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Background: Usher syndrome type 3 (USH3) is an autosomal recessive inherited disorder caused by pathogenic variants in the CLRN1 gene. Object: To evaluate the genotype-phenotype correlation of Usher syndrome type 3 (USH3) in a deaf-blind Chinese family of 3 generations with 2 patients. Methods: We collected blood samples and clinical data from all of the pedigree family members. Genomic DNA was isolated from peripheral leukocytes using standard method. Targeted next generation sequencing and Sanger sequencing were performed to find the pathogenic variants in this family. Digital PCR and plasmid overexpression assay were used to verify the pathogenicity of variant sites in different transcripts. Results: All patients developed bilateral sensorineural hearing loss (SHL), progressive vision loss and nyctalopia. NGS of genes for Usher syndrome, deafness and retinal dystrophy identified a locus mutation in CLRN1 that caused completely different amino acid changes in different transcripts[CLRN1:c.474T > A(P.Cys158Ter) at NM_001256819.2 or c.302T > A(p.Val101Asp) at NM_174878.3], and plasmid overexpression experiments confirmed that the c.474T > A(P.Cys158Ter, NM_001256819.2) was a pathogenic variant which has never been associated with Usher syndrome in China, and the transcript of this mutation was not the version commonly found worldwide. Conclusions: The CLRN1c.474T > A(NM_001256819.2) mutation is the causative variant in the Chinese family with USH3. The pathogenicity of different transcripts should be particularly considered in pathogenicity analysis. [ABSTRACT FROM AUTHOR]

Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A metaanalysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice. [ABSTRACT FROM AUTHOR]

Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: This article presents a review of the main causes of inherited dual sensory impairment (DSI) with an emphasis on the multidisciplinary approach. Methods: A narrative review of English literature published before January 2023 was conducted using PubMed, Medline, and Scopus databases. The different causes of inherited DSI are discussed from a multidisciplinary perspective. Results: There are a wide range of dual sensory impairment (DSI), commonly referred to as blindness and deafness. While Usher syndrome is the most frequent genetic cause, other genetic syndromes such as Alport syndrome or Stickler syndrome can also lead to DSI. Various retinal phenotypes, including pigmentary retinopathy as seen in Usher syndrome, vitreoretinopathy as in Stickler syndrome, and macular dystrophy as in Alport syndrome, along with type of hearing loss (sensorineural or conductive) and additional systemic symptoms can aid in diagnostic suspicion. A thorough ophthalmologic and otorhinolaryngologic examination can help guide diagnosis, which can then be confirmed with genetic studies, crucial for determining prognosis. Effective hearing rehabilitation measures, such as hearing implants, and visual rehabilitation measures, such as low vision optical devices, are crucial for maintaining social interaction and proper development in these patients. Conclusions: While Usher syndrome is the primary cause of inherited dual sensory impairment (DSI), other genetic syndromes can also lead to this condition. A proper diagnostic approach based on retinal phenotypes and types of hearing loss can aid in ruling out alternative causes. Multidisciplinary approaches can assist in reaching a definitive diagnosis, which has significant prognostic implications. [ABSTRACT FROM AUTHOR]

Deaf and hard of hearing (d/DHH) students are often labeled with one or more educationally significant disabilities in addition to their hearing loss. According to the Gallaudet Research Institution's most recent Annual Survey of Deaf and Hard of Hearing Children and Youth (2013), almost 40% of d/DHH students nationwide receive special education services for one or more comorbid disabilities. However, relatively few prevalence rate estimates have been published over the last decade. Knowledge regarding the current prevalence of educationally significant disabilities among d/DHH students is therefore limited. The present study surveyed teachers of the deaf and hard of hearing (TODHHs) in a midwestern state regarding the number of d/DHH students on their caseloads with one or more comorbid disabilities. Within the sample population (N = 451), nearly 65% were reported to receive special education services for disabilities other than deafness or hearing impairment. [ABSTRACT FROM AUTHOR]

