategies, to ascertain the pathogenicity of this candidate variant. Such an approach has demonstrated its effectiveness in achieving an accurate genetic diagnosis and in promoting a more profound comprehension of the mechanisms that underlie the pathophysiology of hearing.

Genetic landscape of hearing loss in prelingual deaf patients of eastern Iran: Insights from exome sequencing analysis.

Hearing loss is one of the most prevalent genetic disorders in humans. Locus and allelic heterogeneity cause fundamental challenges in hearing loss genetic diagnosis and management of patients and their families. This study examined the genetic profile of patients with prelingual hearing loss who were referred to the Genetic Foundation of Khorasan Razavi spanning over a decade. Deleterious variants in GJB2 were evaluated through Sanger sequencing among 745 non-syndromic hearing loss patients. Furthermore, exome sequencing was applied in 250 patients with negative GJB2 sequencing results and 30 patients with syndromic hearing loss. The findings revealed a relatively low frequency of GJB2 variants among the studied patients. Exome sequencing successfully identified the genetic causes of hearing loss in 70% of the patients. Moreover, variants in 10 genes, namely SLC26A4, MYO15A, TMPRSS3, TMC1, OTOF, CDH23, PJVK, MYO7A, TECTA, and PCDH15, accounted for 66% of the positive exome sequencing findings in this study. At least three prevalent founder alleles in the hearing-impaired population of eastern Iran were identified. This study emphasizes the efficiency of exome sequencing as a powerful tool for determining the etiology of prelingual hearing loss in the eastern Iranian population.

Novel Variant of FDXR as a Molecular Etiology of Postlingual Post-Synaptic Auditory Neuropathy Spectrum Disorder via Mitochondrial Dysfunction: Reiteration of the Correlation between Genotype and Cochlear Implantation Outcomes.

FDXR encodes the mitochondrial ferredoxin reductase, which is associated with auditory neuropathy spectrum disorder (ANSD) and optic atrophy. Only two studies have described FDXRrelated hearing loss. The auditory rehabilitation outcomes of this disease entity have not been investigated, and the pathophysiologic mechanism is not well elucidated. Here we report a hearingimpaired subject with co-segregation of the FDXR variant and post-synaptic type ANSD, who underwent cochlear implantation (CI) with favorable outcomes. We suggest a possible pathophysiologic mechanism of adult-onset ANSD via mitochondrial dysfunction. A 35-year-old woman was ascertained to have ANSD. Exome sequencing identified the genetic cause of hearing loss, and functional study measuring mitochondrial activity was performed to provide molecular evidence of pathophysiology. Expression of FDXR in the mouse cochlea was evaluated by immunohistochemistry. Intraoperatively, electrically-evoked compound action potential (ECAP) responses were measured, and mapping parameters were adjusted accordingly. Audiological outcomes were monitored for over 1 year. In lymphoblastoid cell lines (LCLs) carrying a novel FDXR variant, decreased ATP and MtMP levels and increased ROS levels were observed compared to control LCLs. These dysfunctions were restored by administering mitochondria isolated from umbilical cord mesenchymal stem cells, confirming the pathogenic potential of this variant via mitochondrial dysfunction. Partial ECAP responses during CI and FDXR expression in the mouse cochlea indicate that FDXR-related ANSD is postsynaptic. By increasing the pulse width during mapping, the patient's CI outcomes showed significant improvement over 1-year post-CI. Post-synaptic ANSD due to a novel FDXR variant linked to mitochondrial dysfunction was identified first in a Korean, and 1-year post CI outcomes were reported for the first time in the literature. Excellent audiologic results were obtained, and our results reiterate the correlation between genotype and CI outcomes in ANSD.

Reevaluating the splice-altering variant in TECTA as a cause of nonsyndromic hearing loss DFNA8/12 by functional analysis of RNA.

