Search Results (77)

Hearing loss (HL) is a common sensory disorder, with syndromic forms accounting for ~30% of genetic cases. Due to phenotypic and genetic heterogeneity, accurate diagnosis remains challenging. Exome sequencing (ES) offers a powerful tool to uncover the underlying genetic causes. This study aimed to investigate the genetic basis of syndromic hearing loss (SHL) in North African Moroccan patients through ES. Seven individuals with suspected SHL were recruited from Hassan II University Hospital, Fez. After clinical and audiological assessments, ES was performed to identify causal genetic variants. Two of the participating individuals had Usher syndrome, and one each had Cornelia de Lange syndrome, Wolfram syndrome, Jervell and Lange-Nielsen syndrome, CHARGE syndrome, and Waardenburg syndrome. The causes of all these syndromes were determined, with pathogenic variants in MYO7A, USH1G, SMC1A, WFS1, KCNQ1, CHD7, and MITF. Across the combined cohort of reported Moroccan SHL cases, variants in CHD7 and MYO7A were among the most frequently observed, while USH1G and MITF variants were rare. This study enhances the understanding of SHL in North Africa, revealing a high level of locus and allelic heterogeneity. Examining disparate populations yields novel insights into the etiology of SHL, which can subsequently enhance genetic diagnosis and tailored management strategies. Full article

Background: Heimler syndrome (HS) is a rare autosomal recessive disorder representing the mildest end of the peroxisome biogenesis disorder spectrum. It is caused by hypomorphic mutations in peroxisomal assembly genes, most commonly PEX1 and PEX6, and is characterized by sensorineural hearing loss, amelogenesis imperfecta, and retinal dystrophy. Due to phenotypic overlap with other inherited sensory disorders, particularly Usher syndrome, diagnosis of this condition is frequently delayed. Methods: We investigated two unrelated Saudi families presenting with congenital hearing loss and retinal dystrophy who were initially diagnosed with Usher syndrome. Detailed clinical evaluation, including comprehensive ophthalmologic and audiologic assessments, was performed. Whole-exome sequencing (WES) was conducted to identify the underlying genetic cause, followed by variant filtering and in silico pathogenicity prediction. Results: We identified a novel homozygous missense variant, p.Val97Gly (V97G), in the PEX6 gene that co-segregated with the disease phenotype in both families. This variant was absent from major population databases, including dbSNP, the 1000 Genomes Project, ExAC, and gnomAD, and was predicted to be deleterious by multiple in silico prediction tools. Clinically, affected individuals presented with congenital sensorineural hearing loss, pigmentary retinal dystrophy with electrophysiological evidence of cone–rod dysfunction, enamel abnormalities consistent with amelogenesis imperfecta, and mild dysmorphic facial features, supporting a diagnosis within the Heimler syndrome spectrum. Conclusions: Our findings expand the mutational spectrum of PEX6 and highlight Heimler syndrome as an important differential diagnosis in patients presenting with Usher-like phenotypes. To the best of our knowledge, this study represents the first report of the PEX6 p.Val97Gly variant associated with Heimler syndrome in a Saudi population, underscoring the value of whole-exome sequencing for accurate diagnosis and genetic counseling in individuals with inherited sensory disorders. Full article

Background/Objectives: MYO7A is known to be the genetic cause of Usher syndrome type 1, as well as autosomal dominant and autosomal recessive non-syndromic hearing loss. In general, autosomal dominant MYO7A-associated hearing loss shows progressive high-frequency, sloping hearing loss. However, several variants are associated with low-frequency hearing loss. MYO7A-associated low-frequency hearing loss is relatively rare, and the clinical details remain unclear. Methods: A total of 18,475 Japanese patients with hearing loss were recruited. Targeted massively parallel sequencing of 158 deafness-related genes was performed, and individuals with variants related to MYO7A-associated low-frequency hearing loss were identified. Results: Among 18,475 hearing loss patients, we identified 60 patients from 44 unrelated families carrying five variants (p.[Asn140Lys; Glu1835Gln], p.Leu479Pro, p.Leu656Val, p.Gly660Arg, and p.Arg668His) for MYO7A-associated low-frequency hearing loss. Patients identified in this study initially showed postlingual-onset mild-to-moderate low-frequency hearing loss; however, high-frequency hearing also deteriorated after the fourth decade, eventually leading to moderate-to-severe flat-type hearing loss. In addition, we performed haplotype analysis for the recurrent variant c.1436T>C:p.Leu479Pro identified in this study and found that this variant is a founder mutation in the Japanese population. Conclusions: In this study, we were able to clarify the specific features of MYO7A-related low-frequency hearing loss in a significant number of patients. In particular, we clarified the details of hearing deterioration at each frequency. Our findings will be useful for providing more appropriate treatment and follow-up for MYO7A-associated low-frequency hearing loss. Full article

