Abstract:BackgroundUsher syndrome (USH) is a genetically heterogeneous deafness‐blindness syndrome, divided into three clinical subtypes: USH1, USH2 and USH3.MethodsMutations in 21 out of 26 investigated Danish unrelated individuals with USH were identified, using a combination of molecular diagnostic methods.ResultsBefore Next Generation Sequencing (NGS) became available mutations in nine individuals (1 USH1, 7 USH2, 1 USH3) were identified by Sanger sequencing of USH1C,USH2A or CLRN1 or by Arrayed Primer EXtension (A… Show more
“…Combined TES and Sanger-DNA direct sequencing determined that our overall mutation detection rate for the current cohort was 78.2%. This solving proportion is compatible with the reported rates in several previous studies using TES or Sanger-DNA direct sequencing 6,10,11,[26][27][28] ; however, it is still about 15% lower than the 92.7% rate reported recently by Bonnet et al 12 The mutation detection rate is related to the accuracy of the patients' clinical diagnoses. In our study, the mutation detection rate (85%) for USH1 patients was higher than that (76.8%) for USH2 patients.…”
Section: Discussionsupporting
confidence: 90%
“…25 Several studies have proven TES as a highefficiency method of molecular diagnosis of USH, with a detection rate of around 70%. 10,[26][27][28][29] Targeted NGS can detect both point mutations and large genomic DNA rearrangements; its ability to detect CNVs is related to the coverage depth of TES. 10,26 In one Spanish study, six different CNVs of USH2A, CDH23, PCDH15, and GPR98 were detected by their own capture panel TES, with a mean coverage of 1334x.…”
PURPOSE. Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations.
METHODS.A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations.
RESULTS.We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles.
CONCLUSIONS.Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.
“…Combined TES and Sanger-DNA direct sequencing determined that our overall mutation detection rate for the current cohort was 78.2%. This solving proportion is compatible with the reported rates in several previous studies using TES or Sanger-DNA direct sequencing 6,10,11,[26][27][28] ; however, it is still about 15% lower than the 92.7% rate reported recently by Bonnet et al 12 The mutation detection rate is related to the accuracy of the patients' clinical diagnoses. In our study, the mutation detection rate (85%) for USH1 patients was higher than that (76.8%) for USH2 patients.…”
Section: Discussionsupporting
confidence: 90%
“…25 Several studies have proven TES as a highefficiency method of molecular diagnosis of USH, with a detection rate of around 70%. 10,[26][27][28][29] Targeted NGS can detect both point mutations and large genomic DNA rearrangements; its ability to detect CNVs is related to the coverage depth of TES. 10,26 In one Spanish study, six different CNVs of USH2A, CDH23, PCDH15, and GPR98 were detected by their own capture panel TES, with a mean coverage of 1334x.…”
PURPOSE. Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations.
METHODS.A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations.
RESULTS.We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles.
CONCLUSIONS.Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.
“…The distribution of clinical diagnoses is biased due to several previous research projects of specific diagnostic subgroups and diagnostic efforts during the years. Individuals with one of following clinical diagnoses: Stargardt disease 6 , achromatopsia 7 , Usher syndrome 8 , Bardet-Biedl syndrome 9 , Best vitelliform macular dystrophy 10 , choroideremia 11 , Leber congenital amaurosis 12 , XL and AD retinitis pigmentosa 13 , congenital stationary night blindness 14 , cone dystrophy and Åland eye disease 15 were included in previous research projects, and are therefore represented by lower numbers than might be expected.Figure 1( A ) Distribution of 677 individuals in seven groups based on clinical diagnosis. The number in brackets refer to the clinical group, and n = number of individuals.…”
Inherited retinal diseases (IRDs) are a common cause of visual impairment. IRD covers a set of genetically highly heterogeneous disorders with more than 150 genes associated with one or more clinical forms of IRD. Molecular genetic diagnosis has become increasingly important especially due to expanding number of gene therapy strategies under development. Next generation sequencing (NGS) of gene panels has proven a valuable diagnostic tool in IRD. We present the molecular findings of 677 individuals, residing in Denmark, with IRD and report 806 variants of which 187 are novel. We found that deletions and duplications spanning one or more exons can explain 3% of the cases, and thus copy number variation (CNV) analysis is important in molecular genetic diagnostics of IRD. Seven percent of the individuals have variants classified as pathogenic or likely-pathogenic in more than one gene. Possible Danish founder variants in EYS and RP1 are reported. A significant number of variants were classified as variants with unknown significance; reporting of these will hopefully contribute to the elucidation of the actual clinical consequence making the classification less troublesome in the future. In conclusion, this study underlines the relevance of performing targeted sequencing of IRD including CNV analysis as well as the importance of interaction with clinical diagnoses.
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.
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