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Purpose: Structural variants (SVs) play an important role in inherited retinal diseases (IRD). Although the identification of SVs significantly improved upon the availability of genome sequencing, it is expected that involvement of SVs in IRDs is higher than anticipated. We revisited short-read genome sequencing data to enhance the identification of gene-disruptive SVs. Methods: Optical genome mapping was performed to improve SV detection in short-read genome sequencing−negative cases. In addition, reanalysis of short-read genome sequencing data was performed to improve the interpretation of SVs and to re-establish SV prioritization criteria. Results: In a monoallelic USH2A case, optical genome mapping identified a pericentric inversion (173 megabase), with 1 breakpoint disrupting USH2A. Retrospectively, the variant could be observed in genome sequencing data but was previously deemed false positive. Reanalysis of short-read genome sequencing data (427 IRD cases) was performed which yielded 30 pathogenic SVs affecting, among other genes, USH2A (n = 15), PRPF31 (n = 3), and EYS (n = 2). Eight of these (>25%) were overlooked during previous analyses. Conclusion: Critical evaluation of our findings allowed us to re-establish and improve our SV prioritization and interpretation guidelines, which will prevent missing pathogenic events in future analyses. Our data suggest that more attention should be paid to SV interpretation and the current contribution of SVs in IRDs is still underestimated., Genetics in Medicine, 25 (3)

Objective To evaluate the long-term ipsi- and contralateral hearing of patients with a unilateral enlarged vestibular aqueduct (EVA). Study design Multicenter retrospective cohort study. Setting Three tertiary otology and audiology referral centers. Patients and diagnostic interventions A total of 34 children with a unilateral enlarged vestibular aqueduct as identified on CT and/or MR imaging were evaluated with pure tone and speech perception audiometry. Mean outcome measures Radiologic measurements of the vestibular aqueduct, ipsi- and contralateral hearing loss, ipsi- and contralateral hearing loss progression over time and DNA test results. Results All patients in this cohort with unilateral EVA presented with hearing loss. Hearing loss was progressive in 38% of the ipsilateral ears. In 29% of the children, hearing loss was also found in the contralateral ear without EVA. In 90%, the contralateral hearing was stable, with a mean follow up of 4.2 years. We found a significant correlation between the severity of the hearing loss and the size of the EVA. A genetic diagnosis associated with EVA and/or SNHL was found in only 7%. Conclusion About a third of the children with unilateral EVA are at risk of developing hearing loss in the contralateral ear. This indicates that at least in some patients with a unilateral EVA, a bilateral pathogenic process underlies the hearing loss, in contrary to what the imaging results suggest. These findings are important for counseling of EVA patients and their parents and have implications for follow up.

Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype–phenotype correlation, a significant part of cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, we first determined the presence of the previously described EVA-associated haplotype (Caucasian EVA (CEVA)), characterized by 12 single nucleotide variants located upstream of SLC26A4. We found this haplotype and a delimited V1-CEVA haplotype to be significantly enriched in our M1 patient cohort (10/16 cases). The CEVA haplotype was also present in two M0 cases (2/12). Short- and long-read whole genome sequencing and optical genome mapping could not prioritize any of the variants present within the CEVA haplotype as the likely pathogenic defect. Short-read whole-genome sequencing of the six M1 cases without this haplotype and the two M0/CEVA cases only revealed previously overlooked or misinterpreted splice-altering SLC26A4 variants in two cases, who are now genetically explained. No deep-intronic or structural variants were identified in any of the M1 subjects. With this study, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases. For pinpointing the pathogenic effect of the CEVA haplotype, additional analyses are required addressing defect(s) at the RNA, protein, or epigenetic level.

Mutations in USH2A are among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). The two most recurrent mutations in USH2A, c.2299delG and c.2276G > T, both reside in exon 13. Skipping exon 13 from the USH2A transcript presents a potential treatment modality in which the resulting transcript is predicted to encode a slightly shortened usherin protein. Morpholino-induced skipping of ush2a exon 13 in zebrafish ush2(armc1) mutants resulted in the production of usherin Delta exon 13 protein and a completely restored retinal function. Antisense oligonucleotides were investigated for their potential to selectively induce human USH2A exon 13 skipping. Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an Usher syndrome patient homozygous for the c.2299delG mutation. Mouse surrogate mQR-421a reached the retinal outer nuclear layer after a single intravitreal injection and induced a detectable level of exon skipping until at least 6 months post-injection. In conclusion, QR-421a-induced exon skipping proves to be a highly promising treatment option for RP caused by mutations in USH2A exon 13.

Pathogenic variants in SLC26A4 have been associated with autosomal recessive hearing loss (arHL) and a unilateral or bilateral enlarged vestibular aqueduct (EVA). SLC26A4 is the second most frequently mutated gene in arHL. Despite the strong genotype-phenotype correlation, a significant part of SLC26A4 cases remains genetically unresolved. In this study, we investigated a cohort of 28 Dutch index cases diagnosed with HL in combination with an EVA but without (M0) or with a single (M1) pathogenic variant in SLC26A4. To explore the missing heritability, short- and long-read whole genome sequencing and optical genome mapping were performed. We found a previously described EVA-associated haplotype (Caucasian EVA (CEVA)) to be significantly enriched in our M1 patient cohort. The haplotype was also present in two M0 cases. Despite extensive genetic analyses, we were not able to prioritize any of the variants present within the haplotype as the likely pathogenic defect, and therefore additional analyses addressing the defect(s) at the RNA, protein, or epigenetic level are required. Whole genome sequencing also revealed splice-altering SLC26A4 variants in two M1 cases, which are now genetically explained, but no deep-intronic or copy number variants. With these findings, we have provided important insights that will pave the way for elucidating the missing heritability in M0 and M1 SLC26A4 cases.

A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.

Background: Advances in gene therapeutic approaches to treat sensorineural hearing loss (SNHL) confront us with future challenges of translating these animal studies into clinical trials. Little is known on patient attitudes towards future innovative therapies. Objective: We aimed to better understand the willingness of patients with progressive SNHL and vestibular function loss of autosomal dominant (AD) inheritance to participate in potential gene therapy trials to prevent, stabilize, or slow down hearing loss. Methods: A survey was performed in carriers of the P51S and G88E pathogenic variant in the COCH gene (DFNA9). Various hypothetical scenarios were presented while using a Likert scale. Results: Fifty three participants were included, incl. 49 symptomatic patients, one presymptomatic patient, and three participants at risk. Their attitude towards potential trials studying innovative therapies was overall affirmative, even if the treatment would only slow down the decline of hearing and vestibular function, rather than cure the disease. Among the different potential scenarios, the less invasive and less frequent treatments increased the likelihood to enroll. Daily oral medication and annual intravenous infusion were awarded the highest scores. The more invasive, more frequent, and more at-risk treatments were still likely to be accepted but decreased the willingness to participate. The presence of a placebo arm was met with the lowest scores of willingness to participate. Conclusions: Overall, most symptomatic DFNA9 patients would likely consider participation in future innovative inner ear therapy trials, even if it would only slow down the decline of hearing and vestibular function.