Pathological USH2A mutations cause Usher syndrome type II, characterized by progressive retinitis pigmentosa and hearing and balance impairment. This study aims to investigate the cellular mechanisms underlying USH2A-related retinal degeneration using human induced pluripotent stem cell (hiPSC)-derived retinal organoids. The introduction of a homozygous nonsense mutation in the USH2A hotspot exon-13 resulted in normal photoreceptor development but loss of ciliary localization of usherin long form B and its interacting proteins, ADGRV1 and whirlin. Notably, single-cell RNA sequencing revealed unexpected significant transcriptional changes in Müller glial cells (MGCs), suggestive of disruptions in the translation, innate immune response, and endolysosomal system. These findings suggest that, while photoreceptor cells are mildly affected by the exon-13 USH2A mutation, MGCs exhibit major transcriptional changes, potentially contributing to the disease progression and therefore shedding light on potential alternative therapeutic targets. Full article

Cytosine base editors (CBEs) enable precise C-to-T (G-to-A) conversions in genomic DNA, offering significant potential for specific gene editing. This study compared the prototypical Base Editor 3 (BE3) and a modified variant, BE3-Y130F, which utilizes an hA3A deaminase with the Y130F mutation, focusing on their editing efficiency and editing window characteristics using bovine zygotes. Following in vitro fertilization (IVF), sgRNA and Cas9 mRNA were injected as a targeting efficiency control, which resulted in 100% editing with no wild-type sequence. Then, either BE3 or BE3-Y130F mRNA, synthesized via in vitro transcription, and an sgRNA targeting exon 4 of the MYO7A gene was injected into zygotes. Genomic DNA was extracted from both blastocysts and developmentally arrested embryos, and Sanger sequencing was performed to evaluate C-to-T conversion efficiency and editing window. Both BE3 and BE3-Y130F achieved 100% C-to-T conversion efficiency at the primary target cytosine. BE3 displayed a defined editing window, primarily affecting cytosines at positions 7 and 8, indicating a predictable profile. In contrast, BE3-Y130F maintained high efficiency but had a less clearly defined editing window, resulting in incomplete editing and a remaining cytosine on the target sequence. Full article

Background/Objectives: Children with hearing loss (HL) could experience significant fatigue which compromises their performance. The effort related to the combination of HL and visual impairment in children affected by Usher syndrome (USH) could compromise mental health, socio-emotional behavior and academic achievement. The aim of the present study was to analyse the listening effort in USH cases types 1 and 2 and its relation to age, molecular diagnosis, visual field, visual acuity, degree of HL, vestibular impairment and spatial orientation. Methods: This was a retrospective monocentric study. Twenty children with genetically confirmed USH (USH2 in 15/20–75% and USH1 in 5/20–25%), age range 3–17 years (mean 9.6 ± 4.7), underwent: the Vanderbilt fatigue scale questionnaire (VFS), audiological and vestibular assessment including the Oldenburg Matrix test in Italian and video head impulse test (VHIT), sound localization test and ophthalmologic examination. Results: We observed a more pronounced HL and deteriorated vestibular function in those with USH1. They also employed significantly more time and head movements to localize sounds compared to USH2 and had the worst visual field on eye examination. The VFS did not show significant differences between the two groups, with the exception of the physical fatigue reported by parents. Mean VFS was linearly related to age, the hearing threshold of the worse ear, data logging hours of hearing device, time and head movements of the localization test, VHIT asymmetry and balance problems referred by parents and the visual field. USH type 1 had no greater risk of fatigue than USH2. Profound hearing loss, data logging of hearing device < 8 h a day, difficult localization test, balance problems and low retinal sensitivity represented risk factors for listening effort measured with VFS. Conclusions: Listening effort in difficult environments such as school rooms in USH patients is not only associated to hearing function but also to the spatial awareness determined in part by vestibular and visual function. Teachers should be informed and made aware of multiple comorbidities in order to facilitate learning. Full article