The aim of this study was to determine the genetic cause of early onset autosomal dominant hearing loss segregating in five-generation kindred of Chinese descent and provide preimplantation genetic testing (PGT)for them. Clinical examination, pedigree analysis and exome sequencing were carried out on the family. Minigene-based splicing analysis, in vivo RNA analysis and protein structure prediction by molecular modeling were conducted on the candidate variant. PGT for the causative variation and chromosome aneuploidis based on SNP analysis has been used for avoidance of hearing loss in this family. All the affected individuals presented with moderate down-sloping hearing loss and whole-exome sequencing identified a novel splice-site variant c.5383+6T>A in the tested subjects within the TECTA locus. Genotyping of all the 32 family members confirmed segregation of this variant and the hearing loss phenotype in the extended family. Functional analysis of RNA and molecular modeling indicates that c.5383+6T>A is a pathogenic splice-site variant and should be considered as genetic cause of the hearing loss. Furthermore, a successful singleton pregnancy with no variation in TECTA c.5383+6 was established and a healthy male child was born by PGT. We have identified a novel variant c.5383+6T>A in TECTA ZA-ZP inter-domain, which could be attributable to the early-onset autosomal dominant hearing loss. The implications of our study are valuable in elucidating the disrupted RNA splicing and uncovering the genetic cause of hearing loss with TECTA pathogenic variants, as well as providing reproductive approaches to healthy offspring.

Review and research gap identification in genetics causes of syndromic and nonsyndromic hearing loss in Saudi Arabia.

Congenital hearing loss is one of the most common sensory disabilities worldwide. The genetic causes of hearing loss account for 50% of hearing loss. Genetic causes of hearing loss can be classified as nonsyndromic hearing loss (NSHL) or syndromic hearing loss (SHL). NSHL is defined as a partial or complete hearing loss without additional phenotypes; however, SHL, known as hearing loss, is associated with other phenotypes. Both types follow a simple Mendelian inheritance fashion. Several studies have been conducted to uncover the genetic factors contributing to NSHL and SHL in Saudi patients. However, these studies have encountered certain limitations. This review assesses and discusses the genetic factors underpinning NSHL and SHL globally, with a specific emphasis on the Saudi Arabian context. It also explores the prevalence of the most observed genetic causes of NSHL and SHL in Saudi Arabia. It also sheds light on areas where further research is needed to fully understand the genetic foundations of hearing loss in the Saudi population. This review identifies several gaps in research in NSHL and SHL and provides insights into potential research to be conducted.

Variants in Genes Associated with Hearing Loss in Children: Prevalence in a Large Canadian Cohort.

The objective of this study was to assess the prevalence of genetic variants associated with hearing loss in a large cohort of children in Canada using high throughput next generation sequencing (NGS). A total of 485 children with hearing loss underwent NGS testing with an 80 gene panel of syndromic and non-syndromic variants known to be associated with hearing loss. Genetic variants were classified as pathogenic, likely pathogenic, likely benign, benign, or variants of uncertain significance (VUS), according to the American College of Medical Genetics and Genomics guidelines. Across the 80 genes tested, 923 variants, predominantly in 28 genes, were identified in 324 children. Pathogenic variants occurred in 19/80 (23.8%) of the hearing loss related genes tested and confirmed the etiology of hearing loss in 73/485 (15.1%) of children. GJB2 was the most prevalent gene, affecting 28/73 (38.4%) children with confirmed genetic hearing loss in our cohort. Most identified variants (748/923, 81.0%, in 76/80 genes) were of uncertain significance. Genetic testing using NGS identified the etiology in approximately 15% of childhood hearing loss in a Canadian cohort which is lower than what is typically reported. GJB2 was the most common genetic cause of hearing loss. VUS are commonly identified, presenting clinical challenges for counseling. 4 Laryngoscope, 134:3832-3838, 2024.

The natural history, clinical outcomes, and genotype-phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review.

Congenital hearing loss affects one in 500 newborns. Sequence variations in OTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1-8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship between OTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneous OTOF genotypes. Here, we present the first systematic, quantitative literature review of otoferlin-related hearing loss, which analyzes patient-specific data from 422 individuals across 61 publications. While most patients display a typical phenotype of severe-to-profound hearing loss with prelingual onset, 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss. Patients' phenotypic presentations appear to depend on their specific genotypes. For example, non-truncating variants located in and immediately downstream of the C2E calcium-binding domain are more likely to produce atypical phenotypes. Additionally, the prevalence of certain sequence variants and their associated phenotypes varies between populations due to evolutionary founder effects. Our analyses also suggest otoacoustic emissions are less common in older patients and those with two truncating OTOF variants. Critically, our review has implications for the application and limitations of clinical practices, including newborn hearing screenings, hearing aid trials, cochlear implants, and upcoming gene therapy clinical trials. We conclude by discussing the limitations of available research and recommendations for future studies on this genetic cause of hearing loss.

