Common Deafness Genes Research Articles

The prevalence of common genetic deafness related mutation detected by microarray and follow-up in pregnant women in Beijing

Objective To determine the distribution of common deafness gene mutations by microarray-PCR in pregnant women of Beijing, then explore their prevalence and clinical significance. Methods Totally 1 709 pregnant women were prospectively enrolled from the outpatients of Obstetrical Clinical from Peking University Peoples′ Hospital in this study from June 2016 to April 2018. Peripheral blood samples were obtained and DNA templates were extracted from all subjects. The coding region of the GJB2 gene(35del G, 235delC, 176-191del16, 299-300delAT), SLC26A4 gene (IVS7-2 A>G,2168A>G) , 12sRNA gene (1494C>T,1555A>G) and GJB3 gene (538 C>T) were detected by microarray-PCR. Meanwhile, 256 cases firstly recruited in this study were confirmed by Sanger sequencing. The analysis was performed to explore the distribution of deafness gene mutations and the subjects detected to be positive were further followed up until they had given birth to their babies. Results Among 1 709 pregnant women, 89 cases were found to be carrying at least one mutation sites(5.21%).Among them,83 cases were heterozygous mutation(35 cases of GJB2 235delC, 12 cases of GJB2 299-300delAT mutation, one case of GJB2 176-191del 16, 30 cases of SLC26A4 IVS 7-2 A>G, 3 cases of SLC26A4 2168 A>G and two cases of GJB3 538 C>T). There were one case of 235delC homozygous mutation and 2 cases of double mutations(IVS7 -2 A>G/GJB2 299-300delAT, IVS7 -2 A>G/GJB2 235delC). The positive rate of 235delC, 299-300delAT and 176-191del16 was 2.17%, 0.76% and 0.06%, respectively. As to SLC26A4, 1.87% of the pregnant women were carrying IVS 7-2 A>G and 0.18% for 2168 A>G. Two cases were detected carrying GJB3 C>T mutation and three for 12s RNA1555 A>G mutation, respectively. The results of microarray-PCR were identical to those of Sanger sequencing, with the coincidence of 100%.26 spouses of the 56 cases were followed up. Two proved to be carrier of the same gene mutation. One of their babies was born with normal hearing until the end of this research, while another baby was born deafness and implant cochlear when three month old. Conclusions GJB2 235delC and SLC26A4 IVS 7-2 A>G were the most prevalent mutations in pregnant women of Beijing, and it may provide guidance to eugenics and early clinical intervention. Key words: Microarray analysis; Deafness; Connexins; Sulfate transporters; Mutation; Sequence analysis, DNA; Follow-up studies

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.

Application of the real-time fluorescence PCR melting curve method in gene screening of non-syndromic hearing loss

Objective: To detect 20 common deafness gene mutations in non-syndromic hearing loss patients in China using the melting curve method, and analyze and summarize the mutation data to explore the clinical value of this method. Methods: The real-time fluorescence PCR melting curve method was used to detect 20 common mutations of four deafness genes(GJB2,GJB3,SLC26A4 and mtDNA) in 492 patients with non-syndromic hearing loss recruited between March 2014 and September 2016 from the Otolaryngology Department of Xiangya Hospital, Central South University(283 males and 209 females, the age ranged from 1 to 48 years old). The Sanger sequencing method was used to compare the sensitivity, specificity, positive predictive value, negative predictive value, and total coincidence rate of the deafness mutation detected by the real-time fluorescence PCR melting curve method. Results: A total of 492 samples were detected. 193 wild-type samples, 93 homozygous mutant samples, 145 heterozygous mutant samples, 59 composite heterozygous mutant samples and 2 samples with unknown mutations were detected using the real-time fluorescence PCR melting curve method within the range of 20 gene mutations, whichwere identical to the Sanger sequencing results.The two samples were detected as unknown mutations by the real-time fluorescent PCR melting curve method were confirmed by Sanger sequencing, including a composite heterozygous mutant sample and a homogenous mutation sample. GJB2 c.235delC and SLC26A4 c.919-2 A>G were the most common hotspot mutations in this study, followed by mtDNA m.1555 A>G. Compared with the Sanger sequencing method, the sensitivity, specificity, positive predictive value, negative predictive value, and total coincidence rate of the real-time fluorescence PCR melting curve method were 100%, the Youden's index was 1.0, and the Kappa value was 1. Conclusions: The real-time fluorescence PCR melting curve method is suitable for the detection of deafness gene mutations. It has the advantages in terms of simple, rapid, high sensitivity and strong specificity and can accurately detect the 20 gene mutations of 4 common deafness genes in Chinese population, which is expected to be used for the clinical detection of deafness genes in the future.