Background: Congenital deafness could be the first manifestation of a syndrome such as in Usher, Pendred, and Wolfram syndromes. Therefore, a genetic study is crucial in this deficiency to significantly improve its diagnostic efficiency, to predict the prognosis, to select the most adequate treatment required, and to anticipate the development of other associated clinical manifestations. Case presentation: We describe a young girl with bilateral congenital profound deafness, who initially received a single cochlear implant. The genetic study of her DNA using a custom-designed next-generation sequencing (NGS) panel detected a de novo pathogenic heterozygous variant in the WFS1 gene related to Wolfram-like syndrome, which is characterized by the presence of other symptoms such as optic atrophy. Due to this diagnosis, a second implant was placed after the optic atrophy onset. The speech audiometric results obtained with both implants indicate that this work successfully allows the patient to develop normal speech. Deterioration of the auditory nerves has not been observed. Conclusion: The next-generation sequencing technique allows a precise molecular diagnosis of diseases with high genetic heterogeneity, such as hereditary deafness, while this was the only symptom presented by the patient at the time of analysis. The NGS panel, in which genes responsible for both syndromic and non-syndromic hereditary deafness were included, was essential to reach the diagnosis in such a young patient. Early detection of the pathogenic variant in the WFS1 gene allowed us to anticipate the natural evolution of the disease and offer the most appropriate management to the patient. [ABSTRACT FROM AUTHOR]

Next-generation sequencing (NGS) technologies revolutionized the molecular diagnosis of sensorineural hearing loss (SNHL) and are now a standard of care. In this study, 71 Portuguese probands with hereditary SNHL were assessed by whole-exome sequencing (WES) targeting a panel of 158 genes related to SNHL, aiming to evaluate the diagnostic yield of this methodological approach and to report the spectrum of variants. Patients with either nonsyndromic or syndromic SNHL were included. Also, patients were previously screened for variants in the GJB2 gene and for duplications/deletions in the GJB6 gene. Causative variants in 11 different genes were identified in 15 (21.1%) out of 71 probands, 5 of which had associated syndromes. In 6 other patients (8.5%), presumptive causative variants were identified in MYO15A, TMIE, TBC1D24, SPMX, GJB3, PCDH15, and CDH23 genes, uncovering a potential case of digenic Usher syndrome. The study was inconclusive in 20 probands (28.2%), in 19 due to lack of segregation analysis and in one due to uncertain phenotype-genotype matching. In the remaining 30 patients (42.3%) no potentially causative variants were identified. The diagnostic yield did not significantly vary according to the age of hearing-impairment onset. As the first study on the application of NGS technologies in SNHL based on a Portuguese cohort, our results may contribute to characterize the spectrum of variants related to SNHL in the Portuguese population. Additionally, the present study provides new insights into the contribution of MYO3A, TECTA, EDNRB, TBC1D24, and GJB3 genes to SNHL. For the significant number of undiagnosed patients, reanalysis of WES data – either for a broader gene panel or in a non-targeted approach – may be considered. [ABSTRACT FROM AUTHOR]

Purpose: Phonological complexity is known to be a good index of developmental language disorder (DLD) in normalhearing children, who have major difficulties on some complex structures. Some deaf children with cochlear implants (CIs) present a profile that evokes DLD, with persistent linguistic difficulties despite good audiological and environmental conditions. However, teasing apart what is related to auditory deficit or to language disorder remains complex. Method: We compared the performance of three groups of school-age children, 33 children with CI, 22 with DLD, and 24 with typical development, on a nonword repetition (NWR) task based on phonological complexity. Children with CI were studied regarding their linguistic profile, categorized in four subgroups ranging from excellent to very poor performance. Influence of syllable length and phonological structures on the results of all the children were explored. Results: The NWR task correctly distinguished children with DLD from typically developing children, and also children with CI with the poorest linguistic performance from other children with CI. However, most complex phonological structures did not reliably identify children with CI displaying a profile similar to that of children with DLD because these structures were difficult for all of the children with CI. The simplest phonological structures were better at detecting persistent language difficulties in children with CI, as they were challenging only for the children with the poorest language outcomes. Conclusions: The most complex phonological structures are not good indices of language disorder in children with CI. Phonological complexity represents a gradient of difficulty that affects normal-hearing and deaf children differently. [ABSTRACT FROM AUTHOR]

Usher syndrome (USH) typically leads to deaf-blindness, requiring the provision of extensive education and rehabilitation services. Therefore, investigating the prevalence is crucial to requests for proper government support for USH patients. The aim was to perform a nationwide epidemiologic survey of USH in Japan to estimate the prevalence of USH and reveal the relative frequency and characteristics of the three USH subtypes. To estimate the number of USH patients visiting hospitals over a 1-year period, 1,628 hospitals were randomly selected from all Departments of Otorhinolaryngology and Ophthalmology in Japan. Subsequently, we collected data regarding the clinical characteristics of each patient treated and the results of genetic testing, if performed. We found that the prevalence of USH was at least 0.4 per 100,000 population. The frequency of clinical subtypes and causal genes for USH were consistent with previous reports. Also, we demonstrated the feasibility of genetic counseling for USH patients based on the results of genetic testing. USH is a rare disease, but requires social support due to the severity of symptoms. To minimize these issues, understanding the clinical characteristics and performing comprehensive genetic testing could allow early and accurate diagnosis as well as medical intervention. [ABSTRACT FROM AUTHOR]

