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17 januari 2022, Item does not contain fulltext, NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10.

Contains fulltext : 206709.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 169958.pdf (publisher's version ) (Open Access), A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous nonsense mutation, c.4G>T (p.Glu2*), in FITM2 was identified. FITM2 and its paralog FITM1 constitute an evolutionary conserved protein family involved in partitioning of triglycerides into cellular lipid droplets. Despite the role of FITM2 in neutral lipid storage and metabolism, no indications for lipodystrophy were observed in the affected individuals. In order to obtain independent evidence for the involvement of FITM2 in the human pathology, downregulation of the single Fitm ortholog, CG10671, in Drosophila melanogaster was pursued using RNA interference. Characteristics of the syndrome, including progressive locomotor impairment, hearing loss and disturbed sensory functions, were recapitulated in Drosophila, which supports the causative nature of the FITM2 mutation. Mutation-based genetic counseling can now be provided to the family and insight is obtained into the potential impact of genetic variation in FITM2.

Contains fulltext : 174798.pdf (Publisher’s version ) (Open Access), BACKGROUND: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype. MATERIALS AND METHODS: In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity. RESULTS: Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Gln2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum. CONCLUSIONS: We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.

Contains fulltext : 182610.pdf (publisher's version ) (Open Access), Whole exome sequence analysis was performed in a Swedish mother-father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders.

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org.

Hearing-impaired (HI) listeners, as well as elderly listeners, typically have a reduced ability to discriminate the fundamental frequency (F0) of complex tones compared to young normal-hearing (NH) listeners. Several studies have shown that musical training, on the other hand, leads to improved F0-discrimination performance for NH listeners. It is unclear whether a comparable effect of musical training occurs for listeners whose sensory encoding of F0 is degraded. To address this question, F0 discrimination was investigated for three groups of listeners (14 young NH, 9 older NH and 10 HI listeners), each including musicians and non-musicians, using complex tones that differed in harmonic content. Musical training significantly improved F0 discrimination for all groups of listeners, especially for complex tones containing low-numbered harmonics. In a second experiment, the sensitivity to temporal fine structure cues (TFS) was estimated in the same listeners. Although TFS cues were degraded for the two older groups of listeners, musicians showed better performance than non-musicians. Additionally, a significant correlation was obtained between F0-discrimination performance and sensitivity to TFS cues for complex tones with low and intermediate harmonic numbers. These findings suggest that musical training may enhance both sensory encoding of TFS cues and F0 discrimination in young and older listeners with or without hearing loss.

Spatial release from masking (SRM) elicited by interaural timing differences (ITDs) only can be almost normal for listeners with symmetrical hearing loss. This study investigated whether elderly hearing-impaired (HI) listeners still achieve similar SRMs as young normal-hearing (NH) listeners, when SRMs are elicited by small ITDs. Speech reception thresholds (SRTs) and SRM due to ITDs were measured over headphones for 10 young NH and 10 older HI listeners, who had normal or close-to-normal hearing below 1.5 kHz. Diotic target sentences were presented in diotic or dichotic speech-shaped noise or two-talker babble maskers. In the dichotic conditions, maskers were lateralized by delaying the masker waveforms in the left headphone channel. Multiple magnitudes of masker ITDs were tested in both noise conditions. Although deficits were observed in speech perception abilities in speechshaped noise and two-talker babble in terms of SRTs, HI listeners could utilize ITDs to a similar degree as NH listeners to facilitate the binaural unmasking of speech. A slight difference was observed between the group means when target and maskers were separated from each other by large ITDs, but not when separated by small ITDs. Thus, HI listeners do not appear to require larger ITDs than NH listeners do in order to receive a benefit from binaural unmasking.

For cochlear implant users, temporal and place cue are assumed to varyalong two orthogonal perceptual dimensions linked to pitch height and timbre.Here, the effect of electrode place, pulse rate, and amplitude modulationfrequency on those perceptual dimensions was investigated. Combinations ofdifferent electrode places with differing pulse rates or modulation frequencieswere presented to the participants while they were asked to rate pitch heightand sound quality using multiple verbal attributes. The results indicate thattemporal and place cues induce two perceptual dimensions that can be bothlinked to pitch and timbre.

This study investigated the contribution of interaural timing differences (ITDs) in different frequency regions to binaural unmasking (BU) of speech. Speech reception thresholds (SRTs) and binaural intelligibility level differences (BILDs) were measured in two-talker babble in 6 young normal-hearing (NH) and 9 elderly hearing-impaired (HI) listeners with normal or closeto- normal hearing at and below 1.5 kHz. Target sentences were presented diotically, embedded in a stream of diotic or dichotic maskers. Both target and masker sentences were split into frequency regions above and below 1.25 kHz. In the dichotic listening conditions, the maskers were lateralized to the left side by introducing 0.68-ms ITDs in either the low-frequency band, the high-frequency band, or both bands simultaneously. BILDs were found to be similar in both listener groups when the ITDs were imposed on the lowfrequency band only. ITDs in the high-frequency band alone did not produce any BILD in any of the groups. However, when ITDs were imposed in both frequency bands, the NH listeners yielded significantly greater BILDs than the HI listeners. The results suggest that, on a group level, HI listeners relied solely on ITDs in the low-frequency band while NH listeners were able to utilize envelope ITDs above 1.25 kHz to facilitate the BU of speech.