Mutation analysis of common deafness genes among 1,201 patients with non-syndromic hearing loss in Shanxi Province.

BackgroundHearing impairment is one of most frequent birth defects, which affects nearly 1 in every 1,000 live births. However, the molecular etiology of non‐syndromic deafness in China is not well studied. Here, we have investigated the presence of mutations in three genes commonly mutated in non‐syndromic deafness patients in Shanxi Province, which has the highest frequency of birth defects in China.MethodsIn total, 1,201 unrelated non‐syndromic deafness patients and 300 healthy individuals were enrolled. The hearing ability was confirmed by audiologic evaluation. Three major deafness‐related genes (GJB2, SLC26A4 (PDS), and mtDNA 12S rRNA) of all individuals enrolled were analyzed by Sanger sequencing.ResultsThe results showed that GJB2 mutations accounted for 21.23% (255/1,201) in the patient group, with c.235delC, a hotspot mutation, accounting for 10.99% (132/1,201). Moreover, 11 new GJB2 mutations were identified. SLC26A4 mutations accounted for 9.33% (112/1,201) in the patient group, with IVS7‐2A>G as the most prevalent mutation accounting for 4.75% (57/1,201). In addition, 15 patients (1.25%) were found to carry mtDNA 12S rRNA c.1555A>G mutation, while only two cases had the mtDNA 12S rRNA c.1494C>T.ConclusionIn our research, it was found that c.235delC in GJB2 and c.919‐2A>G (IVS7‐2A>G) in SLC26A4 were the highest frequency pathogenic variants in Shanxi Province. Taken together, our data will enrich the database of deafness mutations and will help clinical diagnosis, treatment, and genetic counseling of hearing impairment.

Mutation screening in non-syndromic hearing loss patients with cochlear implantation by massive parallel sequencing in Taiwan.

ObjectivesTo explore the molecular epidemiology of rare deafness genes in Taiwanese sensorineural hearing impairment (SNHI) patients with cochlear implantation (CI) by performing massive parallel sequencing (MPS) and correlating genetic factors and CI outcomes.MethodsWe enrolled 41 Taiwanese non-syndromic deafness patients with CI that lacked known mutations in common deafness genes. All probands were screened by a targeted exon amplification method that used massively parallel sequencing to screen a customized panel that included 40 relatively rare non-syndromic deafness genes.ResultsThirteen candidate variants in nine relatively rare deafness genes (MYO15A, TMC1, MYH14, MYO3A, ACTG1, COL11A2, DSPP, GRHL2, and WFS1) were identified in 24.4% (10/41) of the non-syndromic deafness probands with CI. According to the ACMG Standards and Guidelines, five variants in MYO15A and ACTG1 were classified as likely pathogenic variants. Two of three multi-generational pedigrees exhibiting deafness were analyzed for the segregation of the disorder with the possible disease-causing variants. Patients with variants detected in most of the identified variant-bearing genes showed relatively good CI outcomes.ConclusionsWe successfully identified candidate variants in partially deaf Taiwanese probands who lacked the known mutations in common deafness genes. Comparing the progress of hearing rehabilitation in CI patients with their apparent causative variants and the expression profiles of their altered genes allowed us to speculate on how alterations in specific gene sets may influence outcomes in hearing rehabilitation after CI.

