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Audiology Research Jan 2022Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are... (Review)
Review
Usher syndrome (USH) is the most common genetic condition responsible for combined loss of hearing and vision. Balance disorders and bilateral vestibular areflexia are also observed in some cases. The syndrome was first described by Albrecht von Graefe in 1858, but later named by Charles Usher, who presented a large number of cases with hearing loss and retinopathy in 1914. USH has been grouped into three main clinical types: 1, 2, and 3, which are caused by mutations in different genes and are further divided into different subtypes. To date, nine causative genes have been identified and confirmed as responsible for the syndrome when mutated: , , , , and for Usher type 1; , , and for Usher type 2; for Usher type 3. USH is inherited in an autosomal recessive pattern. Digenic, bi-allelic, and polygenic forms have also been reported, in addition to dominant or nonsyndromic forms of genetic mutations. This narrative review reports the causative forms, diagnosis, prognosis, epidemiology, rehabilitation, research, and new treatments of USH.
PubMed: 35076463
DOI: 10.3390/audiolres12010005 -
International Journal of Molecular... Jun 2021Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular... (Review)
Review
Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to be causative of USH, and six more related to the disease. These genes encode proteins of a diverse nature, which interact and form a dynamic protein network called the "Usher interactome". In the organ of Corti, the USH proteins are essential for the correct development and maintenance of the structure and cohesion of the stereocilia. In the retina, the USH protein network is principally located in the periciliary region of the photoreceptors, and plays an important role in the maintenance of the periciliary structure and the trafficking of molecules between the inner and the outer segments of photoreceptors. Even though some genes are clearly involved in the syndrome, others are controversial. Moreover, expression of some USH genes has been detected in other tissues, which could explain their involvement in additional mild comorbidities. In this paper, we review the genetics of Usher syndrome and the spectrum of mutations in USH genes. The aim is to identify possible mutation associations with the disease and provide an updated genotype-phenotype correlation.
Topics: Animals; Cadherin Related Proteins; Cadherins; Cell Cycle Proteins; Ciliopathies; Cytoskeletal Proteins; Disease Models, Animal; Genetic Association Studies; Humans; Membrane Proteins; Mutation; Myosin VIIa; Protein Interaction Maps; Usher Syndromes
PubMed: 34201633
DOI: 10.3390/ijms22136723 -
Human Genetics Apr 2022Usher syndrome (USH) is the most common cause of deaf-blindness in humans, with a prevalence of about 1/10,000 (~ 400,000 people worldwide). Cochlear implants are... (Review)
Review
Usher syndrome (USH) is the most common cause of deaf-blindness in humans, with a prevalence of about 1/10,000 (~ 400,000 people worldwide). Cochlear implants are currently used to reduce the burden of hearing loss in severe-to-profoundly deaf patients, but many promising treatments including gene, cell, and drug therapies to restore the native function of the inner ear and retinal sensory cells are under investigation. The traditional clinical classification of Usher syndrome defines three major subtypes-USH1, 2 and 3-according to hearing loss severity and onset, the presence or absence of vestibular dysfunction, and age at onset of retinitis pigmentosa. Pathogenic variants of nine USH genes have been initially reported: MYO7A, USH1C, PCDH15, CDH23, and USH1G for USH1, USH2A, ADGRV1, and WHRN for USH2, and CLRN1 for USH3. Based on the co-occurrence of hearing and vision deficits, the list of USH genes has been extended to few other genes, but with limited supporting information. A consensus on combined criteria for Usher syndrome is crucial for the development of accurate diagnosis and to improve patient management. In recent years, a wealth of information has been obtained concerning the properties of the Usher proteins, related molecular networks, potential genotype-phenotype correlations, and the pathogenic mechanisms underlying the impairment or loss of hearing, balance and vision. The advent of precision medicine calls for a clear and more precise diagnosis of Usher syndrome, exploiting all the existing data to develop a combined clinical/genetic/network/functional classification for Usher syndrome.
Topics: Genetic Association Studies; Humans; Mutation; Usher Syndromes
PubMed: 35353227
DOI: 10.1007/s00439-022-02448-7 -
Investigative Ophthalmology & Visual... Feb 2021To describe the molecular epidemiology of nonsyndromic retinitis pigmentosa (RP) and Usher syndrome (US) in Italian patients.
PURPOSE
To describe the molecular epidemiology of nonsyndromic retinitis pigmentosa (RP) and Usher syndrome (US) in Italian patients.
METHODS
A total of 591 probands (315 with family history and 276 sporadics) were analyzed. For 155 of them, we performed a family segregation study, considering a total of 382 relatives. Probands were analyzed by a customized multigene panel approach. Sanger sequencing was used to validate all genetic variants and to perform family segregation studies. Copy number variants of selected genes were analyzed by multiplex ligation-dependent probe amplification. Four patients who tested negative to targeted next-generation sequencing analysis underwent clinical exome sequencing.
RESULTS
The mean diagnostic yield of molecular testing among patients with a family history of retinal disorders was 55.2% while the diagnostic yield including sporadic cases was 37.4%. We found 468 potentially pathogenic variants, 147 of which were unpublished, in 308 probands and 66 relatives. Mean ages of onset of the different classes of RP were autosomal dominant RP, 19.3 ± 12.6 years; autosomal recessive RP, 23.2 ± 16.6 years; X-linked RP, 13.9 ± 9.9 years; and Usher syndrome, 18.9 ± 9.5 years. We reported potential new genotype-phenotype correlations in three probands, two revealed by TruSight One testing. All three probands showed isolated RP caused by biallelic variants in genes usually associated with syndromes such as PERCHING and Senior-Loken or with retinal dystrophy, iris coloboma, and comedogenic acne syndrome.