Hearing loss (HL) is the most common congenital sensory impairment. Usher syndrome (USH) is the leading genetic etiology of congenital deafness combined with progressive vision loss, and individuals presenting with these symptoms are often assumed to have USH. This can be an erroneous assumption, as there are additional genetic causes of deafblindness. Our objective is to describe and accurately diagnose non-USH genetic causes of deaf-blindness. We present three children with hearing and vision loss with clinical and genetic findings suggestive of USH. However, ongoing clinical assessment did not completely support an USH diagnosis, and exome analysis was pursued for all three individuals. Updated genetic testing showed pathogenic variants in ALMS1 in the first individual and TUBB4B in the second and third. Although HL in all three was consistent with USH type 2, vision impairment with retinal changes was noted by age 2 yr, which is unusual for USH. In all three the updated genotype more accurately fit the clinical phenotype. Because USH is the most common form of genetic deaf-blindness, individuals with HL, early vision impairment, and retinal dysfunction are often assumed to have USH. However, additional genes associated with HL and retinal impairment include ALMS1, TUBB4B, CEP78, ABHD12, and PRPS1. Accurate genetic diagnosis is critical to these individuals' understanding of their genetic conditions, prognosis, vision and hearing loss management, and future access to molecular therapies. If clinically or genetically USH seems uncertain, updated genetic testing for non-USH genes is essential. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to explore lived experiences with working life from the perspective of people with deafblindness due to Usher syndrome type 2 (USH2). Background: A limited number of studies have explored working life of people with Usher syndrome. One study of individuals with USH2 showed that work active reported significantly better psychological health compared to non-working individuals. Methods: Seven participants aged 38–50 years with USH2 participated in interviews analysed by interpretative phenomenological analysis. Results: The analyses yielded four themes showing that work is a source of satisfaction and a commitment that needs to be balanced. It is also associated with facing limitations and feelings of uncertainty. Conclusion: Based on the psychology of work model we have demonstrated that work is associated with social connectedness, self-determination and a source of improved health outcomes. There are however also potential health hazards in people with USH2, indicating a need for balance between individual needs and resources, and an adapted environment, for maintaining or regaining health for actively working people with USH2. [ABSTRACT FROM AUTHOR]

Usher syndrome has three subtypes, each being clinically and genetically heterogeneous characterised by sensorineural hearing loss and retinitis pigmentosa (RP), with or without vestibular dysfunction. It is the most common cause of deaf–blindness worldwide with a prevalence of between 4 and 17 in 100 000. To date, 10 causative genes have been identified for Usher syndrome, with MYO7A accounting for >50% of type 1 and USH2A contributing to approximately 80% of type 2 Usher syndrome. Variants in these genes can also cause non-syndromic RP and deafness. Genotype–phenotype correlations have been described for several of the Usher genes. Hearing loss is managed with hearing aids and cochlear implants, which has made a significant improvement in quality of life for patients. While there is currently no available approved treatment for the RP, various therapeutic strategies are in development or in clinical trials for Usher syndrome, including gene replacement, gene editing, antisense oligonucleotides and small molecule drugs. [ABSTRACT FROM AUTHOR]

Background and Objectives: Identification of the pathogenic mutations underlying hereditary hearing loss (HL) is difficult, since causative mutations in 60 different genes have so far been reported.Methods: A comprehensive clinical and pedigree examination was performed on a multiplex family suffering from HL. Direct sequencing of GJB2 and genetic linkage analysis of 5 other most common recessive nonsyndromic HL (ARNSHL) genes were accomplished. Next-generation sequencing (NGS) was utilized to reveal the possible genetic etiology of the disease.Results: NGS results showed a novel rare variant c.2977G>A (p.Asp993Asn) in the CDH23 gene. The variant, which is a missense in exon 26 of the CDH23 gene, fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. Electroretinography rejects the Usher syndrome in the family.Conclusions: The present study shows that an accurate molecular diagnosis based on NGS technologies largely improves molecular-diagnostic outcome and thus genetic counseling, and helps to clarify the recurrence risk in deaf families. [ABSTRACT FROM AUTHOR]