Unique spectra of deafness-associated mutations in Mongolians provide insights into the genetic relationships among Eurasian populations.

Genetic factors are an important cause of idiopathic sensorineural hearing impairment (SNHI). From the epidemiological perspective, mutations of three deafness genes: GJB2, SLC26A4, and MT-RNR1, are much more prevalent than those of other genes worldwide. However, mutation spectra of common deafness genes differ remarkably across different populations. Here, we performed comprehensive genetic examination and haplotype analyses in 188 unrelated Mongolian families with idiopathic SNHI, and compared their mutation spectra and haplotypes to those of other European and Asian cohorts. We confirmed genetic diagnoses in 18 (9.6%) of the 188 families, including 13 with bi-allelic GJB2 mutations, three with bi-allelic SLC26A4 mutations, and two with homoplasmic MT-RNR1 m.1555A>G mutation. Moreover, mono-allelic mutations were identified in 17 families (9.0%), including 14 with mono-allelic GJB2 mutations and three with mono-allelic SLC26A4 mutations. Interestingly, three GJB2 mutations prevalent in other populations, including c.35delG in Caucasians, c.235delC in East Asians, and c.-23+1G>A in Southwest and South Asians, were simultaneously detected in Mongolian patients. Haplotype analyses further confirmed founder effects for each of the three mutations, indicating that each mutation derived from its ancestral origin independently. By demonstrating the unique spectra of deafness-associated mutations, our findings may have important clinical and scientific implications for refining the molecular diagnostics of SNHI in Mongolian patients, and for elucidating the genetic relationships among Eurasian populations.

Screening for hearing loss and deafness-related genes in newborns

To screen the hearing loss and deafness-related genes in newborns, the screenings for hearing loss and the mutations of common deafness-related genes were performed among 8 187 infants born in Shaoxing Maternal and Child Health Care Hospital from August 2013 to November 2014.Twenty mutation spots in deafness-related genes GJB2, GJB3, 12SrRNA and SLC26A4 were detected with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Of 8 187 newborns, hearing loss was confirmed in 10 cases, and mutations in deafness-related genes were detected in 441 cases with a detection rate of 5.39%.Among 441 cases with positive gene mutations, there were 243 cases with GJB2 mutations (2.97%).147 cases with SCL26A4 mutations (1.80%), 43 cases with GJB3 mutations (0.53%)and 15 cases with mutations of mitochondrial gene 12SrRNA (0.18%). The spot of highest detection frequency was GJB2 235delC (2.31%), followed by SCL26A4 IVS72A>G (1.31%). The deafness gene detection rate for newborns who did not pass the hearing tests (8.16%, 79/968) was higher than these who passed (5.01%, 362/7 219; χ2=10.978, P<0.05). Five of 10 newborns with hearing loss were detected carrying deafness genes. The detection rate of the common deafness genes among the newborns is relatively high in this region.Screening for hearing loss and deafness gene may contribute to early diagnosis and intervention, and also to long-term precaution for those carrying heterozygosity deafness genes. Key words: Newborns; Deafness; Gene; Hearing disorder

A novel missense mutation in GIPC3 causes sensorineural hearing loss in an Iranian family revealed by targeted next-generation sequencing