Nowadays, the pure-tone audiogram is the main tool used to characterizehearing loss and to fit hearing aids. However, the perceptual consequencesof hearing loss are typically not only associated with a loss of sensitivity, butalso with a clarity loss that is not captured by the audiogram. A detailedcharacterization of hearing loss has to be simplified to efficiently explore thespecific compensation needs of the individual listener. We hypothesized thatany listener’s hearing can be characterized along two dimensions of distortion:type I and type II. While type I can be linked to factors affecting audibility,type II reflects non-audibility-related distortions. To test our hypothesis,the individual performance data from two previous studies were re-analyzedusing an archetypal analysis. Unsupervised learning was used to identifyextreme patterns in the data which form the basis for different auditoryprofiles. Next, a decision tree was determined to classify the listeners intoone of the profiles. The new analysis provides evidence for the existenceof four profiles in the data. The most significant predictors for profileidentification were related to binaural processing, auditory non-linearity andspeech-in-noise perception. The current approach is promising for analyzingother existing data sets in order to select the most relevant tests for auditoryprofiling.

There is conflicting evidence about the relative benefit of slow- and fast- acting compression for speech intelligibility. It has been hypothesized tha tfast-acting compression improves audibility at low signal-to-noise ratios (SNRs) but may distort the speech envelope at higher SNRs. The present study investigated the effects of compression with nearly instantaneous attack time but either fast (10 ms) or slow (500 ms) release times on consonant identification in hearing-impaired listeners. Consonant-vowel speech tokens were presented at several presentation levels in two conditions: in the presence of interrupted noise and in quiet (with the compressor “shadow controlled” by the corresponding mixture of speech and noise). These conditions were chosen to disentangle the effects of consonant audibility and noise-induced forward masking on speech intelligibility. A small but systematic intelligibility benefit of fast-acting compression was found in both the quiet and the noisy conditions for the lower speech levels. No negative effects of fast-acting compression were observed when the speech level exceeded the level of the noise. These findings suggest that fast-acting compression provides an audibility benefit in fluctuating interferers ascompared to slow-acting compression, while not substantially affecting the perception of consonants at higher SNRs.

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.

There is an ongoing discussion about whether the amount of cochlear compression in humans at low frequencies (below 1 kHz) is as high as that at higher frequencies. It is controversial whether the compression affects the slope of the off-frequency forward masking curves at those frequencies. Here, the Grid method with a 2-interval 1-up 3-down tracking rule was applied to estimate forward masking curves at two characteristic frequencies: 500 Hz and 4000 Hz. The resulting curves and the corresponding basilar membrane input-output (BM I/O) functions were found to be comparable to those reported in literature. Moreover, slopes of the low-level portions of the BM I/O functions estimated at 500 Hz were examined, to determine whether the 500-Hz off-frequency forward masking curves were affected by compression. Overall, the collected data showed a trend confirming the compressive behaviour. However, the analysis was complicated by unexpectedly steep portions of the collected on- and offfrequency forward masking curves.

Dondorp, Wybo de Wert, Guido Bombard, Yvonne Bianchi, Diana W Bergmann, Carsten Borry, Pascal Chitty, Lyn S Fellmann, Florence Forzano, Francesca Hall, Alison Henneman, Lidewij Howard, Heidi C Lucassen, Anneke Ormond, Kelly Peterlin, Borut Radojkovic, Dragica Rogowski, Wolf Soller, Maria Tibben, Aad Tranebjaerg, Lisbeth van El, Carla G Cornel, Martina C eng RP-PG-0707-10107/Department of Health/United Kingdom England 2015/04/02 06:00 Eur J Hum Genet. 2015 Apr 1. pii: ejhg201556. doi: 10.1038/ejhg.2015.56.

Contains fulltext : 154690.PDF (publisher's version ) (Open Access), Nonsyndromic hearing impairment (NSHI) is a highly heterogeneous condition with more than eighty known causative genes. However, in the clinical setting, a large number of NSHI families have unexplained etiology, suggesting that there are many more genes to be identified. In this study we used SNP-based linkage analysis and follow up microsatellite markers to identify a novel locus (DFNA66) on chromosome 6q15-21 (LOD 5.1) in a large Danish family with dominantly inherited NSHI. By locus specific capture and next-generation sequencing, we identified a c.574C>T heterozygous nonsense mutation (p.R192*) in CD164. This gene encodes a 197 amino acid transmembrane sialomucin (known as endolyn, MUC-24 or CD164), which is widely expressed and involved in cell adhesion and migration. The mutation segregated with the phenotype and was absent in 1200 Danish control individuals and in databases with whole-genome and exome sequence data. The predicted effect of the mutation was a truncation of the last six C-terminal residues of the cytoplasmic tail of CD164, including a highly conserved canonical sorting motif (YXXcapital EF, Cyrillic). In whole blood from an affected individual, we found by RT-PCR both the wild-type and the mutated transcript suggesting that the mutant transcript escapes nonsense mediated decay. Functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments, implicating failed endocytosis as a possible disease mechanism. In the mouse ear, we found CD164 expressed in the inner and outer hair cells of the organ of Corti, as well as in other locations in the cochlear duct. In conclusion, we have identified a new DFNA locus located on chromosome 6q15-21 and implicated CD164 as a novel gene for hearing impairment.

Speech comprehension in adverse listening conditions requires cognitive processingdemands. Processing demands can increase with acoustically degraded speech but also depend on linguistic aspects of the speech signal, such as syntactic complexity. In the present study, pupil dilations were recorded in 19 normal-hearing participants while processing sentences that were either syntactically simple or complex and presented in either high- or low-level background noise. Furthermore, the participants were asked to rate the subjectively perceived difficulty of sentence comprehension. The results showed that increasing noise levels had a greater impact on the perceived difficulty than sentence complexity. In contrast, the processing of complex sentences resulted in greater and more prolonged pupil dilations. The results suggest that while pupil dilations may correlate with cognitive processing demands, acoustic noise has a greater impact on the subjective perception of difficulty.