Tmprss3 deficiency does not affect auditory neuron differentiation: Implications for cochlear implantation

Background and Hypothesis:TMPRSS3 variants are one of the most common genetic causes of hearing loss in children and adults undergoing cochlear implantation (CI). Controversy exists regarding the success of CI in patients with TMPRSS3-mediated hearing loss as a prior immunolabeling study localized TMPRSS3 to the spiral ganglion (SGN) neurons. Type I SGNs transmit sound information to the CNS, while Type II SGNs are thought to play a role in amplification. Sensory hair cells (HC) that synapse on the SGN appear normal at birth but rapidly degenerate at the onset of hearing (postnatal day 12) in Tmprss3-mutant mice implicating an extrinsic process in HC death. During development, the precise pattern of SGN subtypes requires spontaneous firing of HCs prior to the onset of hearing. We hypothesize that Tmprss3 does not impact HC mechanotransduction or SGN subtype patterning.Project Methods:Cryosections of control and Tmprss3 mutant (Tmprss3Y2560X/Y260X) mice at P11 and P21 were immunolabeled with antibodies specific for SGN subtypes and all neurons. Cell counts were analyzed including two-tailed unpaired t test with significance of p < 0.05 (n=3 for each condition). Whole mount cochlea from P7 mice were used to test HC mechanotransduction using FM1-43 uptake assay. Tmprss3 gene expression was determined using hybridization chain reaction.Results:There was no difference in subtype patterning at P11 or P21 except Tmprss3 mice had less Type II SGNs at P21. Tmprss3 is not expressed in Type I SGNs and has limited expression in Type II SGNs. FM1-43 uptake was unaffected in Tmprss3-mutant mice.Conclusion/Potential Impact:SGN patterning is normal in Tmprss3-mutant mice suggesting that TMPRSS3 plays no physiologic role in the spontaneous firing or mechanotransduction of HCs. The limited expression of Tmprss3 within SGNs and normal SGN patterning supports CI as an effective treatment option for patients with TMPRSS3-mediated hearing loss.

De novo variants are a common cause of genetic hearing loss

PurposeDe novo variants (DNVs) are a well-recognized cause of genetic disorders. The contribution of DNVs to hearing loss (HL) is poorly characterized. We aimed to evaluate the rate of DNVs in HL-associated genes and assess their contribution to HL. MethodsTargeted genomic enrichment and massively parallel sequencing were used for molecular testing of all exons and flanking intronic sequences of known HL-associated genes, with no exclusions on the basis of type of HL or clinical features. Segregation analysis was performed, and previous reports of DNVs in PubMed and ClinVar were reviewed to characterize the rate, distribution, and spectrum of DNVs in HL. ResultsDNVs were detected in 10% (24/238) of trios for whom segregation analysis was performed. Overall, DNVs were causative in at least ∼1% of probands for whom a genetic diagnosis was resolved, with marked variability based on inheritance mode and phenotype. DNVs of MITF were most common (21% of DNVs), followed by GATA3 (13%), STRC (13%), and ACTG1 (8%). Review of reported DNVs revealed gene-specific variability in contribution of DNV to the mutational spectrum of HL-associated genes. ConclusionDNVs are a relatively common cause of genetic HL and must be considered in all cases of sporadic HL.

Compound heterozygous variants of the SLC26A4 gene in a Chinese family with enlarged vestibular aqueducts

BackgroundTo investigate the genetic causes of hearing loss in patients with enlarged vestibular aqueduct (EVA), the SLC26A4-related genotypes and phenotypes were analyzed. SLC26A4 gene is closely associated with EVA and its homozygous mutations or compound heterozygous mutations may cause deafness and strongly affect quality of life.MethodsThe patients who came to our hospital for hearing test and accompanied by bilateral hearing abnormalities were collected for fifteen deafness-related gene mutations detection. Those who are positive will be verified by Sanger sequencing, combined with family history, hearing test, and computerized tomography (CT) of the temporal bone, aiming to diagnose the enlarged vestibular aqueducts. Whole-exome sequencing were performed when necessary.ResultsOur patient failed hearing screening on both sides twice, and EVA (> 1.5 mm) was diagnosed by CT. This study has identified a novel missense mutation in the SLC26A4 gene, c.2069T>A, which in compound heterozygosity with c.1174A>T is likely to be the cause of hearing loss. The novel heterozygous c.2069T>A mutation of SLC26A4 gene has been submitted to Clinvar with Variation ID 1,048,780.ConclusionOur findings expand the gene mutation spectrum of SLC26A4 and provide additional knowledge for diagnosis and genetic counseling associated with EVA-induced hearing loss.