BackgroundRecent studies have confirmed the utility of targeted next-generation sequencing (NGS), providing a remarkable opportunity to find variants in known disease genes, especially in genetically heterogeneous disorders such as hearing loss (HL). MethodsAfter excluding mutations in the most common autosomal recessive non-syndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis, we performed NGS in the proband an Iranian family with ARNSHL. The NimbleGen sequence capture array captures codingsequences (CDSs) and 100 bp of the flanking sequence of 129 common deafness genes (cat# Oto-DA3). NGSwas performed on the IlluminaHiSeq2000. BWA, SAMtools, Picard, GATK, Variant Tools, ANNOVAR, and IGV were applied for Bioinformatics analyses. Data filtering with allele frequencies (<5% in the 1000 Genomes Project and 5400 NHLBI exomes) and PolyPhen2/SIFTscores (>0.95) prioritized 1indel (insertions/deletions) and 3 missense variants in this family. Eventually, Sanger sequencing, segregation pattern, the frequency in 50 healthy matched normal controls, and evolutionary conservation of amino acid residues revealed the pathogenic variant. ResultsWe identified a novel missenseGIPC3 mutation, c.472G > A (p.Glu158 Lys). The pathogenicity of GIPC3c.472G > A was supported by its absence in the population databases and the healthy-matched controls.Sanger sequencing confirmed co-segregation of the mutation with HL. ConclusionsThis study is the first report of the contribution of theGIPC3 gene to HL in the Iranian population.Targeted NGS allows easier detection of mutations in relatively uncommon deafness genes in families with ARNSHL.

Identification of Pathogenic Genes of Nonsyndromic Hearing Loss in Uyghur Families Using Massively Parallel DNA Sequencing Technique.

We aim to identify the mutations of deafness genes using massively parallel DNA sequencing in the 12 Uyghur families. SNPscan method was used to screen against the 124 sites in the common deafness genes in probands. Subjects with SNPscan negativity were subject to massively parallel DNA sequencing for the sequencing of 97 genes known to be responsible for hearing loss. Eight families (66.7%) showed biallelic mutations in probands, including MYO15A mutation (6892C>T in J02 family, 9514C>T/7894G>T in J07 family, and 9514C>T in J16 family), MYO7A mutation (1258A>T in J03 family), TMC1 mutation (773G>A in J09 family and 1247T>G/1312G>A in J11 family), and PCDH15 mutation (4658delT in J08 and J13 families). Six novel types of mutation were identified including 6892C>T, 9514C>T/7894G>T, and 9514C>T in MYO15A gene, 1258A>T in MYO7A, 773G>A in TMC1, and 4658delT in PCDH15. The ratio of nonsense mutation and frameshift mutation was comparatively high. All these indicated that the mutation types reported in this study were rare. In conclusion, rare deafness genes were identified in the Uyghur families using massively parallel DNA sequencing, part of which were suggested to be related to the pathogenesis of the disease.

Newborn Screening of Genetic Mutations in Common Deafness Genes With Bloodspot-Based Gene Chip Array.

This study screens for deafness gene mutations in newborns in the Northwest China population. The 9 sites of 4 common deafness genes (GJB2, GJB3, SLC26A4, and mt 12S rRNA) were detected by bloodspot-based gene chip array in 2,500 newborns. We detected mutations of the 4 genes in 101 (4.04%) newborns; particularly, 0.20% detected the double mutations. In the Hui population, 4.58% of the newborns tested positive for mutations, whereas 4.01% of Han newborns tested positive for mutations. The detective rates are as follows: 1.44% for GJB2 235delC, 1.08% for SLC26A4 IVS7-2A>G, 0.48% for GJB2 299_300delAT, 0.28% for SLC26A4 2168A>G, 0.2% for mt 12S rRNA 1555A>G, and 0.16% for GJB3 538C>T. The 31.25% (5/16) of infants with GJB2 235delC, 50% (3/6) with GJB2 299_300delAT, and 25% (3/12) with SLC26A4 IVS7-2A>G showed abnormal hearing when tested; only 1 double mutation case received the hearing test, and this infant showed abnormality in both ears on the hearing test. High mutation rates in the common deafness genes were detected in newborns in Northwest China. Our study is helpful in understanding the deafness genomic epidemiology and also provides evidence for prenatal and postnatal care as well as policy making on population health in the region.