CONCLUSIONS
This is the largest molecular study of Italian patients with RP in the literature, thus reflecting the epidemiology of the disease in Italy with reasonable accuracy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; DNA Mutational Analysis; Extracellular Matrix Proteins; Female; Follow-Up Studies; Genetic Association Studies; Genetic Testing; Humans; Incidence; Italy; Male; Middle Aged; Molecular Epidemiology; Mutation; Pedigree; Phenotype; Retinitis Pigmentosa; Retrospective Studies; Usher Syndromes; Exome Sequencing; Young Adult
PubMed: 33576794
DOI: 10.1167/iovs.62.2.13 -
European Journal of Human Genetics :... Dec 2016Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical...
Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.
Topics: Alleles; Comparative Genomic Hybridization; Europe; Exome; Extracellular Matrix Proteins; Genes, Modifier; Genetic Testing; Humans; Mutation; Sensitivity and Specificity; Sequence Analysis, DNA; Usher Syndromes
PubMed: 27460420
DOI: 10.1038/ejhg.2016.99 -
Journal of Medical Genetics Jan 2012Usher syndrome (USH) is an autosomal recessive disorder comprising retinitis pigmentosa, hearing loss and, in some cases, vestibular dysfunction. It is clinically and...
BACKGROUND
Usher syndrome (USH) is an autosomal recessive disorder comprising retinitis pigmentosa, hearing loss and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous with three distinctive clinical types (I-III) and nine Usher genes identified. This study is a comprehensive clinical and genetic analysis of 172 Usher patients and evaluates the contribution of digenic inheritance.
METHODS
The genes MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, GPR98, WHRN, CLRN1 and the candidate gene SLC4A7 were sequenced in 172 UK Usher patients, regardless of clinical type.
RESULTS
No subject had definite mutations (nonsense, frameshift or consensus splice site mutations) in two different USH genes. Novel missense variants were classified UV1-4 (unclassified variant): UV4 is 'probably pathogenic', based on control frequency <0.23%, identification in trans to a pathogenic/probably pathogenic mutation and segregation with USH in only one family; and UV3 ('likely pathogenic') as above, but no information on phase. Overall 79% of identified pathogenic/UV4/UV3 variants were truncating and 21% were missense changes. MYO7A accounted for 53.2%, and USH1C for 14.9% of USH1 families (USH1C:c.496+1G>A being the most common USH1 mutation in the cohort). USH2A was responsible for 79.3% of USH2 families and GPR98 for only 6.6%. No mutations were found in USH1G, WHRN or SLC4A7.
CONCLUSIONS
One or two pathogenic/likely pathogenic variants were identified in 86% of cases. No convincing cases of digenic inheritance were found. It is concluded that digenic inheritance does not make a significant contribution to Usher syndrome; the observation of multiple variants in different genes is likely to reflect polymorphic variation, rather than digenic effects.
Topics: Cohort Studies; DNA Mutational Analysis; Genetic Association Studies; Genotype; Humans; Multifactorial Inheritance; Mutation; Polymorphism, Single Nucleotide; United Kingdom; Usher Syndromes
PubMed: 22135276
DOI: 10.1136/jmedgenet-2011-100468 -
Therapeutic Advances in Ophthalmology 2020Usher syndrome has three subtypes, each being clinically and genetically heterogeneous characterised by sensorineural hearing loss and retinitis pigmentosa (RP), with or... (Review)
Review
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 accounting for >50% of type 1 and 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.
PubMed: 32995707
DOI: 10.1177/2515841420952194 -
Experimental Eye Research Dec 2020Bilallelic variants in the USH2A gene can cause Usher syndrome type 2 and non-syndromic retinitis pigmentosa. In both disorders, the retinal phenotype involves... (Review)
Review
Bilallelic variants in the USH2A gene can cause Usher syndrome type 2 and non-syndromic retinitis pigmentosa. In both disorders, the retinal phenotype involves progressive rod photoreceptor loss resulting in nyctalopia and a constricted visual field, followed by subsequent cone degeneration, leading to the loss of central vision and severe visual impairment. The USH2A gene raises many challenges for researchers and clinicians due to a broad spectrum of mutations, a large gene size hampering gene therapy development and limited knowledge on its pathogenicity. Patients with Usher type 2 may benefit from hearing aids or cochlear implants to correct their hearing defects, but there are currently no approved treatments available for the USH2A-retinopathy. Several treatment strategies, including antisense oligonucleotides and translational readthrough inducing drugs, have shown therapeutic promise in preclinical studies. Further understanding of the pathogenesis and natural history of USH2A-related disorders is required to develop innovative treatments and design clinical trials based on reliable outcome measures. The present review will discuss the current knowledge about USH2A, the emerging therapeutics and existing challenges.
Topics: DNA; DNA Mutational Analysis; Disease Management; Electroretinography; Extracellular Matrix Proteins; Genotype; Humans; Mutation; Phenotype; Retinal Cone Photoreceptor Cells; Retinal Diseases
PubMed: 33121974
DOI: 10.1016/j.exer.2020.108330