Mutations in myosin-VIIa (MYO7A) cause Usher syndrome type 1, characterized by combined deafness and blindness. MYO7A is proposed to function as a motor that tensions the hair cell mechanotransduction (MET) complex, but conclusive evidence is lacking. Here we report that multiple MYO7A isoforms are expressed in the mouse cochlea. In mice with a specific deletion of the canonical isoform (Myo7a-ΔC mouse), MYO7A is severely diminished in inner hair cells (IHCs), while expression in outer hair cells is affected tonotopically. IHCs of Myo7a-ΔC mice undergo normal development, but exhibit reduced resting open probability and slowed onset of MET currents, consistent with MYO7A's proposed role in tensioning the tip link. Mature IHCs of Myo7a-ΔC mice degenerate over time, giving rise to progressive hearing loss. Taken together, our study reveals an unexpected isoform diversity of MYO7A expression in the cochlea and highlights MYO7A's essential role in tensioning the hair cell MET complex. How the ear achieves its remarkable sensitivity is still not fully understood. In this study, the authors demonstrate that the deafness protein myosin-VIIa and its isoforms are essential for tensioning the tip link, thereby sensitizing the auditory receptor cell's mechanotransduction process. [ABSTRACT FROM AUTHOR]

Usher's syndrome is an autosomal recessive disorder characterized by dual sensory impairment involving both the ears and eyes. Cochlear implantation paves a way to restore hearing loss in such individuals but poor vision among these patients poses additional challenges for the habilitationists. This study aimed to compare the habilitation outcomes and hearing-related quality of life scores of cochlear implantees having Usher syndrome with age-matched cochlear implantees with no such syndromic association. 27 patients aged 1–6 years with Usher syndrome underwent cochlear Implantation over a period of 10 years from 2006 to 2016 and were included in this study along with an age-matched cohort of 30 implantees with no additional disabilities. Category of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores were compared at 3, 6, 9 and 12 months respectively. Glasgow Benefit Inventory and Health Utility Index (HUI 3.0) questionnaires were used to assess the hearing-related quality of life in both groups at 1 year post implantation. There was significant difference in CAP and SIR scores between children with Usher's syndrome and the control group (p < 0.05). The overall scores in terms of quality of life as well were statistically different (p < 0.05). Though there was improvement in speech and language acquisition after cochlear Implantation this was found to be of lesser extent than the normative cohort. These children with additional visual disabilities required intensive, individualized therapy catering to their complex needs. Their family's perception of expected benefit from cochlear Implantation was guarded and needed to be appraised in detail prior to surgery. This experience helped prepare an institutional protocol for counseling such implantees in future. [ABSTRACT FROM AUTHOR]

Usher syndrome (USH) is a clinically common autosomal recessive disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction. In this study, we identified a Hunan family of Chinese descent with two affected members clinically diagnosed with Usher syndrome type 3 (USH3) displaying hearing, visual acuity, and olfactory decline. Whole-exome sequencing (WES) identified a nonsense variant in ABHD12 gene that was confirmed to be segregated in this family by Sanger sequencing and exhibited a recessive inheritance pattern. In this family, two patients carried homozygous variant in the ABHD12 (NM_015600: c.249C>G). Mutation of ABHD12 , an enzyme that hydrolyzes an endocannabinoid lipid transmitter, caused incomplete PHARC syndrome, as demonstrated in previous reports. Therefore, we also conducted a summary based on variants in ABHD12 in PHARC patients, and in PHARC patients showing that there was no obvious correlation between the genotype and phenotype. We believe that this should be considered during the differential diagnosis of USH. Our findings predicted the potential function of this gene in the development of hearing and vision loss, particularly with regard to impaired signal transmission, and identified a novel nonsense variant to expand the variant spectrum in ABHD12. • A novel ABHD12 nonsense variant has been found in an Usher syndrome type 3 family. • A genotype-phenotype spectrum review based on variants in ABHD12 • ABHD12 may be involved in interactions with Usher proteins. [ABSTRACT FROM AUTHOR]

Abstract Introduction MYO7A gene has been shown to be associated with Usher syndrome 1B and nonsyndromic deafness. Although a lot of mutations have been reported in MYO7A gene, novel MYO7A mutations are continuously to be identified. Methods Targeted next generation sequencing was performed on the two unrelated patients with Usher syndrome 1B and nonsyndromic deafness respectively. The identified mutations from targeted next generation sequencing were further validated by Sanger sequencing, and analyzed by bioinformatics tools, like SIFT, Polyphen-2, PyMOL, I-Mutant 2.0 and so on. Results By analyzing the sequencing data of these two patients, four novel MYO7A mutations were revealed: (i) MYO7A p.Tyr560Ser and p.Ala2039Pro were associated with Usher syndrome 1B. (ii) MYO7A c.2187 + 2_+8 delTGAGCAC and p.Leu728Pro were related to nonsyndromic hearing loss. These mutations were further proved to be possibly disease-causing by segregation analysis, conservation analysis and bioinformatics tools. Conclusions Four novel MYO7A mutations were identified in the present study. These findings provided new evidence for the genetic counseling of Usher syndrome 1B and nonsyndromic deafness. [ABSTRACT FROM AUTHOR]