Etiologic and Audiologic Characteristics of Patients With Pediatric-Onset Unilateral and Asymmetric Sensorineural Hearing Loss

Pediatric-onset unilateral and asymmetric sensorineural hearing loss (SNHL) is a common condition, but in most patients, the cause remains unclear; thus, determination of the hearing outlook is difficult. To analyze the etiologic and audiologic characteristics of pediatric-onset unilateral and asymmetric SNHL. In this retrospective cohort study performed from January 1, 2008, through December 31, 2016, patients at a tertiary referral center who were diagnosed with pediatric-onset unilateral or asymmetric SNHL were divided into 3 groups according to their hearing levels: unilateral hearing loss with scaled-out levels (UHL-SO), unilateral hearing loss with residual hearing (UHL-RH), and asymmetric hearing loss (AHL). Basic demographic data, family and medical histories, audiologic results, imaging findings, and genetic results were ascertained and compared among patients of the 3 groups. A total of 133 patients (mean [SD] age, 9.1 [10.9] years; 63 [47.4%] male and 70 [52.6%] female), including 50 with UHL-SO, 42 with UHL-RH, and 41 with AHL, were enrolled for analyses. Of 50 patients with UHL-SO, 49 (98.0%) had stable hearing levels with time, whereas 10 of 42 patients with UHL-RH (23.8%) and 18 of 41 patients with AHL (43.9%) revealed progressive or fluctuating hearing loss. Inner ear malformations detected with temporal bone high-resolution computed tomography, particularly cochlear aperture stenosis, were detected at higher rates in patients with UHL-SO (9 of 31 [29.0%]) and UHL-RH (6 of 24 [25.0%]) than in those with AHL (1 of 30 [3.3%]). In contrast, screening for mutations in 3 common deafness genes-GJB2, SLC26A4, and MTRNR1-achieved definite diagnosis in a higher percentage of patients with AHL (10 of 37 [27.0%]) than patients with UHL-SO (0 of 33) and UHL-RH (1 of 25 [4.0%]). The UHL-SO and UHL-RH conditions share a common or similar etiopathogenesis different from that of AHL. Imaging studies and genetic testing might be prioritized during the respective general etiologic workups for patients with UHL and AHL. Regular hearing checkups are warranted for patients with UHL and AHL because a certain proportion of patients might sustain progression in SNHL.

Mutation analysis of common GJB2, SCL26A4 and 12S rRNA genes among 380 deafness patients in northern China

ObjectivesThe molecular etiology of nonsyndromic deafness in Chinese population has not been investigated systematically, our study is aim to investigate the molecular etiology of nonsyndromic deafness patients from Northern China (Heilongjiang province), in order to provide genetic test and counseling to families. Methods380 unrelated patients with hearing loss who attended to the Department of Otolaryngology, The Fourth Affiliated Hospital of Harbin Medical University were enrolled to our study. All patients were diagnosed with nonsyndromic deafness by audiologic evaluation, 202 normal-hearing individuals were taken as controls. Mutations in three common deafness-causing genes (GJB2, SLC26A4 and 12S rRNA) were screened by direct sequencing. ResultsMutations (homozygote or compound heterozygote) in GJB2 accounted for 8.9% (34/380) of the patients, mutations in SLC26A4 accounted for 10.0% (38/380) of the patients screened. Only one case was found to carry 12S rRNA 1555A > G (1/380, 0.26%). Five types of mutations in GJB2 were identified, GJB2 235delC was the most prevalent mutation in our patient group (76/380, 20.0%), followed by 299-300delAT with a frequency of 7.4% (28/380). Two types of mutations in SLC26A4 were detected in our patient group (IVS7-2A > G and 2168A > G). IVS7-2A > G was identified in 27 patients (27/380, 7.1%) and 2168A > G was identified in 14 patients (14/380, 3.7%). ConclusionsOur results demonstrate that 19.2% patients with nonsyndromic deafness were caused by mutations in three common deafness genes (GJB2, SLC26A4 and 12S rRNA) in our northern China patient group. GJB2 235delC was the most prevalent mutation, same as in the most Asian populations. These data enrich the database of deafness mutations and provide the standard for clinical diagnose, treatment and genetic counseling in Northern China population.