Predictors of Early Language Outcomes in Children with Connexin 26 Hearing Loss across Three Countries.

GJB2-associated hearing loss (GJB2-HL) is the most common genetic cause of hearing loss in children. However, little is known about the clinical characteristics and early language outcomes in population-oriented samples including children with different degrees of hearing loss. Insight into these characteristics are relevant for the counselling of parents. Our sample consisted of 66 children at approximately 2 years of age (17–32 months) with bilateral hearing loss due to GJB2 from three population-based cohorts in Austria, Australia and the Netherlands. Predictors of early vocabulary, including demographic, audiological, genetic and intervention variables and the role of medical comorbidities and nonverbal cognition were examined. The vocabulary scores of children with GJB2-HL were approximately 0.7 standard deviations (SDs) below the norms of children with typical hearing. Age at access to family-centered early intervention and first-born position among siblings predicted language outcomes, whereas the degree of hearing loss and genetic subtype were not significantly correlated with expressive vocabulary. In children with GJB2-HL, early access to family-centered early intervention significantly affected language outcomes at the age of two.

Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco.

Deafness is the most prevalent human sensorineural defect. It may occur as a result of an external auditory canal involvement, or a deficiency in the sound conduction mechanism, or an impairment of the cochlea, the cochlear nerve or central auditory perception. The genetic causes are the most common, as approximately 70% of hearing disorders are of hereditary origin, divided into two groups, syndromic (associated with other symptoms) and no syndromic (isolated deafness). A whole exome sequencing was performed to identify the genetic cause of hearing loss in six Moroccan families and Sanger sequencing was used to validate mutations in these genes. The results of four out of the six families revealed four genetic variants in the genes GJB2, COL4A3, ATP6V1B1 and EDNRB responsible for non-syndromic and syndromic hearing loss. Multiple Bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. We identified in Moroccan deaf patients four homozygous mutations. These results show the importance of whole exome sequencing to identify pathogenic mutations in heterogeneous disorders with multiple genes responsible.

A newly identified mutation (c.2029 C\u2009>\u2009T) in SLC26A4 gene is associated with enlarged vestibular aqueducts in a Chinese family

BackgroundThe enlarged vestibular aqueduct (EVA), associated with mutations in the SLC26A4 gene, characterized by non-syndromic hearing loss, is an autosomal recessive disorder. Here, we intended to investigate genetic causes of hearing loss in a Han Chinese man.MethodFirst, whole-exome sequencing was performed to identify the gene mutations responsible for hearing loss in the proband. Sanger sequencing was used to verify the candidate mutations detected in the family. Next, we collected blood samples and clinical data from the three-generation pedigree. Finally, SLC26A4 mRNA and protein expression levels were detected by qPCR and western blotting.ResultThe proband suffered from bilateral progressive sensorineural hearing loss with EVA. The sequence analysis of SLC26A4 revealed that the proband and his sister both harbored a compound heterozygous mutation of c.2168A > G/c.2029C > T, inherited from their father and mother respectively. c.2029C > T mutation has not been recorded in the relevant literature previously. Relative mRNA levels of the SLC26A4 gene in individuals carrying a compound heterozygous mutation were significantly lower compared to a heterozygous mutation. SLC26A4 protein levels of 293t cells which transfected with recombinant plasmids [GV219-SLC26A4-mut (c.2029C > T) and GV219-SLC26A4-mut (c.2168A > G/c.2029C > T)] were significantly lower than normal control recombinant plasmids (GV219-SLC26A4-wt).ConclusionThis study found a novel heterozygous mutation c.2029 (exon17) C > T compound with c.2168 (exon19) A > G in the SLC26A4 gene in a patient with EVA. The c.2029 (exon17) C > T mutation is proved to be pathogenic. This finding broadens the spectrum of variants in SLC26A4 gene.