Supplemental Digital Content is available in the text., Introduction: DFNA9 is characterized by adult-onset progressive sensorineural hearing loss (SNHL) and vestibular impairment. More than 15 years ago, genotype-phenotype correlation studies estimated the initial age of hearing deterioration in the fourth to fifth decade (ranging from 32 to 43 years). However, these analyses were based on relatively limited numbers of mainly symptomatic carriers using markedly different methodologies. The starting point for the hearing deterioration is more correctly determined with larger numbers of carriers and with a more clearly defined starting point of the hearing deterioration. Aim: The aim of this study was to determine milestone ages (start and maximal hearing deterioration, potential eligibility for hearing aids and cochlear implants based on pure-tone average [PTA]) in a large series of p.Pro51Ser COCH variant carriers. The degree of individual interaural asymmetry and the degree of variability (interquartile range) with which the hearing deterioration progresses across ages were also studied, and age-related typical audiograms (ARTA) were constructed. Material and methods: One hundred eleven Belgian and Dutch p.P51S variant carriers were identified and recruited for audiological investigation. Their hearing thresholds were compared with p50th, p95th, and p97.5th percentile values of presbyacusis (ISO 7029 standards). The onset and degree of hearing deterioration were defined and assessed for each frequency and with three PTAs (PTA0.5–4 [0.5, 1, 2, and 4 kHz]; PTA4–8 [4 and 8 kHz]; and PTA6–8 [6 and 8 kHz]). The milestones ages were derived from nonlinear regression model of hearing thresholds against age, for male and female carriers separately, because of different age-referenced limits. Interaural right-left asymmetry was assessed, and variability of hearing thresholds were calculated using interquartile range. ARTAs were built with both observed data and a prediction model. Results: Hearing dysfunction in p.P51S carriers begins at about 38 years of age (ranging from 28 to 43 years) on average in female and 46 years (ranging from 42 to 49 years) in male carriers (third decade: female, fifth decade: male carriers), depending on the hearing frequency and with differences in deterioration sequence between both genders. These differences, however, were mainly due to more stringent age-referenced limits for men. In contrast, predictions (ARTA) did not show any difference of phenotypic expression between genders. At about 48 to 50 years of age on average, the majority of DFNA9 patients may need conventional hearing aids (PTA ≥ 40 dB HL), whereas this is about 56 to 59 years for cochlear implants (PTA ≥ 70 dB HL). There is a high degree of individual interaural asymmetry and interindividual variability throughout all ages. Conclusion: This study demonstrates that the onset of sensorineural hearing deterioration starts in the third decade and probably even earlier. Regardless of differences in estimates, DFNA9 expresses similarly in male and female carriers, but male carriers are much more difficult to identify in early stages of the disease. Comprehensive assessment of the natural course of DFNA9 is of particular interest to predict the age of onset or critical period of most significant function deterioration in individual carriers of the pathogenic variant. This will help to design studies in the search for disease-modifying therapies.

The c.151C>T founder mutation in COCH is a frequent cause of late-onset, dominantly inherited hearing impairment and vestibular dysfunction (DFNA9) in the Dutch/Belgian population. The initial clinical symptoms only manifest between the 3rd and 5th decade of life, which leaves ample time for therapeutic intervention. The dominant inheritance pattern and established non-haploinsufficiency disease mechanism indicate that suppressing translation of mutant COCH transcripts has high therapeutic potential. Single-molecule real-time (SMRT) sequencing resulted in the identification of 11 variants with a low population frequency (T mutant COCH allele. Proof of concept was obtained that gapmer antisense oligonucleotides (AONs), directed against the c.151C>T mutation or mutant allele-specific intronic variants, are able to induce mutant COCH transcript degradation when delivered to transgenic cells expressing COCH minigenes. The most potent AON, directed against the c.151C>T mutation, was able to induce a 60% decrease in mutant COCH transcripts without affecting wild-type COCH transcript levels. Allele specificity decreased when increasing concentrations of AON were delivered to the cells. With the proven safety of AONs in humans, and rapid advancements in inner ear drug delivery, our in vitro studies indicate that AONs offer a promising treatment modality for DFNA9., Graphical abstract, The c.151C>T founder mutation in COCH is a frequent cause of late-onset, dominantly inherited hearing impairment and vestibular dysfunction (DFNA9). We designed and in vitro validated gapmer AONs that are able to target the mutant COCH transcript for degradation. Our results describe the first step toward an AON-based treatment for DFNA9.

In mammals, sound is detected by mechanosensory hair cells that are activated in response to vibrations at frequency-dependent positions along the cochlear duct. We demonstrate that inner ear supporting cells provide a structural framework for transmitting sound energy through the cochlear partition. Humans and mice with mutations in GAS2, encoding a cytoskeletal regulatory protein, exhibit hearing loss due to disorganization and destabilization of microtubule bundles in pillar and Deiters' cells, two types of inner ear supporting cells with unique cytoskeletal specializations. Failure to maintain microtubule bundle integrity reduced supporting cell stiffness, which in turn altered cochlear micromechanics in Gas2 mutants. Vibratory responses to sound were measured in cochleae from live mice, revealing defects in the propagation and amplification of the traveling wave in Gas2 mutants. We propose that the microtubule bundling activity of GAS2 imparts supporting cells with mechanical properties for transmitting sound energy through the cochlea.