Mutation Analysis of the Common Deafness Genes in Patients with Nonsyndromic Hearing Loss in Republic of Macedonia

Abstract Hearing impairment is the most common sensory disorder, which occurs in 1 of 1000 newborns. It is caused by heterogeneous conditions with more than a half due to genetic etiology. Although hundreds of genes are implicated in hearing process and have been found to be associated with nonsyndromic hearing loss, pathogenic variants in GJB2 gene have been considered as the main cause of deafness among nonsyndromic hearing loss (NSHL) population worldwide. Pathogenic variants in MT-RNR1 or mtDNA12SrRNA gene were also implicated predominantly in postlingual progresive deafness. The aim of this study was to analyze the implication of GJB2 and MT-RNR1 genes in the molecular etiology of deafness among 130 NSHL patients in the Republic of Macedonia. The presence of the del (GJB6-D13S1830) was also analysed. We performed SSCP and/or sequence analysis of GJB2 and identified sequence variants in 62 out of 130 patients (47.7%); (51 homozygous or compound heterozygous and 11 with only one variant allele). We found 8 different allelic variants, the most prevalent being c.35delG (65.49%), and p.W24*(23.01%), followed by other less frequent alleles (p.V27I, p.V37I, p. P175T and cd. delE120 or delGAG at 360). In addition, two polymorphic substitutions in the GJB2 gene with no clinical significance (p.V153I and p.R127H) were detected. No del(GJB6-D13S1830) was found. SNaPshot analysis was used to screen for the five most frequent allelic variants in the MT-RNR1 gene. Two MT-RNR1 mutations (A827G and T961G) were detected in three patients where only one GJB2 pathogenic variant was found. A new MT-RNR1 gene variant G1303A was also detected. In conclusion, MT-RNR1 mutations were not a significant contributor to the etiology of deafness in Macedonia, although could be considered as a modifier gene affecting the expression of deafness in patients carrying one GJB2 variant. On the other hand, the high percenttage of GJB2 pathogenic variants identified among NSHL cases indicates the necessity of molecular newborn screening for the two most common GJB2 variants (c.35delG and p.W24*) in the Republic of Macedonia.

The relationship between high jugular bulb and tinnitus and hearing disorder

Objective:To investigate the relationship between high jugular bulb and tinnitus and hearing disorder. Method:Forty-nine inpatient patients with hearing disorder were selected as the case group,and 50 cases as the control group,two groups of patients conducted temporal CT, audiogram to find out the patients who had hearing disorder,and then acoustic immittance, DPOAE, ABR,genetic screening for deafness and tinnitus questionnaire were conducted to the patients with hearing disorder. Result:Sixteen cases of these 99 patients had high jugular bulb,the total incidence was 16.16%, 14 cases in the case group had high jugular bulb, the incidence was 28.57%,only 2 cases in the control group, the incidence was 4.00%, there was significant difference(χ²=11.027，P<0.01)between two groups.For the cases group, 8 cases(57.14%) had hearing loss in the high frequencies, 4 cases(28.57%) in the low frequencies,2 cases(14.29%) in all frequencies；all of these 14 cases with high jugular bulb also had different degrees of tinnitus,12 of which had pulsatile tinnitus(85.71%), vascular pulsatile tinnitus was most common type,2 of which had non pulsatile tinnitus(14.29%).Four common deafness genes GJB2, SLC26A4, mtDNA12srRNA and GJB3 9 mutation screening tests showed no positive mutation in both groups. Conclusion:High jugular bulb has higher incidence in patients with hearing disorder,which may be a risk factor for hearing disorder.Attention should be paid to the influence of high jugular bulb in clinical diagnosis and treatment of hearing disorder.