Whirlin is a protein essential to sensory neurons. Its defects are responsible for nonsyndromic deafness or for the Usher syndrome, a condition associating congenital deafness and progressive blindness. This large multidomain scaffolding protein is expressed in three isoforms with different functions and localizations in stereocilia bundles of hearing hair cells or in the connecting cilia of photoreceptor cells. The HHD2 domain of whirlin is the only domain shared by all isoforms, but its function remains unknown. In this article, we report its crystal structure in two distinct conformations, a monomeric five‐helix bundle, similar to the known structure of other HHD domains, and a three‐helix bundle organized as a swapped dimer. Most of the hydrophobic contacts and electrostatic interactions that maintain the globular monomeric form are conserved at the protomer interface of the dimer. NMR experiments revealed that the five‐helix conformation is predominant in solution, but exhibits increased dynamics on one face encompassing the hinge loops. Using NMR and SAXS, we also show that HHD2 does not interact with its preceding domains. Our findings suggest that structural plasticity might play a role in the function of the HHD2 domain. Whirlin is a large multidomain scaffolding protein essential for sound and light perception. One of its domains, the second Harmonin Homology Domain (HHD2), can adopt two conformations: a monomeric five‐helix bundle and a three‐helix bundle organized as a swapped dimer. The HHD2 domain does not interact with adjacent domains of the protein, but its structural plasticity might play a role in regulating whirlin oligomerization or scaffolding function. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study is to report on the results of color vision testing in a European cohort of patients with Usher syndrome (USH). We describe the results in relation to Usher type (USH1 and USH2), age and visual acuity. Methods and methods: The color vision of 220 genetically confirmed adult USH patients, aged 18-70 years, was analyzed with one of three methods: the Farnsworth D-15 Dichotomous test (D-15) along with the Lanthony desaturated 15 Hue tests (D-15d), the Roth 28-Hue test, or the Ishihara 14-plate test. Visual acuity was measured with either the ETDRS or the SNELLEN charts. The Confusion index, the Selectivity index and the Confusion angle were calculated for the panel tests and used for analysis. The numbers of plates that could not be read were analyzed for the Ishihara test. Results: For the panel tests, the degree of color loss (Confusion index) is similar in both subtypes of USH, but the polarization of error scores (Selectivity index) is significantly lower in USH1 than USH2, showing more diffuse errors than those found in USH2. There is no significant correlation between logMAR visual acuity and the Confusion or the Selectivity indices. Additionally, we find a significant correlation between patient age and the degree and the polarity of the loss only in USH2. There was no difference between USH1 and USH2 in the results of the Ishihara test. Conclusions: The examination of color vision in patients with USH shows a significant difference in the pattern of color vision loss in USH1 and USH2 patients, but not in the severity of the loss. In USH2, we find a correlation between patient age and the degree and the polarity of the loss. These results may be due to differences in the pathogenesis of retinal dystrophy in USH1 and USH2. [ABSTRACT FROM AUTHOR]

Introduction: Mutations in USH2A cause both isolated Retinitis Pigmentosa (RP) and Usher syndrome (that implies RP and hearing impairment). One of the most frequent variants identified in this gene and among these patients is the p.(Cys759Phe) change. However, the pathogenic role of this allele has been questioned since it was found in homozygosity in two healthy siblings of a Spanish family. To assess the causative role of USH2A p.(Cys759Phe) in autosomal recessive RP (ARRP) and Usher syndrome type II (USH2) and to establish possible genotype-phenotype correlations associated with p.(Cys759Phe), we performed a comprehensive genetic and clinical study in patients suffering from any of the two above-mentioned diseases and carrying at least one p.(Cys759Phe) allele. Materials and methods: Diagnosis was set according to previously reported protocols. Genetic analyses were performed by using classical molecular and Next-Generation Sequencing approaches. Probands of 57 unrelated families were molecularly studied and 63 patients belonging to these families were phenotypically evaluated. Results: Molecular analysis characterized 100% of the cases, identifying: 11 homozygous patients for USH2A p.(Cys759Phe), 42 compound heterozygous patients (12 of them with another missense USH2A pathogenic variant and 30 with a truncating USH2A variant), and 4 patients carrying the p.(Cys759Phe) allele and a pathogenic variant in another RP gene (PROM1, CNGB1 or RP1). No additional causative variants were identified in symptomatic homozygous patients. Statistical analysis of clinical differences between zygosity states yielded differences (p≤0.05) in age at diagnosis of RP and hypoacusis, and progression of visual field loss. Homozygosity of p.(Cys759Phe) and compound heterozygosity with another USH2A missense variant is associated with ARRP or ARRP plus late onset hypoacusis (OR = 20.62, CI = 95%, p = 0.041). Conclusions: The present study supports the role of USH2A p.(Cys759Phe) in ARRP and USH2 pathogenesis, and demonstrates the clinical differences between different zygosity states. Phenotype-genotype correlations may guide the genetic characterization based upon specific clinical signs and may advise on the clinical management and prognosis based upon a specific genotype. [ABSTRACT FROM AUTHOR]

