Congenital Sensorineural Hearing Impairment Research Articles

Is there an unmet medical need for improved hearing restoration?

Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health care professionals on establishing novel therapies. We summarize upcoming CI innovations, gene therapies, and regenerative approaches and evaluate the chances for clinical translation of these novel strategies. We conclude that there remains an unmet medical need for improving hearing restoration and that we are likely to witness the clinical translation of gene therapy and major CI innovations within this decade.

Language Processing in Toddlers with Permanent Congenital Sensorineural Hearing Impairment: A Preliminary Functional Magnetic Resonance Imaging (fMRI) Study

Language Processing in Toddlers with Permanent Congenital Sensorineural Hearing Impairment: A Preliminary Functional Magnetic Resonance Imaging (fMRI) Study

Pseudodominance in a Czech family with Usher syndrome type II

PurposeUsher syndrome is an autosomal recessive genetically heterogeneous disorder with congenital sensorineural hearing impairment and retinitis pigmentosa developing in late childhood and adolescense. We have identified a Czech family not aware of consanguinity with four members in two subsequent generations clinically diagnosed with Usher syndrome type II. The major aim of our study was to determine the disease‐causing mutation(s) in this family.MethodsAs an initial approach Sanger sequencing of USH2A exons 6, 7, 11, 13, 20, 61 was performed in the proband, followed by next‐generation sequencing of a panel testing 286 genes known to cause various inherited ocular disorders. Available relatives were screened by Sanger sequencing for the detected mutations. 1,161 population specific controls were used to check for allele frequencies of the identified sequence variants.ResultsThe proband was found to harbour compound heterozygous mutations c.11864G>A; p.(Trp3955*) and c.13342_13347del; p.(Asp4448_Ser4449del) in USH2A while her affected daughter and son were homozygous for the c.11864G>A mutation. Segregation analysis confirmed that father of the affected children was a heterozygous carrier of the USH2A c.11864G>A. Affected brother of the proband was not available for our investigation. Mutation c.11864G>A has been previously observed in patients with Usher syndrome type II. Geographical origin in a particular region in Moravia was noted for parents of both the affected proband and her spouse. None of the two mutations were detected in Czech controls.ConclusionsPseudodominance may occur in outbred families. The estimation of the chance that a person will be a heterozygote carrier of a recessive disorder needs to be implemented into counselling. Geographic distribution of pathogenic alleles may display regional differences.

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.

Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa

USH2A mutations are an important cause of retinitis pigmentosa (RP) with or without congenital sensorineural hearing impairment. We studied genotype-phenotype correlations and compared visual prognosis in Usher syndrome type IIa and nonsyndromic RP. Clinic-based, longitudinal, multicenter study. Consecutive patients with Usher syndrome type IIa (n= 152) and nonsyndromic RP (n= 73) resulting from USH2A mutations from ophthalmogenetic clinics in the Netherlands and Belgium. Data on clinical characteristics, visual acuity, visual field measurements, retinal imaging, and electrophysiologic features were extracted from medical charts over a mean follow-up of 9 years. Cumulative lifetime risks of low vision and blindness were estimated using Kaplan-Meier survival analysis. Low vision and blindness. Participant groups had similar distributions of gender (48% vs. 45% males in Usher syndrome type IIa vs. nonsydromic RP; P= 0.8), ethnicity (97% vs. 99% European; P= 0.3), and median follow-up time (6.5years vs. 3 years; P=0.3). Usher syndrome type IIa patients demonstrated symptoms at a younger age (median age, 15 years vs. 25 years; P < 0.001), were diagnosed earlier (median age, 26 years vs. 36.5 years; P < 0.001), and became visually impaired 13 years earlier (median age, 41 years vs. 54 years; P < 0.001) based on VF and 18 years earlier based on VA (median age, 54 years vs. 72 years; P < 0.001) than nonsyndromic RP patients. The presence of 2 truncating mutations in USH2A was associated mostly with the syndromic phenotype, whereas other combinations were present in both groups. We found novel variants in Usher syndrome type IIa (25%) and nonsyndromic RP (19%): 29 missense mutations, 10 indels, 14 nonsense mutations, 9 frameshift mutations, and 5 splice-site mutations. Most patients with USH2A-associated RP have severe visual impairment by age 50. However, those with Usher syndrome type IIa have an earlier decline of visual function and a higher cumulative risk of visualimpairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes toUsher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss.

Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3

BackgroundUsher syndrome (USH) is an autosomal recessive genetically heterogeneous disorder with congenital sensorineural hearing impairment and retinitis pigmentosa (RP). We have identified a consanguineous Lebanese family with two affected members displaying progressive hearing loss, RP and cataracts, therefore clinically diagnosed as USH type 3 (USH3). Our study was aimed at the identification of the causative mutation in this USH3-like family.MethodsCandidate loci were identified using genomewide SNP-array-based homozygosity mapping followed by targeted enrichment and next-generation sequencing.ResultsUsing a capture array targeting the three identified homozygosity-by-descent regions on chromosomes 1q43-q44, 20p13-p12.2 and 20p11.23-q12, we identified a homozygous nonsense mutation, p.Arg65X, in ABHD12 segregating with the phenotype.ConclusionMutations of ABHD12, an enzyme hydrolyzing an endocannabinoid lipid transmitter, cause PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract). After the identification of the ABHD12 mutation in this family, one patient underwent neurological examination which revealed ataxia, but no polyneuropathy. ABHD12 is not known to be related to the USH protein interactome. The phenotype of our patient represents a variant of PHARC, an entity that should be taken into account as differential diagnosis for USH3. Our study demonstrates the potential of comprehensive genetic analysis for improving the clinical diagnosis.

Harmonin (Ush1c) is required in zebrafish Müller glial cells for photoreceptor synaptic development and function

SUMMARYUsher syndrome is the most prevalent cause of hereditary deaf-blindness, characterized by congenital sensorineural hearing impairment and progressive photoreceptor degeneration beginning in childhood or adolescence. Diagnosis and management of this disease are complex, and the molecular changes underlying sensory cell impairment remain poorly understood. Here we characterize two zebrafish models for a severe form of Usher syndrome, Usher syndrome type 1C (USH1C): one model is a mutant with a newly identified ush1c nonsense mutation, and the other is a morpholino knockdown of ush1c. Both have defects in hearing, balance and visual function from the first week of life. Histological analyses reveal specific defects in sensory cell structure that are consistent with these behavioral phenotypes and could implicate Müller glia in the retinal pathology of Usher syndrome. This study shows that visual defects associated with loss of ush1c function in zebrafish can be detected from the onset of vision, and thus could be applicable to early diagnosis for USH1C patients.

Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment

A homozygous reciprocal translocation, 46,XY,t(10;11),t(10;11), was detected in a boy with non-syndromic congenital sensorineural hearing impairment. Both parents and their four other children were heterozygous translocation carriers, 46,XX,t(10;11) and 46,XY,t(10;11), respectively. Fluorescence in situ hybridization of region-specific clones to patient chromosomes was used to localize the breakpoints within bacterial artificial chromosome (BAC) RP11-108L7 on chromosome 10q24.3 and within BAC CTD-2527F12 on chromosome 11q23.3. Junction fragments were cloned by vector ligation and sequenced. The chromosome 10 breakpoint was identified within the PDZ domain containing 7 (PDZD7) gene, disrupting the open reading frame of transcript PDZD7-C (without PDZ domain) and the 5'-untranslated region of transcript PDZD7-D (with one PDZ and two prolin-rich domains). The chromosome 11 breakpoint was localized in an intergenic segment. Reverse transcriptase-polymerase chain reaction analysis revealed PDZD7 expression in the human inner ear. A murine Pdzd7 transcript that is most similar in structure to human PDZD7-D is known to be expressed in the adult inner ear and retina. PDZD7 shares sequence homology with the PDZ domain-containing genes, USH1C (harmonin) and DFNB31 (whirlin). Allelic mutations in harmonin and whirlin can cause both Usher syndrome (USH1C and USH2D, respectively) and congenital hearing impairment (DFNB18 and DFNB31, respectively). Protein-protein interaction assays revealed the integration of PDZD7 in the protein network related to the human Usher syndrome. Collectively, our data provide strong evidence that PDZD7 is a new autosomal-recessive deafness-causing gene and also a prime candidate gene for Usher syndrome.

Molecular analysis of hearing loss associated with enlarged vestibular aqueduct in the mainland Chinese: a unique SLC26A4 mutation spectrum

It has been shown that mutations in the SLC26A4 gene are involved in syndromic deafness characterized by congenital sensorineural hearing impairment and goitre (Pendred's syndrome), as well as in congenital isolated deafness (DFNB4), both of which are associated with enlarged vestibular aqueduct (EVA). The prevalence of SLC26A4 mutations in Pendred's syndrome is clearly established in many ethnic groups, but the data from Mainland Chinese patients with deafness and EVA remain poor. In this report, 15 patients from 13 unrelated Chinese families with deafness and EVA were analyzed for SLC26A4 using direct sequencing. A total of 15 pathogenic mutations were observed in 11 unrelated families, 4 of which were novel. One mutation, IVS7-2A>G, was most common, accounting for 22.3% (5/22) of all the mutant alleles, and H723R was infrequent. To date, a total of 23 mutations have been reported among the Chinese, 13 of which were unique. In conclusion, EVA could be a radiological marker for SLC26A4 analysis among Mainland Chinese hearing-loss patients, and the SLC26A4 mutation spectrum in the Chinese was different from other reported populations.

SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations

Sensorineural hearing loss is the most frequent sensory deficit of childhood and is of genetic origin in up to 75% of cases. It has been shown that mutations of the SLC26A4 (PDS) gene were involved in syndromic deafness characterized by congenital sensorineural hearing impairment and goitre (Pendred's syndrome), as well as in congenital isolated deafness (DFNB4). While the prevalence of SLC26A4 mutations in Pendred's syndrome is clearly established, it remains to be studied in large cohorts of patients with nonsyndromic deafness and detailed clinical informations. In this report, 109 patients from 100 unrelated families, aged from 1 to 32 years (median age: 10 years), with nonsyndromic deafness and enlarged vestibular aqueduct, were genotyped for SLC26A4 using DHPLC molecular screening and sequencing. In all, 91 allelic variants were observed in 100 unrelated families, of which 19 have never been reported. The prevalence of SLC26A4 mutations was 40% (40/100), with biallelic mutation in 24% (24/100), while six families were homozygous. All patients included in this series had documented deafness, associated with EVA and without any evidence of syndromic disease. Among patients with SLC26A4 biallelic mutations, deafness was more severe, fluctuated more than in patients with no mutation. In conclusion, the incidence of SLC26A4 mutations is high in patients with isolated deafness and enlarged vestibular aqueduct and could represent up to 4% of nonsyndromic hearing impairment. SLC26A4 could be the second most frequent gene implicated in nonsyndromic deafness after GJB2, in this Caucasian population.

Ten-year outcome of newborn hearing screening in Austria

Current health care standards recommend that congenital hearing loss be confirmed before age three months and intervened for before age six months. This study evaluated to what extent the Austrian universal neonatal hearing screening (UNHS) program achieves this goal. The Austrian UNHS program is a hospital-based, two-stage screen based on transient oto-acoustic emissions, as promoted in 1995 in a position paper of the Austrian ENT Society. Retrospective chart review and data analysis. All Austrian institutions engaged in the diagnosis and treatment of childhood hearing loss were requested to provide their data on children with permanent congenital sensorineural hearing impairment registered since 1990. Children who had undergone hearing screening, were compared to those who had not. Main outcome measures were age at confirmation of and age at intervention for the hearing loss. In each group, the percentage of children, whose hearing loss was confirmed by age three months, and intervened for by age six months, was determined. Data from 321 hearing-impaired children were useable. Of these children, 167 were screened and 154 were not. At age three months, a hearing loss was diagnosed in 35% of screened children, but in only 2% of unscreened. These percentages rose to 69% and 6%, respectively, at age six months and to 81% and 12%, respectively, at age one year. Intervention mostly started within less than one month after diagnosis. At age six months, 61% of screened children, but only 4% of unscreened children, had undergone intervention. Hearing screening enormously increases the number of early-detected children. However, in quite a few screened children hearing loss is neither confirmed within three months after birth, nor intervened for within six months after birth. Reasons for the delay must be paid attention in order to warrant that UNHS can be as effective as possible.

Cx26 deafness: mutation analysis and clinical variability

Mutations in the gap junction protein connexin 26 (Cx26) gene (GJB2) seem to account for many cases of congenital sensorineural hearing impairment, the reported prevalence being 34-50% in autosomal recessive...

Late diagnosis of congenital sensorineural hearing impairment: why are detection methods failing?

This study was designed to look in detail at the paths to diagnosis for a group of 197 children with congenital sensorineural hearing impairment (SNHI), who were diagnosed between 1989 and 1991 in the state of Victoria, Australia. Despite the existence of universal infant screening at 7-9 months by distraction test or questionnaire, the median age at diagnosis for the study group was 18.0 months, with median age at aid fitting of 20.8 months, and median age at commencement of specialised intervention programmes of 22.3 months. Parent questionnaires completed for 143 (73%) of these children showed that 49% had known risk factors for hearing loss yet only 20% of them had been referred for audiological assessment before the 7-9 month screen. Only 63% of those eligible for the 7-9 month screen had received it. Of those children who were screened by distraction test 46% passed as did 57% of those screened by questionnaire. Twenty four parents (17%) described how they had initially 'denied' their own observations of their infants' abnormal hearing behaviour. When concerns were raised with professionals, 10% of parents were falsely reassured without audiological assessment. Detection methods are failing through a combination of poor screen test efficacy, incomplete population coverage, and parental and professional denial.

Importance of an Eye Examination in Identifying the Cause of Congenital Hearing Impairment

The medical records of 84 children with severe-to-profound bilateral congenital sensorineural hearing loss were reviewed. Records of an eye examination were available for 64 children. In 5 patients (8% of those examined), an eye examination confirmed a previously suspected cause of deafness, and in another 5 children (8%), a diagnosis that had not been suspected was made. Congenital syndromes caused by environmental or hereditary factors, which involve sensorineural hearing impairment and abnormal eye findings, are reviewed. The importance of an eye examination for all children with congenital sensorineural hearing impairment is stressed.