Supplemental Digital Content is available in the text., Introduction: DFNA9 is characterized by adult-onset hearing loss and evolution toward bilateral vestibulopathy (BVP). The genotype-phenotype correlation studies were conducted 15 years ago. However, their conclusions were mainly based on symptomatic carriers and the vestibular data exclusively derived from the horizontal (lateral) semicircular canal (SCC). The last decade was marked by the emergence of new clinical diagnostic tools, such as the video head impulse test (vHIT) and vestibular-evoked myogenic evoked potentials (VEMPs), expanding our evaluation to all six SCCs and the otolith organs (saccule and utricule). Aim: The aim of this study was to comprehensively evaluate vestibular function in the largest series presymptomatic as well as symptomatic p.P51S variant carriers, to determine which labyrinthine part shows the first signs of deterioration and which SCC function declines at first and to determine the age at which p.P51S variant carriers develop caloric areflexia on VNG and vHIT vestibulo-ocular reflex (VOR)-gain dysfunction as defined by the Barany Society criteria for BVP. Material and methods: One hundred eleven p.P51S variant carriers were included. The following vestibular function tests were applied in two different centers: ENG/VNG, vHIT, and VEMPs. The following parameters were analyzed: age (years), hearing loss (pure-tone average of 0.5–4 kHz [PTA0.5–4, dB HL]), sum of maximal peak slow-phase eye velocity obtained with bi-thermal (30°C and 44°C, water irrigation; 25°C and 44°C, air irrigation) caloric test (°/s), vHIT VOR-gain on LSCC, superior SCC and posterior SCC, C-VEMP both numerical (threshold, dB nHL) and categorical (present or absent), and O-VEMP as categorical (present or absent). The age of onset of vestibular dysfunction was determined both with categorical (onset in decades using Box & Whisker plots) and numeric approach (onset in years using regression analysis). The same method was applied for determining the age at which vestibular function declined beyond the limits of BVP, as defined by the Barany Society. Results: With the categorical approach, otolith function was declining first (3rd decade), followed by caloric response (5th decade) and vHIT VOR-gains (5th–6th decade). Estimated age of onset showed that the deterioration began with C-VEMP activity (31 years), followed by caloric responses (water irrigation) (35 years) and ended with vHIT VOR-gains (48–57 years). Hearing deterioration started earlier than vestibular deterioration in female carriers, which is different from earlier reports. BVP was predicted at about 53 years of age on average with VNG caloric gain (water irrigation) and between 47 and 57 years of age for the three SCCs. Loss of C-VEMP response was estimated at about 46 years of age. Conclusion: Former hypothesis of vestibular decline preceding hearing deterioration by 9 years was confirmed by the numeric approach, but this was less obvious with the categorical approach. Wide confidence intervals of the regression models may explain deviation of the fits from true relationship. There is a typical vestibular deterioration hierarchy in p.P51S variant carriers. To further refine the present findings, a prospective longitudinal study of the auditory and vestibular phenotype may help to get even better insights in this matter.

Contains fulltext : 231650.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To study the genotype and phenotype of a Dutch family with autosomal dominantly inherited hearing loss. STUDY DESIGN: Genotype-phenotype correlation study. Genetic analysis consisted of linkage analysis, variable number of tandem repeats analysis, and Sanger sequencing. Audiovestibular function was examined. Regression analysis was performed on pure tone audiometry and speech recognition scores and correlated with the age and/or level of hearing loss. SETTING: Tertiary referral center. PATIENTS: A large Dutch family presenting with sensorineural hearing loss. MAIN OUTCOME MEASURES: Identification of the underlying genetic defect of the hearing loss in this family. Results of pure tone and speech audiometry, onset age, progression of hearing loss and vestibular (dys)function. RESULTS: A novel mutation in COCH, c.1312C > T p.(Arg438Cys), cosegregates with hearing loss and a variable degree of vestibular (dys)function in this family. The reported mean age of onset of hearing loss is 33 years (range, 18-49 yr). Hearing loss primarily affects higher frequencies and its progression is relatively mild (0.8 dB/yr). Speech perception is remarkably well preserved in affected family members when compared with other DFNA9 families with different COCH mutations. CONCLUSION: These findings expand the genotypic and phenotypic spectrum of DFNA9. The c.1312C > T mutation, which affects the vWFA2 domain, causes a relatively mild audiovestibular phenotype when compared with other COCH mutations.

Contains fulltext : 229881.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To assess the effect of cochlear implantation on the function of the semicircular canals (SCC) and on experienced vestibular symptoms. Second, to determine the relation between vestibular test results. DESIGN: Retrospective cohort study assessing absolute and categorised results of caloric irrigation test, video Head Impulse Test (vHIT) and Dizziness Handicap Inventory (DHI) before and after cochlear implantation.Study sample: 192 patients, aged ≥7 years old, without preoperative areflexia. RESULTS: Mean maximum slow phase velocity decreased with 3.1°/s and 4.7°/s for warm and cold caloric irrigation respectively. About 37.4% of the patients deteriorated one or more categories on caloric testing. Complete caloric postoperative areflexia was found in 6.2%. Mean vHIT gain decreased with 0.06, 0.04 and 0.05 for anterior, lateral and posterior SCC, respectively. Seven patients (7.7%) acquired an abnormal gain value for the anterior SCC. Only mean score on DHI's physical subdomain rose significantly (1.4 points). Overall, 9.0% of the patients deteriorated one or two categories on DHI. Only few weak correlations were found between caloric test, vHIT and DHI shifts. CONCLUSIONS: Although mean objective and subjective-physical vestibular deteriorations were significant, its clinical impact seems limited. However, 9% of patients experience vestibular deterioration, thus, advocate assessment. Vestibular test results show no or merely weak mutual correlations.

Contains fulltext : 169850.pdf (Publisher’s version ) (Closed access) Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

Item does not contain fulltext OBJECTIVES: Usher syndrome type IIa (USH2a) is characterized by congenital moderate to severe hearing impairment and retinitis pigmentosa. Hearing rehabilitation starts in early childhood with the application of hearing aids. In some patients with USH2a, severe progression of hearing impairment leads to insufficient speech intelligibility with hearing aids and issues with adequate communication and safety. Cochlear implantation (CI) is the next step in rehabilitation of such patients. This study evaluates the performance and benefit of CI in patients with USH2a. DESIGN: Retrospective case-control study to evaluate the performance and benefit of CI in 16 postlingually deaf adults (eight patients with USH2a and eight matched controls). Performance and benefit were evaluated by a speech intelligibility test and three quality-of-life questionnaires. RESULTS: Patients with USH2a with a mean age of 59 years at implantation exhibited good performance after CI. The phoneme scores improved significantly from 41 to 87% in patients with USH2a (p = 0.02) and from 30 to 86% in the control group (p = 0.001). The results of the questionnaire survey demonstrated a clear benefit from CI. There were no differences in performance or benefit between patients with USH2a and control patients before and after CI. CONCLUSIONS: CI increases speech intelligibility and improves quality of life in patients with USH2a.

Objectives Usher syndrome is the leading cause of hereditary deaf-blindness. Most patients with Usher syndrome type IIa start using hearing aids from a young age. A serious complaint refers to interference between sound localisation abilities and adaptive sound processing (compression), as present in today's hearing aids. The aim of this study was to investigate the effect of advanced signal processing on binaural hearing, including sound localisation. Design and participants In this prospective study, patients were fitted with hearing aids with a nonlinear (compression) and linear amplification programs. Data logging was used to objectively evaluate the use of either program. Performance was evaluated with a speech-in-noise test, a sound localisation test and two questionnaires focussing on self-reported benefit. Results Data logging confirmed that the reported use of hearing aids was high. The linear program was used significantly more often (average use: 77%) than the nonlinear program (average use: 17%). The results for speech intelligibility in noise and sound localisation did not show a significant difference between type of amplification. However, the self-reported outcomes showed higher scores on ‘ease of communication’ and overall benefit, and significant lower scores on disability for the new hearing aids when compared to their previous hearing aids with compression amplification. Conclusions Patients with Usher syndrome type IIa prefer a linear amplification over nonlinear amplification when fitted with novel hearing aids. Apart from a significantly higher logged use, no difference in speech in noise and sound localisation was observed between linear and nonlinear amplification with the currently used tests. Further research is needed to evaluate the reasons behind the preference for the linear settings.