Deaf-blindness, particularly in progressive conditions such as Usher syndrome, presents profound challenges to communication, independence, and access to information. Existing tactile communication technologies for individuals with Usher syndrome are often limited by the need for close physical proximity to trained interpreters, typically requiring hand-to-hand contact. In this study, we introduce a novel, cloud-based, AI-assisted gesture recognition and haptic communication system designed for long-term use by individuals with Usher syndrome, whose auditory and visual abilities deteriorate with age. Central to our approach is a wearable haptic interface that relocates tactile input and output from the hands to an arm-mounted sleeve, thereby preserving manual dexterity and enabling continuous, bidirectional tactile interaction. The system uses surface electromyography (sEMG) to capture user-specific muscle activations in the hand and forearm and employs lightweight, personalized convolutional neural networks (CNNs), hosted on a centralized server, to perform real-time gesture classification. A key innovation of the system is its ability to adapt over time to each user’s evolving physiological condition, including the progressive loss of vision and hearing. Experimental validation using a public dataset, along with real-time testing involving seven participants, demonstrates that personalized models consistently outperform cross-user models in terms of accuracy, adaptability, and usability. This platform offers a scalable, longitudinally adaptable solution for non-visual communication and holds significant promise for advancing assistive technologies for the deaf-blind community. Full article

Purpose: To analyze the structural changes in the brain related to combined hearing and vision loss in patients with Usher syndrome (USH) obtained by 7 Tesla MRI. Methods: Twenty patients with a diagnosis of USH and fifteen normal age- and gender-matched subjects were included in this study. USH patients underwent ophthalmological examination. All subjects underwent 7 Tesla MRI of the brain in two sequences: 3D BRAVO T1-weighted and 3D MT-weighted SILENT sequence. Results: Mean values of LGN volumes (right 95.65 mm³, left 88.61 mm³) are significantly (p < 0.001) lower in the USH group than in the control group (right 126.64 mm³, left 120.37 mm³). The average volumes of the left cuneus (4102.85 mm³), right parsorbitalis (2133.95 mm³), and right rostralanteriorcingulate cortex (ACC) (1727.60 mm³) in the patient group are significantly (p = 0.03673, 0.02434, and 0.04204, respectively) lower than in the control group (4673.73 mm³, 2485.13 mm³, and 2060.00 mm³, respectively). Mean lengths of the left lingual cortex (1.99 mm) and right pericalcarine cortex (1.84 mm) in the patient group are significantly (p = 0.02449 and 0.03153, respectively) smaller than in the control group (2.09 mm and 2.0 mm, respectively). Average lengths of the right insula (2.74 mm) in the patient group are significantly (p = 0.00041) greater than in the control group (2.49 mm). Conclusions: Parts of the brain engaged in the visual processing as LGN, pericalcarine cortex, lingual gyrus, and cuneus, are decreased, as well as those involved in hearing and language processing, such as parsorbitalis and ACC. The insula, a higher-order brain area possessing a crucial role in olfactory processing, is increased in USH patients. Our findings enhance the understanding of structural brain abnormalities related to combined hearing and vision loss and suggest complex adaptive changes that should be considered in the development of new visual rehabilitation and restitution strategies in USH patients. Full article

Usher syndrome, a rare genetic disorder causing both hearing and vision loss, presents significant diagnostic and therapeutic challenges due to its complex genetic basis. The identification of reliable biomarkers for early detection and intervention is crucial for improving patient outcomes. In this study, we present a machine learning-based hybrid sequential feature selection approach to identify key mRNA biomarkers associated with Usher syndrome. Beginning with a dataset of 42,334 mRNA features, our approach successfully reduced dimensionality and identified 58 top mRNA biomarkers that distinguish Usher syndrome from control samples. We employed a combination of feature selection techniques, including variance thresholding, recursive feature elimination, and Lasso regression, integrated within a nested cross-validation framework. The selected biomarkers were further validated using multiple machine learning models, including Logistic Regression, Random Forest, and Support Vector Machines, demonstrating robust classification performance. To assess the biological relevance of the computationally identified mRNA biomarkers, we experimentally validated candidates from the top 10 selected mRNAs using droplet digital PCR (ddPCR). The ddPCR results were consistent with expression patterns observed in the integrated transcriptomic metadata, reinforcing the credibility of our machine learning-driven biomarker discovery framework. Our findings highlight the potential of machine learning-driven biomarker discovery to enhance the detection of Usher syndrome. Full article