BACKGROUND: Research has demonstrated that persons with Usher syndrome type 1 (USH1) have significantly poorer physical and psychological health compared to a reference group. PURPOSE: To explore the relation between work, health, social trust, and financial situation in USH1 compared to a reference group. MATERIAL: Sixty-six persons (18–65 y) from the Swedish Usher database received a questionnaire and 47 were included, 23 working and 24 non-working. The reference group comprised 3,049 working and 198 non-working persons. METHODS: The Swedish Health on Equal Terms questionnaire was used and statistical analysis with multiple logistic regression was conducted. RESULTS: The USH1 non-work group had a higher Odds ratio (95% CI) in poor psychological and physical health, social trust, and financial situation compared to the USH1 work group and reference groups. Age, gender, hearing, and vision impairment did not explain the differences. The relation between the USH1 work and non-work groups showed the same pattern as the reference groups, but the magnitude of problems was significantly higher. CONCLUSIONS: Both disability and unemployment increased the risk of poor health, social trust and financial situation in persons with USH1, but having an employment seemed to counteract the risks related to disability. [ABSTRACT FROM AUTHOR]

The genetic, mutational and phenotypic spectrum of deafness‐causing genes shows great diversity and pleiotropy. The best examples are the group of genes, which when mutated can either cause non‐syndromic hearing loss (NSHL) or the most common dual sensory impairment, Usher syndrome (USH). Variants in the CIB2 gene have been previously reported to cause hearing loss at the DFNB48 locus and deaf‐blindness at the USH1J locus. In this study, we characterize the phenotypic spectrum in a multiethnic cohort with autosomal recessive non‐syndromic hearing loss (ARNSHL) due to variants in the CIB2 gene. Of the 6 families we ascertained, 3 segregated novel loss‐of‐function (LOF) variants, 2 families segregated missense variants (1 novel) and 1 family segregated a previously reported pathogenic variant in trans with a frameshift variant. This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients. Here, we provide evidence disqualifying CIB2 as an USH‐causing gene. [ABSTRACT FROM AUTHOR]

Usher syndrome, Type 1C (USH1C) is an autosomal recessive inherited disorder in which a mutation in the gene encoding harmonin is associated with multi-sensory deficits (i.e., auditory, vestibular, and visual). USH1C (Usher) mice, engineered with a human USH1C mutation, exhibit these multi-sensory deficits by circling behavior and lack of response to sound. Administration of an antisense oligonucleotide (ASO) therapeutic that corrects expression of the mutated USH1C gene, has been shown to increase harmonin levels, reduce circling behavior, and improve vestibular and auditory function. The current study evaluates the organization of exploratory movements to assess spatial organization in Usher mice and determine the efficacy of ASO therapy in attenuating any such deficits. Usher and heterozygous mice received the therapeutic ASO, ASO-29, or a control, non-specific ASO treatment at postnatal day five. Organization of exploratory movements was assessed under dark and light conditions at two and six-months of age. Disruptions in exploratory movement organization observed in control-treated Usher mice were consistent with impaired use of self-movement and environmental cues. In general, ASO-29 treatment rescued organization of exploratory movements at two and six-month testing points. These observations are consistent with ASO-29 rescuing processing of multiple sources of information and demonstrate the potential of ASO therapies to ameliorate topographical disorientation associated with other genetic disorders. [ABSTRACT FROM AUTHOR]