OBJECTIVE: To evaluate short- and long-term hearing results of surgery for acquired atresia of the external auditory canal (EAC) in a large patient cohort and to define preoperative audiometric conditions useful for patient counseling.STUDY DESIGN: Retrospective cohort study.SETTING: Academic tertiary referral center.PATIENTS: Seventy-eight ears from 72 patients with postinflammatory acquired atresia of the EAC who underwent canal- and meatoplasty were included. Patients with involvement of the ossicular chain, (syndromic) external ear malformations, or congenital aural atresia were excluded.INTERVENTION: Canal- and meatoplasty.MAIN OUTCOME MEASURES: Mean pure-tone averages of thresholds at 0.5, 1, 2, and 3 kHz (PTA0.5,1,2,3) for air conduction (AC), bone conduction, and air-bone gap (ABG) were calculated preoperatively and at short-term (≤0.55 yr) and long-term follow-up (>0.55 yr). Additionally, the numbers of ears with a closed ABG ≤10 dB and ≤20 dB, and with Social hearing (defined as: AC PTA0.5,1,2,3 ≤35 dB) were assessed.RESULTS: At short-term follow-up AC PTA0.5,1,2,3 improved by 18 dB. Social hearing was obtained in 81% of the ears. Postoperatively, 35% of the ears had a closed ABG ≤10 dB, 83% was closed ≤20 dB. During follow-up, significant deterioration of 5 to 7 dB occurred for AC thresholds at 0.25, 0.5, and 1 kHz.CONCLUSIONS: Surgery for acquired atresia of the EAC is often beneficial. This study suggests overall advantageous surgery when the preoperative indication criteria ABG PTA0.5,1,2,3 >20 dB and AC PTA0.5,1,2,3 >35 dB are applied.

Purpose To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. Methods We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. Results Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006–0.0060). Conclusion MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families. Electronic supplementary material The online version of this article (10.1007/s00439-018-1880-5) contains supplementary material, which is available to authorized users.

To analyze the results of malleostapedotomy performed by applying the self-fixing and articulated titanium piston according to Hausler. Retrospective case review. Tertiary referral center. This study concerns a retrospective analysis of the results of malleostapedotomy with the use of a self-fixing articulated titanium piston in 16 ears of 16 consecutively treated patients between 2005 and 2009. The medical files were used for the acquisition of data on medical and surgical history and to obtain pre- and postoperative audiometry. Diagnosis and outcomes of mainly revision surgeries are presented and compared to the literature. Effect of (revision) malleostapedotomy by evaluating postoperative audiometry and air–bone gap closure. The postoperative air–bone gap closure was ≤ 10 dB in 9/16 (56%) ears and within ≤ 20 dB in 13/16 (81%) ears. The mean postoperative air–bone gap was 14.3 dB HL (0.5–2.0 kHz) and 17.3 dB HL (0.5–4.0 kHz). Postoperatively, there was no increase in bone conduction thresholds larger than 3 dB (0.5–2.0 kHz) and postoperative dizziness was absent or very limited and transient. The malleostapedotomy procedure has become surgically less demanding over time by the technical improvements present in the nowadays available pistons. The design of the self-fixing and articulated titanium piston used in the present group of patients allows a safe and straight-forward malleostapedotomy procedure. Present hearing outcomes match with results presented in the literature.

This study focuses on further characterization of the audiovestibular phenotype and on genotype-phenotype correlations of DFNB77, an autosomal recessive type of hearing impairment (HI). DFNB77 is associated with disease-causing variants in LOXHD1, and is genetically and phenotypically highly heterogeneous. Heterozygous deleterious missense variants in LOXHD1 have been associated with late-onset Fuchs corneal dystrophy (FCD). However, up to now screening for FCD of heterozygous carriers in DFNB77 families has not been reported. This study describes the genotype and audiovestibular phenotype of 9 families with DFNB77. In addition, carriers within the families were screened for FCD. Fifteen pathogenic missense and truncating variants were identified, of which 12 were novel. The hearing phenotype showed high inter- and intrafamilial variation in severity and progression. There was no evidence for involvement of the vestibular system. None of the carriers showed (pre-clinical) symptoms of FCD. Our findings expand the genotypic and phenotypic spectrum of DFNB77, but a clear correlation between the type or location of the variant and the severity or progression of HI could not be established. We hypothesize that environmental factors or genetic modifiers are responsible for phenotypic differences. No association was found between heterozygous LOXHD1 variants and the occurrence of FCD in carriers.

Objective Genetic testing for hereditary hearing impairment has become more routinely available as a diagnostic tool in the outpatient clinic. However, little is known about the psychological impact of a genetic diagnosis. To evaluate this impact, an exploratory study was conducted. Design Prospectively, 48 individuals who underwent genetic testing for hereditary hearing impairment were included in this study. Study participants were asked to fill out the following questionnaires: Hospital Anxiety Depression Scale, Impact of Event Scale, Self-Efficacy 24, Illness Cognition Questionnaire and the Inventory for Social Reliance. Questionnaires were filled out on three occasions: before genetic testing, directly after counselling on either positive or negative test results, and six weeks thereafter. Results No significant differences were found between the group that received a genetic diagnosis for their hearing impairment and the group that did not. Conclusion This study did not demonstrate differences between receiving a genetic diagnosis or not, however, special attention to psychological well-being should be offered to hearing-impaired patients who seek a genetic diagnosis for their hearing impairment. Additionally, the psychological impact of sensorineural hearing impairment might be greater than the impact of a genetic diagnosis itself. Based on the current exploratory study, there are no psychological reasons in favour of or against genetic testing for hereditary hearing impairment. This article is protected by copyright. All rights reserved.