Circadian rhythms govern cellular metabolism, redox balance, and endocrine signaling in numerous tissues. However, chronic disturbance of these biological rhythms, mediated by modern lifestyle factors including shift work, sleep irregularity, and prolonged light exposure, has been increasingly associated with oxidative stress, metabolic dysregulation, and the pathogenesis of chronic diseases. This review discusses recent mechanistic advances that link circadian misalignment with tissue-specific metabolic reprogramming and impaired proteostasis, focusing on metabolic inflammation and associated pathologies. Emerging work reveals a close interdependence between the circadian clock and proteasome-mediated protein turnover and highlights this interplay’s importance in maintaining redox homeostasis. Furthermore, circadian modulation of the activity of the inflammasome complex is suggested to represent an important, but largely unexplored, risk factor in the pathobiology of both malignancy and metabolic syndrome. Recently, researchers have proposed them as novel endocrine regulators of systemic energy balance and inflammation, with a focus on their circadian regulation. In addition, the emerging domains of chrono-epigenetics and tissue-specific programming of the clock pathways may serve to usher in novel therapies through precision medicine. Moving ahead, circadian-based therapeutic approaches, including time-restricted feeding, chronopharmacology, and metabolic rewiring, have high potential for re-establishing physiological domain homeostasis linked to metabolic inflammation pathologies. Elucidating this reciprocal relationship between circadian biology and cellular stress pathways may one day facilitate the generation of precise interventions aiming to alleviate the health burden associated with circadian disruption. Full article

Background: Syndromic inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders, involving the retina and additional organs. Over 80 forms of syndromic IRD have been described. Methods: We aimed to phenotypically and genotypically characterize a cohort of 171 individuals from 140 Israeli families with syndromic IRD. Ophthalmic examination included best corrected visual acuity, fundus examination, visual field testing, retinal imaging and electrophysiological evaluation. Most participants were also evaluated by specialists in fields relevant to their extra-retinal symptoms. Genetic analyses included haplotype analysis, homozygosity mapping, Sanger sequencing and next-generation sequencing. Results: In total, 51% of the families in the cohort were consanguineous. The largest ethnic group was Muslim Arabs. The most common phenotype was Usher syndrome (USH). The most common causative gene was USH2A. In 29% of the families, genetic analysis led to a revised or modified clinical diagnosis. This included confirmation of an atypical USH diagnosis for individuals with late-onset retinitis pigmentosa (RP) and/or hearing loss (HL); diagnosis of Heimler syndrome in individuals with biallelic pathogenic variants in PEX6 and an original diagnosis of USH or nonsyndromic RP; and diagnosis of a mild form of Leber congenital amaurosis with early-onset deafness (LCAEOD) in an individual with a heterozygous pathogenic variant in TUBB4B and an original diagnosis of USH. Novel genotype–phenotype correlations included biallelic pathogenic variants in KATNIP, previously associated with Joubert syndrome (JBTS), in an individual who presented with kidney disease and IRD, but no other features of JBTS. Conclusions: Syndromic IRDs are a highly heterogeneous group of disorders. The rarity of some of these syndromes on one hand, and the co-occurrence of several syndromic and nonsyndromic conditions in some individuals, on the other hand, complicates the diagnostic process. Genetic analysis is the ultimate way to obtain an accurate clinical diagnosis in these individuals. Full article

Background/Objectives: Inherited retinal diseases (IRDs) are a heterogeneous group of rare eye disorders characterized by progressive photoreceptor degeneration, leading to severe visual impairment or even blindness. This study aims to investigate the prevalence, types, and clinical significance of ophthalmic comorbidities in Portuguese patients with IRDs. Methods: This nationwide Portuguese population-based retrospective study was based on the IRD-PT registry (retina.com.pt). Statistical analysis was conducted using Microsoft^® Excel^® for Microsoft 365 and IBM SPSS Statistics version 29.0.2.0. Informed consent was obtained from all participants. Results: A total of 1531 patients (1254 families) from six centers were enrolled. The cohort consisted of 51% males, with a mean age of 45.8 ± 19.3 years and a mean age at diagnosis of 39.4 ± 19.5 years. Overall, ocular comorbidities were reported in 644 patients (42.1%). In 176 individuals (11.5%), multiple concurrent comorbidities were found. Cataract was the most common comorbidity (21.3%), followed by amblyopia (6.3%) and high myopia (5.9%). Statistically significant associations with ocular comorbidities were observed in isolated progressive IRDs. Specifically, AR RP was associated with cataract (p < 0.001), and gene analysis revealed several significant associations. CRB1 was statistically linked to epiretinal membrane (ERM) (p = 0.003), EYS with cataract (p = 0.001), PROM1 with choroidal neovascularization (CNV) (p = 0.0026), and USH2A with macular hole (p = 0.01). Patients with the RPE65 mutation in Leber congenital amaurosis were associated with ERM (p = 0.019). There was also a significant association between X-linked RP and high myopia (p < 0.001) and CNV in Best disease (p < 0.001); in syndromic IRDs, cataract, cystoid macular edema, and ERM were observed in Usher syndrome, p = 0.002, p = 0.002, and p = 0.005, respectively, and the MYO7A gene was linked to cataract (p = 0.041) and strabismus (p = 0.013); pseudoxanthoma elasticum was significantly associated with CNV (p = 0.002); and foveal hypoplasia was associated with anterior segment dysgenesis (p < 0.001). Conclusions: This study enhances the current understanding of ocular comorbidities in IRDs in Portuguese patients. Common findings were cataract, refractive error, and CME. Stationary IRDs and pattern dystrophies showed fewer concomitant comorbidities, supporting their classification as non-progressive or benign conditions. The significance of registries like IRD-PT cannot be overstated, particularly in the context of rare diseases. These databases serve multiple crucial functions in enabling detailed documentation of disease characteristics and long-term monitoring of disease progression. Full article