Objective: To assess the outcome and efficacy of cochlear implantation in children with genetic syndromes.Method: Study design: case–control study.Setting: A cochlear implantation tertiary referral center.Patients: All pediatric cochlear implantation recipients with Waardenburg syndrome, Usher syndrome, Dandy–Walker syndrome, or albinism. A control group was appropriately matched to the syndromic group with regard to age at implantation and duration of device use.Intervention: Cochlear implantation.Main outcome measures: Subjects’ auditory abilities, speech intelligibility, and pure tone thresholds were compared between the syndromic and non-syndromic group.Results: A total of 25 subjects (13 syndromic and 12 non-syndromic) participated in the study. Neither auditory ability nor speech intelligibility scores differed significantly by group. The final PTA of both the groups showed normal-to-mild hearing loss: 26 dB HL in the syndromic group and 23 dB HL for the control group.Conclusions: Cochlear implant recipients with genetic syndromes achieved similar levels auditory perception and speech intelligibility as their peers with a genetic syndrome. The presence of any of the genetic syndromes described herein should not be a contraindication to cochlear implant provision, as it would have a positive impact on the patients’ sensory perception and lifestyle. [ABSTRACT FROM AUTHOR]

Objectives We aimed to investigate the genetic causes of hearing loss in a Chinese proband with autosomal recessive congenital deafness. Methods The targeted capture of 159 known deafness genes and next-generation sequencing were performed to study the genetic causes of hearing loss in the Chinese family. Sanger sequencing was employed to verify the variant mutations in members of this family. Results The proband harbored two mutations in the MYO7A gene in the form of compound heterozygosity. She was found to be heterozygous for a novel insertion mutation c.3847_3848 ins TCTG (p.N1285LfsX24) in exon 30 and for the known mutation c.2239_2240delAG (p.R747S fsX16)in exon 19. The novel mutation was absent in the 1000 Genomes Project. These variants were carried in the heterozygous state by the parents and were therefore co-segregated with the genetic disease. Clinical re-assessment, including detailed audiologic and ocular examinations, revealed congenital deafness and retinitis pigmentosa in the proband. Collectively, the combination of audiometric, ophthalmologic and genetic examinations successfully confirmed the phenotype of Usher syndrome type 1 (USH1). Conclusion This study demonstrates that the novel mutation c.3847_3848insTCTG (p. N1285LfsX24) in compound heterozygosity with c.2239_2240delAG in the MYO7A gene is the main cause of USH1 in the proband. Our study expands the mutational spectrum of MYO7A and provides a foundation for further investigations elucidating the MYO7A -related mechanisms of USH1. [ABSTRACT FROM AUTHOR]

The MYO7A gene encodes a protein belonging to the unconventional myosin super family. Mutations within MYO7A can lead to either non syndromic hearing loss or to the Usher syndrome type 1B (USH1B). Here, we report the results of genetic analyses performed on Moroccan families with autosomal recessive non syndromic hearing loss that identified two families with compound heterozygous MYO7A mutations. Five mutations (c.6025delG, c.6229T>A, c.3500T>A, c.5617C>T and c.4487C>A) were identified in these families, the latter presenting two differently affected branches. Multiple bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. In conclusion, the absence of vestibular and retinal symptom in the affected patients suggests that these families have the isolated non-syndromic hearing loss DFNB2 (nonsyndromic autosomal recessive hearing loss) presentation, instead of USH1B. [ABSTRACT FROM AUTHOR]

The genetic underpinnings of recessively inherited moderate to severe sensorineural hearing loss are not well understood, despite its higher prevalence in comparison to profound deafness. We recruited 92 consanguineous families segregating stable or progressive, recessively inherited moderate or severe hearing loss. We utilized homozygosity mapping, Sanger sequencing, targeted capture of known deafness genes with massively parallel sequencing and whole exome sequencing to identify the molecular basis of hearing loss in these families. Variants of the known deafness genes were found in 69% of the participating families with the SLC26A4, GJB2, MYO15A, TMC1, TMPRSS3, OTOF, MYO7A and CLDN14 genes together accounting for hearing loss in 54% of the families. We identified 20 reported and 21 novel variants in 21 known deafness genes; 16 of the 20 reported variants, previously associated with stable, profound deafness were associated with moderate to severe or progressive hearing loss in our families. These data point to a prominent role for genetic background, environmental factors or both as modifiers of human hearing loss severity. [ABSTRACT FROM AUTHOR]