DOOFNL Consortium., In a Dutch consanguineous family with recessively inherited nonsyndromic hearing impairment (HI), homozygosity mapping combined with whole-exome sequencing revealed a MPZL2 homozygous truncating variant, c.72del (p.Ile24Metfs∗22). By screening a cohort of phenotype-matched subjects and a cohort of HI subjects in whom WES had been performed previously, we identified two additional families with biallelic truncating variants of MPZL2. Affected individuals demonstrated symmetric, progressive, mild to moderate sensorineural HI. Onset of HI was in the first decade, and high-frequency hearing was more severely affected. There was no vestibular involvement. MPZL2 encodes myelin protein zero-like 2, an adhesion molecule that mediates epithelial cell-cell interactions in several (developing) tissues. Involvement of MPZL2 in hearing was confirmed by audiometric evaluation of Mpzl2-mutant mice. These displayed early-onset progressive sensorineural HI that was more pronounced in the high frequencies. Histological analysis of adult mutant mice demonstrated an altered organization of outer hair cells and supporting cells and degeneration of the organ of Corti. In addition, we observed mild degeneration of spiral ganglion neurons, and this degeneration was most pronounced at the cochlear base. Although MPZL2 is known to function in cell adhesion in several tissues, no phenotypes other than HI were found to be associated with MPZL2 defects. This indicates that MPZL2 has a unique function in the inner ear. The present study suggests that deleterious variants of Mplz2/MPZL2 affect adhesion of the inner-ear epithelium and result in loss of structural integrity of the organ of Corti and progressive degeneration of hair cells, supporting cells, and spiral ganglion neurons., This work was supported by a grant from the Heinsius Houbolt Foundation (to H.K., R.J.E.P., and H.P.M.K.) and partially by grants from the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (Fonds Europeen de Developpement Economique et Regional, [FEDER]: SAF2014-53979-R) and from FEDER, CIBERER, and Instituto de Salud Carlos III (ISCIII) (to I.V.N.), and a grant from ISCIII to I.d.C. (PI14/01162; Plan Estatal de IþDþI 2013-2016, with co-funding from the European Regional Development Fund). S.M., A.M.C., and E.G.R. hold CIBERER ISCIII researcher contracts.

Hearing implant technology is evolving at a rapid rate and more than ever patients with hearing loss are benefiting from these emerging hearing devices. Active middle ear implants are alternatives to hearing aids and bone conducting devices, offering patients an expanded range in improving their hearing. This chapter looks at the devices currently available, their indications and the literature regarding their outcomes.

DFNA9 is a rare progressive autosomal dominantly inherited vestibulo-cochlear disorder, resulting in a homogeneous group of patients with hearing impairment and bilateral vestibular function loss. These patients suffer from a deteriorated sense of spatial orientation, leading to balance problems in darkness, especially on irregular surfaces. Both behavioral and functional imaging studies suggest that the remaining sensory cues could compensate for the loss of vestibular information. A thorough model-based quantification of this reweighting in individual patients is, however, missing. Here we psychometrically examined the individual patient’s sensory reweighting of these cues after complete vestibular loss. We asked a group of DFNA9 patients and healthy control subjects to judge the orientation (clockwise or counterclockwise relative to gravity) of a rod presented within an oriented square frame (rod-in-frame task) in three different head-on-body tilt conditions. Our results show a cyclical frame-induced bias in perceived gravity direction across a 90° range of frame orientations. The magnitude of this bias was significantly increased in the patients compared with the healthy control subjects. Response variability, which increased with head-on-body tilt, was also larger for the patients. Reverse engineering of the underlying signal properties, using Bayesian inference principles, suggests a reweighting of sensory signals, with an increase in visual weight of 20–40% in the patients. Our approach of combining psychophysics and Bayesian reverse engineering is the first to quantify the weights associated with the different sensory modalities at an individual patient level, which could make it possible to develop personal rehabilitation programs based on the patient’s sensory weight distribution.NEW & NOTEWORTHY It has been suggested that patients with vestibular deficits can compensate for this loss by increasing reliance on other sensory cues, although an actual quantification of this reweighting is lacking. We combine experimental psychophysics with a reverse engineering approach based on Bayesian inference principles to quantify sensory reweighting in individual vestibular patients. We discuss the suitability of this approach for developing personal rehabilitation programs based on the patient’s sensory weight distribution.

A recent systematic review of treatments of Eustachian tube dysfunction commissioned by the UK NIHR Health Technology Assessment (HTA) Programme revealed that an important limitation with the available evidence is a lack of consensus on the definition and diagnosis of this disorder.1 The HTA report recommended that key to advancing research in this field is achieving consensus on diagnostic criteria for Eustachian tube dysfunction (to identify eligible patients for future trials) and on important clinical outcomes. To address this need, an international forum of scientists and physicians with expertise in the field of Eustachian tube disorders met at a workshop in Amsterdam on 21 June 2014 and was tasked to come to an agreement on the definition, clinical presentation and diagnosis of Eustachian tube dysfunction, and areas for future research. This study summarises the outcomes of that meeting.

Contains fulltext : 153746.pdf (Publisher’s version ) (Closed access) In a consanguineous Turkish family diagnosed with autosomal recessive nonsyndromic hearing impairment (arNSHI), a homozygous region of 47.4 Mb was shared by the two affected siblings on chromosome 6p21.1-q15. This region contains 247 genes including the known deafness gene MYO6. No pathogenic variants were found in MYO6, neither with sequence analysis of the coding region and splice sites nor with mRNA analysis. Subsequent candidate gene evaluation revealed CLIC5 as an excellent candidate gene. The orthologous mouse gene is mutated in the jitterbug mutant that exhibits progressive hearing impairment and vestibular dysfunction. Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T>A (p.(Cys32Ter)) that segregated with the hearing loss. Further analysis of CLIC5 in 213 arNSHI patients from mostly Dutch and Spanish origin did not reveal any additional pathogenic variants. CLIC5 mutations are thus not a common cause of arNSHI in these populations. The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade. Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction. Although we demonstrate that CLIC5 is expressed in many other human tissues, no additional symptoms were observed in these patients. In conclusion, our results show that CLIC5 is a novel arNSHI gene involved in progressive hearing impairment, vestibular and possibly mild renal dysfunction in a family of Turkish origin.

The objective of this study was to achieve uniform reporting of complications and failures in cochlear implantation, to analyze complications and failures and to identify risk factors for complications in a series of over 1300 cochlear implantations. In a retrospective chart review and observational study, data from all cochlear implantations from 1987 to 2015 were entered in a custom-made database. Complications were classified using the contracted form of the Clavien–Dindo system and risk factors were identified by statistical analysis. A complication rate of 18.4% and a device failure rate of 2.9% were found. There was a higher rate of hematoma in patients with a clotting disorder and when a subtotal petrosectomy was performed, a higher rate of wound infections in patients who were not vaccinated against Streptococcus pneumoniae and a higher rate of meningitis in patients with an inner ear malformation. The use of a strict definition of a medical complication and device failure—in combination with the Clavien–Dindo classification system—enables uniform and objective registration of adverse events and prevents any tendency to downgrade complications. Complication and failure rates in this series are comparable to those reported in the literature. These results stress the need for pneumococcal vaccination, which may prevent general wound infections, but is especially important for patients with inner ear malformation, who have an increased risk of (postoperative) meningitis.