Mutations in the pathogenic gene CDH23 are known to cause Usher syndrome, affecting both auditory and visual functions. Our previous results provided valuable insights into the mechanisms underlying congenital hearing loss associated with CDH23 mutations. However, the molecular mechanisms and signaling pathways that influence vision remain largely unknown. In this study, transcriptional sequencing and bioinformatics analysis were conducted to compare gene expression between the control and cdh23^−/−. Additionally, RT-qPCR experiments were performed to further validate the bioinformatics analysis results. The comparative transcriptomic analysis identified differentially expressed genes associated with photoreceptor degeneration and the mitogen-activated protein kinase (MAPK) signaling pathway. Embryos were subjected to hematoxylin and eosin (H&E) staining to assess their histological changes. The results showed that the cdh23^−/− retina was morphologically indistinguishable from the control. Apoptosis was assessed using TUNEL staining, which revealed an increase in total cell death in the cdh23^−/− retina. Our results revealed that the cell death was induced by Ca²⁺ and MAPK signaling interactions following photoreceptor degeneration. This study provides insights into the mechanisms underlying the role of cdh23 in vision. Full article

Usher syndrome (USH) is a rare genetic disorder affecting vision, hearing, and balance. Identifying reliable biomarkers is crucial for early diagnosis and understanding disease mechanisms. MicroRNAs (miRNAs), key regulators of gene expression, hold promise as biomarkers for USH. This study aimed to identify a minimal subset of miRNAs that could serve as biomarkers to effectively differentiate USH from controls. We employed ensemble feature selection techniques to select the top miRNAs appearing in at least three algorithms. Machine learning models were trained and tested using this subset, followed by validation on an independent 10% sample. Our approach identified 10 key miRNAs as potential biomarkers for USH. To further validate their biological relevance, we conducted pathway analysis, which revealed significant pathways associated with USH. Furthermore, our approach achieved high classification performance, with an accuracy of 97.7%, sensitivity of 98%, specificity of 92.5%, F1 score of 95.8%, and an AUC of 97.5%. These findings demonstrate that combining ensemble feature selection with machine learning provides a robust strategy for miRNA biomarker discovery, advancing USH diagnosis and molecular understanding. Full article

Background: Usher syndrome (USH), the most common cause of combined deaf-blindness, is a genetically and phenotypically heterogeneous disorder characterized by congenital hearing impairment and progressive vision loss due to rod-cone dystrophy. Although the original classification in three subtypes (USH I, USH II, and USH III) is still valid, recent findings have changed and widened perspectives in its classification, genotype–phenotype correlations, and management strategies: Objective: This study aims to provide new insights into the classification of Usher syndrome, explore the genotype-phenotype correlations, and review current and emerging management strategies. Methods: A comprehensive literature review has been conducted, incorporating data from clinical studies, genetic databases, and patient registries. Results: Recent studies have led to the identification of several novel pathogenic variants in the USH genes, leading to refined subclassifications of Usher syndrome. Interactions between different genes being part of the network of this ciliopathy have been investigated and new mechanisms unveiled. Significant correlations were found between certain genotypes and the presentation of both auditory and visual phenotypes. For instance, pathogenic variants in the MYO7A gene (USH1B) were generally associated with more severe hearing impairment and earlier onset of retinal dystrophy, if compared to other USH genes-related forms. Other genes, such as USH1G, traditionally considered as causing a specific subtype, can display phenotypic heterogeneity in some patients. Conclusions: This review provides insights into a better understanding of Usher syndrome that considers recent findings regarding its genetic causes and clinical features. Precise genotype–phenotype correlations can lead to better genetic counselling, more precise characterization of the natural history of the condition, and a personalized and effective management approach. Recent progress has been made in research into gene-specific therapies that appear promising for improving the quality of life for individuals affected by Usher syndrome. Full article