A novel missense variant in ESRRB gene causing autosomal recessive non-syndromic hearing loss: in silico analysis of a case

BackgroundHereditary hearing loss (HHL) is a common heterogeneous disorder affecting all ages, ethnicities, and genders. The most common form of HHL is autosomal recessive non-syndromic hearing loss (ARNSHL), in which there is no genotype–phenotype correlation in the majority of cases. This study aimed to identify the genetic causes of hearing loss (HL) in a family with Iranian Azeri Turkish ethnicity negative for gap junction beta-2 (GJB2), gap junction beta-6 (GJB6), and mitochondrially encoded 12S rRNA (MT-RNR1) deleterious mutations.MethodsTargeted genome sequencing method was applied to detect genetic causes of HL in the family. Sanger sequencing was employed to verify the segregation of the variant. Finally, we used bioinformatics tools and American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines to determine whether the detected variant might affect the corresponding protein or not.ResultsA novel homozygous missense mutation, c.499G>A (p.G167R), was identified in exon 5 of the ESRRB (estrogen-related receptor beta) gene. Healthy and affected family members confirmed the co-segregation of the variant with ARNSHL. Eventually, the variant's pathogenicity was confirmed by the in silico analysis and the ACMG/AMP guidelines.ConclusionThe study suggests that the detected variant, c.499G>A, plays a crucial role in the development of ARNSHL, emphasizing the clinical significance of the ESRRB gene in ARNSHL patients. Additionally, it would be helpful for genetic counseling and clinical management of ARNSHL patients and providing preventive opportunities.

Clinicians' Views and Experiences with Offering and Returning Results from Exome Sequencing to Parents of Infants with Hearing Loss.

Exome sequencing (ES) is an effective method for identifying the genetic cause of hearing loss in infants diagnosed through newborn hearing screening programs. ES has the potential to be integrated into routine clinical care, yet little is known about the experiences of clinicians offering this test to families. To address this gap, clinicians involved in a clinical study using ES to identify the cause of infants’ hearing loss were interviewed to explore their experiences with offering and returning results to parents. Interview transcripts were analysed using inductive content analysis. Twelve clinicians participated: seven genetic counsellors, four clinical geneticists, and one paediatrician. Most clinicians were supportive of offering ES to infants with hearing loss, primarily because results may inform the child’s clinical management. However, some expressed concerns, questioning the utility of this information, particularly for isolated hearing loss. Clinicians had differing views regarding the optimal time to offer ES to families; while some felt that families can manage everything at once, others recommended delaying testing until parents have come to terms with their child’s diagnosis. These findings show the complexity involved in determining how ES should be offered to families following the diagnosis of a child with hearing loss, particularly with regards to when testing is suggested.

Evaluation of copy number variants for genetic hearing loss: a review of current approaches and recent findings.

Structural variation includes a change in copy number, orientation, or location of a part of the genome. Copy number variants (CNVs) are a common cause of genetic hearing loss, comprising nearly 20% of diagnosed cases. While large deletions involving the gene STRC are the most common pathogenic CNVs, a significant proportion of known hearing loss genes also contain pathogenic CNVs. In this review, we provide an overview of currently used methods for detection of CNVs in genes known to cause hearing loss including molecular techniques such as multiplex ligation probe amplification (MLPA) and digital droplet polymerase chain reaction (ddPCR), array-CGH and single-nucleotide polymorphism (SNP) arrays, as well as techniques for detection of CNVs using next-generation sequencing data analysis including targeted gene panel, exome, and genome sequencing data. In addition, in this review, we compile published data on pathogenic hearing loss CNVs to provide an up-to-date overview. We show that CNVs have been identified in 29 different non-syndromic hearing loss genes. An understanding of the contribution of CNVs to genetic hearing loss is critical to the current diagnosis of hearing loss and is crucial for future gene therapies. Thus, evaluation for CNVs is required in any modern pipeline for genetic diagnosis of hearing loss.

Peripheral Vestibular Dysfunction Is a Common Occurrence in Children With Non-syndromic and Syndromic Genetic Hearing Loss.