Contains fulltext : 174528.pdf (Publisher’s version ) (Closed access) DFNB28 is characterized by prelingual, severe to profound sensorineural hearing impairment (HI). It is associated with mutations in exon 6 and 7 of TRIOBP and has not been reported in the European population. Here, we describe two isolated cases of Dutch origin with congenital, moderate HI and compound heterozygous mutations in TRIOBP. Three of the mutations are novel, one nonsense mutation (c.5014G>T (p.Gly1672*)) and two frameshift mutations (c.2653del (p.Arg885Alafs*120) and c.3460_3461del (p.Leu1154Alafs*29)). The fourth mutation is the known c.3232dup (p.Arg1078Profs*6) mutation. Longitudinal audiometric analyses in one of the subjects revealed that HI was stable over a period of 15 years. Vestibular function was normal. Predicted effects of the mutations do not explain the relatively mild phenotype in the presented subjects, whereas location of the mutation might well contribute to the milder HI in one of the subjects. It is known that isoform classes TRIOBP-4 and TRIOBP-5 are important for stereocilia stability and rigidity. To our knowledge, p.Gly1672* is the first pathogenic variant identified in DFNB28 that does not affect isoform class TRIOBP-4. This suggests that a single TRIOBP copy to encode wildtype TRIOBP-4 is insufficient for normal hearing, and that at least one TRIOBP copy to encode TRIOBP-5 is indispensable for normal inner ear function. Furthermore, this study demonstrates that DFNB28 can be milder than reported so far and that mutations in TRIOBP are thus associated with a heterogeneous phenotype.

We present the case of a Dutch family with a new mutation (c523_528dup) in GATA3 causing HDR syndrome. HDR syndrome is characterised by hypoparathyroidism, deafness and renal defects. In this study, we describe the audiometric characteristics of 5 patients from this family. Their hearing impairment was congenital, bilateral and symmetric. Audiograms showed mild-to-moderate hearing impairment with a flat audiogram configuration. Higher frequencies tended to be affected more strongly. Cross-sectional analyses showed no progression, and a mean audiogram was established. Psychophysical measurements in 3 HDR patients - including speech reception in noise, loudness scaling, gap detection and difference limen for frequency - were obtained to assess hearing function in greater detail. Overall, the results of the psychophysical measurements indicated characteristics of outer hair cell loss. CT scanning showed no anomalies in 3 of the HDR patients. Although 2 patients displayed vestibular symptoms, no anomalies in the vestibular system were found by vestibulo-ocular examination. Our results are in agreement with the theory that outer hair cell malfunctioning can play a major role in HDR syndrome.

Contains fulltext : 136916.pdf (Publisher’s version ) (Open Access) The olfactory bulb (OB) receives odor information from the olfactory epithelium and relays this to the olfactory cortex. Using a mouse model, we found that development and maturation of OB interneurons depends on the zinc finger homeodomain factor teashirt zinc finger family member 1 (TSHZ1). In mice lacking TSHZ1, neuroblasts exhibited a normal tangential migration to the OB; however, upon arrival to the OB, the neuroblasts were distributed aberrantly within the radial dimension, and many immature neuroblasts failed to exit the rostral migratory stream. Conditional deletion of Tshz1 in mice resulted in OB hypoplasia and severe olfactory deficits. We therefore investigated olfaction in human subjects from families with congenital aural atresia that were heterozygous for TSHZ1 loss-of-function mutations. These individuals displayed hyposmia, which is characterized by impaired odor discrimination and reduced olfactory sensitivity. Microarray analysis, in situ hybridization, and ChIP revealed that TSHZ1 bound to and regulated expression of the gene encoding prokineticin receptor 2 (PROKR2), a G protein-coupled receptor essential for OB development. Mutations in PROKR2 lead to Kallmann syndrome, characterized by anosmia and hypogonadotrophic hypogonadism. Our data indicate that TSHZ1 is a key regulator of mammalian OB development and function and controls the expression of molecules involved in human Kallmann syndrome.

Item does not contain fulltext Since deafness is the most common sensorineural disorder in humans, better understanding of the underlying causes is necessary to improve counseling and rehabilitation. A Dutch family with autosomal dominantly inherited sensorineural hearing loss was clinically and genetically assessed. The MYO6 gene was selected to be sequenced because of similarities with other, previously described DFNA22 phenotypes and a pathogenic c.3610C > T (p.R1204W) mutation was found to co-segregate with the disease. This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life. The age-related typical audiograms (ARTA) constructed for this family resemble presbyacusis. Speech audiometry and results of loudness scaling support the hypothesis that the phenotype of this specific MYO6 mutation mimics presbyacusis.

Objective: To analyse the benefit of cochlear implantation in young deaf children with Waardenburg syndrome (WS) compared to a reference group of young deaf children without additional disabilities. Method: A retrospective study was conducted on children with WS who underwent cochlear implantation at the age of 2 years or younger. The post-operative results for speech perception (phonetically balanced standard Dutch consonant-vocal-consonant word lists) and language comprehension (the Reynell Developmental Language Scales, RDLS), expressed as a language quotient (LQ), were compared between the WS group and the reference group by using multiple linear regression analysis. Results: A total of 14 children were diagnosed with WS, and 6 of them had additional disabilities. The WS children were implanted at a mean age of 1.6 years and the 48 children of the reference group at a mean age of 1.3 years. The WS children had a mean phoneme score of 80% and a mean LQ of 0.74 at 3 years post-implantation, and these results were comparable to those of the reference group. Only the factor additional disabilities had a significant negative influence on auditory perception and language comprehension. Conclusions: Children with WS performed similarly to the reference group in the present study, and these outcomes are in line with the previous literature. Although good counselling about additional disabilities concomitant to the syndrome is relevant, cochlear implantation is a good rehabilitation method for children with WS.

Contains fulltext : 168161.pdf (Publisher’s version ) (Open Access) Usher syndrome (USH) is the most common cause of combined deaf-blindness in man. The hearing loss can be partly compensated by providing patients with hearing aids or cochlear implants, but the loss of vision is currently untreatable. In general, mutations in the USH2A gene are the most frequent cause of USH explaining up to 50% of all patients worldwide. The first deep-intronic mutation in the USH2A gene (c.7595-2144A>G) was reported in 2012, leading to the insertion of a pseudoexon (PE40) into the mature USH2A transcript. When translated, this PE40-containing transcript is predicted to result in a truncated non-functional USH2A protein. In this study, we explored the potential of antisense oligonucleotides (AONs) to prevent aberrant splicing of USH2A pre-mRNA as a consequence of the c.7595-2144A>G mutation. Engineered 2'-O-methylphosphorothioate AONs targeting the PE40 splice acceptor site and/or exonic splice enhancer regions displayed significant splice correction potential in both patient derived fibroblasts and a minigene splice assay for USH2A c.7595-2144A>G, whereas a non-binding sense oligonucleotide had no effect on splicing. Altogether, AON-based splice correction could be a promising approach for the development of a future treatment for USH2A-associated retinitis pigmentosa caused by the deep-intronic c.7595-2144A>G mutation.