Compound heterozygous MYO7A mutations segregating Usher syndrome type 2 in a Han family

ObjectiveIdentification of rare deafness genes for inherited congenital sensorineural hearing impairment remains difficult, because a large variety of genes are implicated. In this study we applied targeted capture and next-generation sequencing to uncover the underlying gene in a three-generation Han family segregating recessive inherited hearing loss and retinitis pigmentosa. MethodsAfter excluding mutations in common deafness genes GJB2, SLC26A4 and the mitochondrial gene, genomic DNA of the proband of a Han family was subjected to targeted next-generation sequencing. The candidate mutations were confirmed by Sanger sequencing and subsequently analyzed with in silico tools. ResultsAn unreported splice site mutation c.3924+1G > C compound with c.6028G > A in the MYO7A gene were detected to cosegregate with the phenotype in this pedigree. Both mutations, located in the evolutionarily conserved FERM domain in myosin VIIA, were predicted to be pathogenic. In this family, profound sensorineural hearing impairment and retinitis pigmentosa without vestibular disorder, constituted the typical Usher syndrome type 2. ConclusionIdentification of novel mutation in compound heterozygosity in MYO7A gene revealed the genetic origin of Usher syndrome type 2 in this Han family.

Attitudes toward carrier screening and prenatal diagnosis for recessive hereditary deafness among the educated population in urban China.

Approximately 80% of hereditary deafness is recessive, in which case most mutation carriers were unaware of their carrier status. Though parental attitudes toward genetic testing and prenatal diagnosis are overall positive in those with deaf children, there is little information about that in the general population. To this end, we designed a self-completed questionnaire and distributed it in two colleges in Shanghai, China. A total of 975 completed surveys were returned in print or online forms. Our results showed that 98.7% of the respondents without family history of early onset deafness did not know or underestimated their likelihood to carry a recessive mutation in common deafness genes. After brief written information was given using GJB2, the most common recessive deafness gene as the example, 67.7% of the respondents expressed interest in knowing if they are carriers of GJB2 mutations through genetic testing. In hypothetical circumstance of carrying a recessive GJB2 mutation, 86.9% would suggest their partners to also take the test. In case that both were carriers, 88.7% would consider prenatal diagnosis and 80.7% would consider terminating an affected pregnancy. On the basis of these results, it was concluded that despite the poor awareness to the risk of recessive hereditary deafness, the majority of the educated population in urban China likely hold a positive view toward carrier screening and prenatal diagnosis of recessive deafness genes. © 2016 Wiley Periodicals, Inc.

Efficiency of hearing screening combined with gene mutation screening in neonates with high-risk of hearing impairment

Objective To investigate the significance of hearing screening combined with gene screening for neonates with high-risk of hearing impairment. Methods Neonates admitted to the Neonatal Department of Guangdong Women and Children Hospital between July 2013 and June 2014 were enrolled in this study. They were divided into high-risk group (with high-risk for hearing impairment) (n=3 129), and control group (n=5 106). Neonate hearing screening was carried out using otoacoustic emission and automated auditory brainstem response. Blood samples were collected using a standard protocol for detecting the mutations of four common deafness genes, including GJB2, GJB3, SLC26A4 and mitochondrial 12s rRNA. Chi-square test was used to compare the differences of the pass rate of hearing screening and positive rate of gene mutations between the two groups. Results The rates of failure on otoacoustic emission, automated auditory brainstem response or both in the high-risk group were 11.92% (373/3 129), 10.32% (323/3 129) and 4.83% (151/3 129), respectively, higher than those in the control group [5.03%(257/5 106), 6.56%(335/5 106) and 2.02% (103/5 106)] (χ2=130.265, 37.354 and 51.196, all P=0.000). In the high-risk group, the overall positive rate of gene mutations was 5.63% (176/3 129), and the GJB2 and SLC26A4 gene mutation rates were 3.04% (95/3 129) and 2.40% (75/3 129)], all higher than the control group [3.15% (161/5 106), 2.04% (104/5 106) and 1.06% (54/5106)] (χ2=30.301, 8.216 and 22.517, all P 0.05]. The rates of failure on otoacoustic emission and automated auditory brainstem response of the neonates with deafness gene mutations were 9.50% (32/337) and 10.39% (35/337), respectively, higher than the neonates without [1.14% (90/7 898) and 1.29% (102/7 898)] (χ2=154.621 and 163.399, both P=0.000). Conclusion Combined hearing screening is of clinical significance for neonates with high-risk of hearing impairment. Key words: Hearing disorders; Deafness; Connexins; Membrane transport proteins; Mutation; Genetic predisposition to disease; Neonatal screening

Long-Term Cochlear Implant Outcomes in Children with GJB2 and SLC26A4 Mutations.