Usher syndrome (USH) is an autosomal recessive disorder characterized by a dual sensory impairment affecting hearing and vision. USH is clinically and genetically heterogeneous. Ten different causal genes have been reported. We studied the molecular bases of the disease in 18 unrelated Algerian patients by targeted-exome sequencing, and identified the causal biallelic mutations in all of them: 16 patients carried the mutations at the homozygous state and 2 at the compound heterozygous state. Nine of the 17 different mutations detected in MYO7A (1 of 5 mutations), CDH23 (4 of 7 mutations), PCDH15 (1 mutation), USH1C (1 mutation), USH1G (1 mutation), and USH2A (1 of 2 mutations), had not been previously reported. The deleterious consequences of a missense mutation of CDH23 (p.Asp1501Asn) and the in-frame single codon deletion in USH1G (p.Ala397del) on the corresponding proteins were predicted from the solved 3D-structures of extracellular cadherin (EC) domains of cadherin-23 and the sterile alpha motif (SAM) domain of USH1G/sans, respectively. In addition, we were able to show that the USH1G mutation is likely to affect the binding interface between the SAM domain and USH1C/harmonin. This should spur the use of 3D-structures, not only of isolated protein domains, but also of protein-protein interaction interfaces, to predict the functional impact of mutations detected in the USH genes. [ABSTRACT FROM AUTHOR]

BECAUSE LITTLE is known about teacher-student relationships that involve students with acquired deafblindness, the authors performed a multiple case study with a multiple-method design to investigate the relationship between need-supportive teaching behaviors and student en- gagement. Using self-determination theory (Deci & Ryan, 2000), they analyzed video observations of interactions. It was found that teachers' provision of structure, autonomy support, and involvement often co-occurs with higher levels of student engagement. Moreover, varying degrees of need support over time seem to result in varying levels of student engagement. Examples are provided of need-supportive teaching behaviors that can be used to foster the motivation of students with acquired deafblindness. [ABSTRACT FROM AUTHOR]

Usher syndrome is a group of autosomal recessive diseases characterized by congenital deafness and retinitis pigmentosa. In a mouse model for Usher syndrome, KMush/ush, discovered in our laboratory, we measured the phenotypes, characterized the architecture and morphology of the retina, and quantified the level of expression of pde6b and ush2a between postnatal (P) days 7, and 56. Electroretinograms and auditory brainstem response were used to measure visual and auditory phenotypes. Fundus photography and light microscopy were used to measure the architecture and morphology of the retina. Quantitative real-time PCR was used to measure the expression levels of mRNA. KMush/ush mice had low amplitudes and no obvious waveforms of Electroretinograms after P14 compared with controls. Thresholds of auditory brainstem response in our model were higher than those of controls after P14. By P21, the retinal vessels of KMush/ush mice were attenuated and their optic discs had a waxy pallor. The retinas of KMush/ush mice atrophied and the choroidal vessels were clearly visible. Notably, the architecture of each retinal layer was not different as compared with control mice at P7, while the outer nuclear layer (ONL) and other retinal layers of KMush/ush mice were attenuated significantly between P14 and P21. ONL cells were barely seen in KMush/ush mice at P56. As compared with control mice, the expression of pde6b and ush2a in KMush/ush mice declined significantly after P7. This study is a first step toward characterizing the progression of disease in our mouse model. Future studies using this model may provide insights about the etiology of the disease and the relationships between genotypes and phenotypes providing a valuable resource that could contribute to the foundation of knowledge necessary to develop therapies to prevent the retinal degeneration in patients with Usher Syndrome. [ABSTRACT FROM AUTHOR]

Objectives Mutations in MYO7A gene have been reported to be associated with Usher Syndrome type 1B (USH1B) and nonsyndromic hearing loss (DFNB2, DFNA11). Most mutations in MYO7A gene caused USH1B, whereas only a few reported mutations led to DFNB2 and DFNA11. The current study was designed to investigate the mutations among a Chinese family with autosomal recessive hearing loss. Methods In this study, we present the clinical, genetic and molecular characteristics of a Chinese family. Targeted capture of 127 known deafness genes and next-generation sequencing were employed to study the genetic causes of two siblings in the Chinese family. Sanger sequencing was employed to examine those variant mutations in the members of this family and other ethnicity-matched controls. Results We identified the novel compound heterozygous mutant alleles of MYO7A gene: a novel missense mutation c.3671C > A (p.A1224D) and a reported insert mutation c.390_391insC (p.P131PfsX9). Variants were further confirmed by Sanger sequencing. These two compound heterozygous variants were co-segregated with autosomal recessive hearing loss phenotype. The gene mutation analysis and protein sequence alignment further supported that the novel compound heterozygous mutations were pathogenic. Conclusion The novel compound heterozygous mutations (c.3671C > A and c.390_391insC) in MYO7A gene identified in this study were responsible for the autosomal recessive sensorineural hearing loss of this Chinese family. [ABSTRACT FROM AUTHOR]