Contains fulltext : 167662.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Usher syndrome is an inherited disorder that is characterized by hearing impairment (HI), retinitis pigmentosa, and in some cases vestibular dysfunction. Usher syndrome type IIa is caused by mutations in USH2A. HI in these patients is highly heterogeneous and the present study evaluates the effects of different types of USH2A mutations on the audiometric phenotype. Data from two large centres of expertise on Usher Syndrome in the Netherlands and Sweden were combined in order to create a large combined sample of patients to identify possible genotype-phenotype correlations. DESIGN: A retrospective study on HI in 110 patients (65 Dutch and 45 Swedish) genetically diagnosed with Usher syndrome type IIa. We used methods especially designed for characterizing and testing differences in audiological phenotype between patient subgroups. These methods included Age Related Typical Audiograms (ARTA) and a method to evaluate the difference in the degree of HI developed throughout life between subgroups. RESULTS: Cross-sectional linear regression analysis of last-visit audiograms for the best hearing ear demonstrated a gradual decline of hearing over decades. The congenital level of HI was in the range of 16-33 dB at 0.25-0.5 kHz, and in the range of 51-60 dB at 1-8 kHz. The annual threshold deterioration was in the range of 0.4-0.5 dB/year at 0.25-2 kHz and in the range of 0.7-0.8 dB/year at 4-8 kHz. Patients with two truncating mutations, including homozygotes for the common c.2299delG mutation, developed significantly more severe HI throughout life than patients with one truncating mutation combined with one nontruncating mutation, and patients with two nontruncating mutations. CONCLUSIONS: The results have direct implications for patient counselling in terms of prognosis of hearing and may serve as baseline measures for future (genetic) therapeutic interventions.

Contains fulltext : 165635.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Non-syndromic sensorineural hearing impairment is inherited in an autosomal recessive fashion in 75-85% of cases. To date, 61 genes with this type of inheritance have been identified as related to hearing impairment, and the genetic heterogeneity is accompanied by a large variety of clinical characteristics. Adequate counselling on a patient's hearing prognosis and rehabilitation is part of the diagnosis on the genetic cause of hearing impairment and, in addition, is important for the psychological well-being of the patient. TYPE OF REVIEW: Traditional literature review. DATA SOURCE: All articles describing clinical characteristics of the audiovestibular phenotypes of identified genes and related loci have been reviewed. CONCLUSION: This review aims to serve as a summary and a reference for counselling purposes when a causative gene has been identified in a patient with a non-syndromic autosomal recessively inherited sensorineural hearing impairment.

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Item does not contain fulltext PURPOSE: 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. DESIGN: Clinic-based, longitudinal, multicenter study. PARTICIPANTS: 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. METHODS: 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. MAIN OUTCOME MEASURES: Low vision and blindness. RESULTS: 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 (6.5 years 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. CONCLUSIONS: 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 visual impairment than those without nonsyndromic RP. Complete loss of function of the USH2A protein predisposes to Usher syndrome type IIa, but remnant protein function can lead to RP with or without hearing loss.

Item does not contain fulltext OBJECTIVE: To evaluate hearing impairment and cochlear function in non-ocular Stickler syndrome. STUDY DESIGN: Multifamily study. PATIENTS & METHODS: Ten patients from two different families with non-ocular Stickler syndrome (Stickler syndrome type 3) were included. Six members of the first family and four members of the second family participated in this study. Otorhinolaryngologic examinations were performed. Pure-tone and speech audiograms were obtained. Longitudinal analysis was performed. Psychophysical measurements, including loudness scaling, gap detection, difference limen for frequency and speech perception in noise were administered to assess cochlear function at a deeper level. RESULTS: Affected individuals in the first family were carriers of a heterozygous splice donor mutation in the COL11A2 gene. Affected individuals in the second family were carriers of a novel heterozygous missense mutation in COL11A2. Both families showed bilateral, non-progressive hearing impairment with childhood onset. The severity of the hearing impairment exhibited inter- and intrafamilial variability and was mostly mild to moderate. The results of the psychophysical measurements were similar to those previously published for DFNA8/12 (TECTA) and DFNA13 (COL11A2) patients and thus consistent with an intra-cochlear conductive hearing impairment. This is in line with the theory that mutations in COL11A2 affect tectorial membrane function. CONCLUSION: Hearing impairment in non-ocular Stickler syndrome is characterized by non-progressive hearing loss, present since childhood, and mostly mild to moderate in severity. Psychophysical measurements in non-ocular Stickler patients were suggestive of intra-cochlear conductive hearing impairment. 01 september 2012

Clin. Otolaryngol. 2011, 36, 442-449 Objectives: The influence of an extended preoperative trial of bone-anchored hearing aid (BAHA) and headband on the decision to proceed with surgery in cases of unilateral sensorineural hearing loss is studied. Design: In this prospective study, the headband was introduced after assessment confirmed suitable candidacy. Those who had an initially favourable response to the headband trial were encouraged to complete a 2-week home trial of device and headband. Patients were asked to pay special attention to situations where they perceived high demands on their hearing, e.g. at the dinner table, in the car, walking outside etc. Counselling regarding the BAHA placement, the need for daily care of the implant site and the financial implications of acquiring the device was also given. Setting: Tertiary university hospital. Participants: Patients with unilateral sensorineural hearing loss, fulfilling criteria for BAHA surgery, with favourable response to initial 'office trial' of headband. Main outcome measures: After 2-week home trial, BAHA and headband were returned with a statement of the patient's intentions. Results: Sixteen of 50 (32%) patients who expressed definite interest in BAHA surgery after a positive introduction to the headband in the office did not wish to proceed to surgery having completed a more thorough 2-week trial of device at home. Most patients cited a failure of the device to meet their hearing requirements. Subsequently, we found further attrition with nine more patients (18%) deciding at a still later date, not to proceed with surgery. Ultimately, just 25 of 50 (50%) of our initially enthusiastic group chose not to proceed to surgery. In the group who did proceed, there were no non-users. Conclusions: We propose the importance of an extended preoperative trial where BAHA is considered in the rehabilitation of unilateral sensorineural hearing loss. The trial may foster more realistic expectations of device performance in this challenging group. A 'cooling-off' period before surgery also appears to lead to further attrition with the ultimate reward of no non-users in those proceeding to surgery.