Hearing loss (HL) is the most common sensory deficit in humans and is frequently accompanied by peripheral vestibular loss (PVL). While often overlooked, PVL is an important sensory dysfunction that may impair development of motor milestones in children and can have a significant negative impact on quality of life. In addition, many animal and in vitro models of deafness use vestibular hair cells as a proxy to study cochlear hair cells. The extent of vestibular end organ dysfunction associated with genetic pediatric hearing loss is not well-understood. We studied children with a known genetic cause of hearing loss who underwent routine preoperative vestibular testing prior to cochlear implantation between June 2014 and July 2020. Vestibular testing included videonystagmography, rotary chair, video head impulse testing, and/or vestibular evoked myogenic potentials. Etiology of HL was determined through history, physical examination, imaging, laboratory testing, and/or genetic testing. Forty-four children (21 female/23 male) met inclusion criteria; 24 had genetic non-syndromic and 20 had genetic syndromic forms of HL. Mean age at the time of testing was 2.8 ± 3.8 years (range 7 months−17 years). The most common cause of non-syndromic HL was due to mutations in GJB2 (n = 13) followed by MYO15A (3), MYO6 (2), POU3F4 (2), TMPRSS3 (1), CDH23 (1), TMC1 (1), and ESRRB (1). The most common forms of syndromic HL were Usher syndrome (4) and Waardenburg (4), followed by SCID/reticular dysgenesis (3), CHARGE (2), CAPOS (1), Coffin-Siris (1), Jervell and Lange-Nielsen (1), Noonan (1), peroxisome biogenesis disorder (1), Perrault (1), and Trisomy 21 (1). Overall, 23 patients (52%) had PVL. A larger proportion of children with syndromic forms of HL had PVL (12/20, 60%) compared with children with genetic non-syndromic HL (11/24, 46%), though without statistical significant (p = 0.3). The occurrence of PVL varied by affected gene. In conclusion, PVL is a common finding in children with syndromic and non-syndromic genetic HL undergoing vestibular evaluation prior to cochlear implantation. Improved understanding of the molecular physiology of vestibular hair cell dysfunction is important for clinical care as well as research involving vestibular hair cells in model organisms and in vitro models.

Identification of Novel and Recurrent Variants in MYO15A in Ashkenazi Jewish Patients With Autosomal Recessive Nonsyndromic Hearing Loss.

Hearing loss is a genetically and phenotypically heterogeneous disorder. The purpose of this study was to determine the genetic cause underlying hearing loss in four Ashkenazi Jewish families. We screened probands from each family using a combination of targeted mutation screening and exome sequencing to identifiy the genetic cause of hearing loss in each family. We identified four variants in MYO15A, two novel variants never previously linked to deafness (c.7212+5G>A and p.Leu2532ArgfsTer37) and two recurrent variants (p.Tyr2684His and p.Gly3287Gly). One family showed locus heterogeneity, segregrating two genetic forms of hearing loss. Mini-gene assays revealed the c.7212+5G>A variant results in abnormal splicing and is most likely a null allele. We show that families segregrating the p.Gly3287Gly variant show both inter and intra-familial phenotypic differences. These results add to the list of MYO15A deafness-causing variants, further confirm the pathogenicity of the p.Gly3287Gly variant and shed further light on the genetic etiology of hearing loss in the Ashkenazi Jewish population.

Difference of SLC26A4 gene mutation frequency between patients with large vestibular aqueduct syndrome and/or Mondini dysplasia

Objective:The purpose of this study was to evaluate the mutation frequency of SLC26A4 gene in patients with enlarged vestibular aqueduct syndrome（EVAS） and/or Mondini dysplasia（MD）, so as to provide evidence for molecular diagnosis of deafness. Methods:In total, 74 patients with sensorineural hearing loss were included in this study. All patients underwent thin-layer CT examination of temporal bone. The coding exons of SLC26A4 were analyzed by second-generation sequencing in all subjects. Results:Among them, 37 patients with EVAS and MD（E+M group）, 28 patients with EVAS and without MD（E group）, and 9 patients with isolated MD（M group） were identified. In 74 cases, 66 cases（89.2%） were found to have mutation, including 64 cases（86.5%） of biallelic mutation and two cases（2.7%） of single allele mutation. The detection rate of SLC26A4 in different groups was statistically significant（P<0.001）. The mutation rate in group M was significantly lower than that in Group E and E+M（P<0.001）. In Group E, 27 cases（96.4%） had SLC26A4 biallelic mutations and one case（3.6%） had SLC26A4 single allele mutation, respectively; in Group E+M, 37 cases（100%） had SLC26A4 biallelic mutations; in group M, only one patient（11.1%） carried monoallelic mutations of the SLC26A4 gene. Conclusion:There are totally different pathogenesis in Chinese EVAS patients with or without MD, or isolated MD. Early clinical genetic diagnosis of patients with EVAS and/or MD helps to provide accurate information about the genetic causes of hearing loss, provide genetic counseling, and implement appropriate disease control and prevention measures. Next generation sequencing technology plays an increasingly important role in molecular diagnosis of deafness.