ObjectivesTo investigate speech and language outcomes in children with cochlear implants (CIs) who had mutations in common deafness genes and to compare their performances with those without mutations.Study DesignProspective study.MethodsPatients who received CIs before 18 years of age and had used CIs for more than 3 years were enrolled in this study. All patients underwent mutation screening of three common deafness genes: GJB2, SLC26A4 and the mitochondrial 12S rRNA gene. The outcomes with CIs were assessed at post-implant years 3 and 5 using the Categories of Auditory Performance (CAP) scale, Speech Intelligibility Rating (SIR) scale, speech perception tests and language skill tests.ResultsForty-eight patients were found to have confirmative mutations in GJB2 or SLC26A4, and 123 without detected mutations were ascertained for comparison. Among children who received CIs before 3.5 years of age, patients with GJB2 or SLC26A4 mutations showed significantly higher CAP/SIR scores than those without mutations at post-implant year 3 (p = 0.001 for CAP; p = 0.004 for SIR) and year 5 (p = 0.035 for CAP; p = 0.038 for SIR). By contrast, among children who received CIs after age 3.5, no significant differences were noted in post-implant outcomes between patients with and without mutations (all p > 0.05).Conclusion GJB2 and SLC26A4 mutations are associated with good post-implant outcomes. However, their effects on CI outcomes may be modulated by the age at implantation: the association between mutations and CI outcomes is observed in young recipients who received CIs before age 3.5 years but not in older recipients.

Targeted next-generation sequencing in Uyghur families with non-syndromic sensorineural hearing loss.

The mutation spectrum of deafness genes may vary in different ethnical groups. In this study, we investigated the genetic etiology of nonsyndromic deafness in four consanguineous and two multiplex Uyghur families in which mutations in common deafness genes GJB2, SLC26A4 and MT-RNR1 were excluded. Targeted next-generation sequencing of 97 deafness genes was performed in the probands of each family. Novel pathogenic mutations were identified in four probands including the p.L416R/p.A438T compound heterozygous mutations in TMC1, the homozygous p.V1880E mutation in MYO7A, c.1238delT frameshifting deletion in PCDH15 and c.9690+1G>A splice site mutation in MYO15A. Co-segregation of the mutations and the deafness were confirmed within each family by Sanger sequencing. No pathogenic mutations were identified in one multiplex family and one consanguineous family. Our study provided a useful piece of information for the genetic etiology of deafness in Uyghurs.

Novel mutation located in EC7 domain of protocadherin-15 uncovered by targeted massively parallel sequencing in a family segregating non-syndromic deafness DFNB23

ObjectiveHereditary hearing loss is a clinically and genetically heterogeneous disorder associated with mutations of a large number of diverse genes. In this study we applied targeted capture and massively parallel sequencing to identify the disease-causing gene of a Chinese family segregating recessive inherited deafness. MethodsAfter excluding mutations in common deafness genes GJB2, SLC26A4, mitochondrial m.1555A>G, genomic DNA of the proband of family GDSW24 was subjected to targeted next-generation sequencing. Subsequently, a candidate homozygous mutation was confirmed by Sanger sequencing. ResultsA novel PCDH15 c.2367_2369delTGT/p.V788-homozygous mutation was detected. In this family, no obvious vestibular disorder was found. The in-frame mutation c.2367_2369delTGT is located in the evolutionarily conserved EC7 domain of Protocadherin-15 and was predicted to be pathogenic. ConclusionThe novel homozygous mutation in a family segregating non-syndromic hearing loss family supports previous reported observations that PCDH15 does not only causes Usher syndrome type 1F, but also DFNB23.