Congenital aural atresia (CAA) can occur as an isolated congenital malformation or in the context of a number of monogenic and chromosomal syndromes. CAA is frequently seen in individuals with an 18q deletion, which is characterized by intellectual disability, reduced white-matter myelination, foot deformities, and distinctive facial features. Previous work has indicated that a critical region for CAA is located in 18q22.3. We studied four individuals (from two families) with CAA and other features suggestive of an 18q deletion, and we detected overlapping microdeletions in 18q22.3 in both families. The minimal region of deletion overlap (72.9-73.4 Mb) contained only one known gene, TSHZ1, which was recently shown to be important for murine middle-ear development. Sequence analysis of the coding exons in TSHZ1 in a cohort of 11 individuals with isolated, nonsyndromic bilateral CAA revealed two mutations, c.723G>A (p.Trp241X) and c.946_947delinsA (p.Pro316ThrfsX16), and both mutations predicted a loss of function. Together, these results demonstrate that hemizygosity of TSHZ1 leads to congenital aural atresia as a result of haploinsufficiency.

BACKGROUND: Intracanalicular vestibular schwannomas have a range of treatment options that can preserve hearing: microsurgery, stereotactic radiotherapy, and conservative observation. OBJECTIVE: To evaluate the natural course of hearing deterioration during a period of conservative observation. METHODS: A retrospective case review was performed on 47 patients with a unilateral intracanalicular vestibular schwannoma. Evaluation of growth was monitored by repeat MRI scanning. Repeated pure-tone and speech audiometry results were evaluated for subgroups of patients showing growth or no growth and by subsite location of tumor in the internal auditory canal. RESULTS: Patients had a mean follow-up of 3.6 years. Over the entire population, the pure-tone average thresholds at 0.5, 1, 2, and 3 kHz and the word recognition scores both significantly deteriorated from 38 to 51 dB HL, and from 66% to 55%, respectively. Overall, 74% of subjects with good hearing, according to the 50/50 rule, maintained hearing above this rule. There were no significant differences in hearing loss by subsite in the internal auditory canal (porus, fundus, central) or by growth status (stable, growing, shrinking). Only 6 patients showed a large hearing change. This happened early during follow-up, with relatively stable hearing after this. CONCLUSION: Hearing will deteriorate in some intracanalicular vestibular schwannomas, regardless of tumor growth. Hearing deterioration, if on a large scale, most likely occurs early in follow-up. The present results using conservative management in these tumors appear similar to those reported for stereotactic radiotherapy or microsurgery.

In the present study, genotype–phenotype correlations in eight Dutch DFNB8/10 families with compound heterozygous mutations in TMPRSS3 were addressed. We compared the phenotypes of the families by focusing on the mutation data. The compound heterozygous variants in the TMPRSS3 gene in the present families included one novel variant, p.Val199Met, and four previously described pathogenic variants, p.Ala306Thr, p.Thr70fs, p.Ala138Glu, and p.Cys107Xfs. In addition, the p.Ala426Thr variant, which had previously been reported as a possible polymorphism, was found in one family. All affected family members reported progressive bilateral hearing impairment, with variable onset ages and progression rates. In general, the hearing impairment affected the high frequencies first, and sooner or later, depending on the mutation, the low frequencies started to deteriorate, which eventually resulted in a flat audiogram configuration. The ski-slope audiogram configuration is suggestive for the involvement of TMPRSS3. Our data suggest that not only the protein truncating mutation p.T70fs has a severe effect but also the amino acid substitutions p.Ala306Thr and p.Val199Met. A combination of two of these three mutations causes prelingual profound hearing impairment. However, in combination with the p.Ala426Thr or p.Ala138Glu mutations, a milder phenotype with postlingual onset of the hearing impairment is seen. Therefore, the latter mutations are likely to be less detrimental for protein function. Further studies are needed to distinguish possible phenotypic differences between different TMPRSS3 mutations. Evaluation of performance of patients with a cochlear implant indicated that this is a good treatment option for patients with TMPRSS3 mutations as satisfactory speech reception was reached after implantation. Electronic supplementary material The online version of this article (doi:10.1007/s10162-011-0282-3) contains supplementary material, which is available to authorized users.

Contains fulltext : 97159.pdf (Publisher’s version ) (Closed access) In a Dutch family with an X-linked postlingual progressive hearing impairment, a critical linkage interval was determined to span a region of 12.9 Mb flanked by the markers DXS7108 and DXS7110. This interval overlaps with the previously described DFNX4 locus and contains 75 annotated genes. Subsequent next-generation sequencing (NGS) detected one variant within the linkage interval, a nonsense mutation in SMPX. SMPX encodes the small muscle protein, X-linked (SMPX). Further screening was performed on 26 index patients from small families for which X-linked inheritance of nonsyndromic hearing impairment (NSHI) was not excluded. We detected a frameshift mutation in SMPX in one of the patients. Segregation analysis of both mutations in the families in whom they were found revealed that the mutations cosegregated with hearing impairment. Although we show that SMPX is expressed in many different organs, including the human inner ear, no obvious symptoms other than hearing impairment were observed in the patients. SMPX had previously been demonstrated to be specifically expressed in striated muscle and, therefore, seemed an unlikely candidate gene for hearing impairment. We hypothesize that SMPX functions in inner ear development and/or maintenance in the IGF-1 pathway, the integrin pathway through Rac1, or both.

Item does not contain fulltext The aim of the study was to report otologic and audiologic characteristics in a group of children with Turner syndrome (TS) and correlate these findings to karyotype. Additionally, we give recommendations for the otologic care of these children. Sixty children (age 1.7-21.2 years) were included in this retrospective study. Medical history and karyotypes were recorded and otologic and audiologic evaluation was performed. A history of recurrent otitis media was reported in 41/60 (68%) children and 3/60 (5%) had suffered from cholesteatoma. Audiometric data in 56 children revealed that normal hearing was only present in 33/112 (29%) ears. All other ears 79/112 (71%) were classified in five different audiometric categories for hearing loss. Hearing thresholds in general appeared to be about 10-11 dB worse in children with a monosomy 45,X or isochromosome (both have a total deletion of the short (p) arm of the X-chromosome) compared to those having a mosaicism or structural anomaly (partial deletion, or total deletion in only a few cells). Our findings support the hypothesis that hearing can be affected by loss of the p-arm of the X-chromosome. It is for the first time that a relation between hearing problems and karyotype is statistically confirmed in a large group of children with TS.

Objectives: We studied the results of postauricular approach atticotomy in patients with cholesteatoma of the anterior epitympanum. Methods: Twenty-six patients were selected for removal of cholesteatoma of the anterior epitympanum by postauricular approach atticotomy, a closed transcanal procedure that is used to expose and remove cholesteatoma. After removal of cholesteatoma, reconstruction of the scutum is performed with cymbal cartilage. Results: Postauricular approach atticotomy can be performed as part of a canal wall–up procedure in selected cases in which cholesteatoma invades the anterior epitympanum. Especially if the ossicular chain is intact and if there is an anteriorly curved medial outer canal wall, this technique is useful in avoiding an open technique. A second-look procedure is recommended because of a relatively high percentage of recurrent and residual disease. Conclusions: Postauricular approach atticotomy with reconstruction of the scutum is a useful technique to remove cholesteatoma from the anterior epitympanum.