Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype–phenotype correlation

Bernal, Sara; Medà, Carme; Solans, Teresa Torrent; Ayuso, Carmen; Garcı́a-Sandoval, Blanca; Valverde, Diana; Río, E. Del; Baiget, Montserrat

doi:10.1111/j.1399-0004.2005.00481.x

Cited by 40 publications

(23 citation statements)

References 33 publications

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“…58 It is also known that there is both interfamilial and intrafamilial phenotypic variation among subjects with the same USH2A mutated genotype. 58,60 In accordance with previous reports, we were not able to assign any phenotypic variation to the particular mutations detected in this study. This observation implies that the clinical manifestations of USH2A may be modulated by environmental or genetic modifiers or stochastic factors.…”

Section: Discussionsupporting

confidence: 91%

Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II

et al. 2009

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Usher syndrome type II (USH2) is an autosomal recessive disorder characterized by moderate to severe hearing impairment and progressive visual loss due to retinitis pigmentosa (RP). To identify novel mutations and determine the frequency of USH2A mutations as a cause of USH2, we have carried out mutation screening of all 72 coding exons and exon–intron splice sites of the USH2A gene. A total of 20 USH2 American probands of European descent were analyzed using single strand conformational polymorphism (SSCP) and direct sequencing methods. Ten different USH2A mutations were identified in 55% of the probands, five of which were novel mutations. The detected mutations include three missense, three frameshifts and four nonsense mutations, with c.2299delG/p.E767fs mutation, accounting for 38.9% of the pathological alleles. Two cases were homozygotes, two cases were compound heterozygotes and one case had complex allele with three variants. In seven probands, only one USH2A mutation was detected and no pathological mutation was found in the remaining eight individuals. Altogether, our data support the fact that c.2299delG/p.E767fs is indeed the most common USH2A mutation found in USH2 patients of European Caucasian background. Thus, if screening for mutations in USH2A is considered, it is reasonable to screen for the c.2299delG mutation first.

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Section: Discussionsupporting

confidence: 91%

Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II

et al. 2009

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“…Progressive hearing loss was reported in patients who are heterozygous for the most common mutation in the USH2A gene, 2299delG, and another frequent mutation of the gene, C759F. 64–66 The C759F mutation in homozygous state was reported to cause nonsyndromic RP. 67–69 The protein encoded by the VLGRI (very large G-protein coupled receptor 1) gene at the USH2C locus is a member of the serpentine G-protein coupled receptor superfamily.…”

Section: Ush Is Clinically and Genetically Heterogeneousmentioning

confidence: 99%

Genetics and pathological mechanisms of Usher syndrome

2010

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Usher syndrome (USH) comprises a group of autosomal recessively inherited disorders characterized by a dual sensory impairment of the audiovestibular and visual systems. Three major clinical subtypes (USH type I, USH type II and USH type III) are distinguished on the basis of the severity of the hearing loss, the presence or absence of vestibular dysfunction and the age of onset of retinitis pigmentosa (RP). Since the cloning of the first USH gene (MYO7A) in 1995, there have been remarkable advances in elucidating the genetic basis for this disorder, as evidence for 11 distinct loci have been obtained and genes for 9 of them have been identified. The USH genes encode proteins of different classes and families, including motor proteins, scaffold proteins, cell adhesion molecules and transmembrane receptor proteins. Extensive information has emerged from mouse models and molecular studies regarding pathogenesis of this disorder and the wide phenotypic variation in both audiovestibular and/or visual function. A unifying hypothesis is that the USH proteins are integrated into a protein network that regulates hair bundle morphogenesis in the inner ear. This review addresses genetics and pathological mechanisms of USH. Understanding the molecular basis of phenotypic variation and pathogenesis of USH is important toward discovery of new molecular targets for diagnosis, prevention and treatment of this debilitating disorder.

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“…Following the data filtering workflow (see Methods section), we were able to detect 3 mutations previously reported as pathogenic in 14 IRD-affected individuals: 6/14 with a p.Cys759Phe mutation (rs80338902) [24,25] in the Usher syndrome-related gene, USH2A, 2/14 with a p.Arg257* stop codon mutation (rs121909398) [26,27] in the RP-related gene, CERKL, and 3/14 with a p.Met390Arg mutation (rs113624356) [28] in the BBS-related gene, BBS1. Two of these 3 findings in the BBS1 gene correspond to positive control patients previously diagnosed using high-resolution melting analysis [22].…”

Section: Resultsmentioning

confidence: 99%

A Cost-Effective Mutation Screening Strategy for Inherited Retinal Dystrophies

Barandika

Irigoyen²,

Anasagasti³

et al. 2016

Ophthalmic Res

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Objective: We developed a simple, time- and cost-effective Excel-based genetic screening strategy for the diagnosis of inherited retinal dystrophies (IRD). Design: 76 patients diagnosed with IRD and 112 nonaffected family members, from 55 unrelated families, were included. DNA samples were analyzed using Axiom Exome Genotyping Array Plates (Affymetrix) that contain over 300,000 genetic variants, including more than 5,000 variants present in 181 genes involved in IRD. We used a simple Excel-based data mining strategy in order to screen IRD variants likely involved in the development of IRD. Results: A total of 5 relevant genetic variants were found in 5 IRD genes. Four variants were reported either as pathogenic or with a prediction of probably damaging, and 1 variant was reported to affect a regulatory region. These variants were present in 14 patients and in 11 carriers, in 10 unrelated families. Conclusion: Using our Excel-based data screening strategy, we were able to assign likely genetic diagnoses in a fast and cost-effective manner to over 18% of patients analyzed, with a comparable ratio of genetic findings to that reported with retina-specific arrays for about 1/5 of the cost. Our approach proved efficient in reducing costs and time for IRD diagnosis as a first tier genetic screening method.

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Clinical and genetic studies in Spanish patients with Usher syndrome type II: description of new mutations and evidence for a lack of genotype–phenotype correlation

Cited by 40 publications

References 33 publications

Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II

Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II

Genetics and pathological mechanisms of Usher syndrome

A Cost-Effective Mutation Screening Strategy for Inherited Retinal Dystrophies

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