Genetic screening of Russian Usher syndrome patients toward selection for gene therapy

Ivanova, Mariya; Trubilin, Vladimir N.; Атарщиков, Д. С.; Demchinsky, A. M.; Стрельников, В. В.; Танас, А. С.; Orlova, Olga; Machalov, Anton S; Overchenko, Kira V; Маркова, Т. В.; Golenkova, Daria M; Anoshkin, K.I.; Volodin, I.V.; Zaletaev, D. V.; Пулин, А А; Nadelyaeva, Irina I.; Калинкин, А.И.; Barh, Debmalya

doi:10.1080/13816810.2018.1532527

Cited by 13 publications

(7 citation statements)

References 21 publications

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“…The most common pathogenic variant of the USH2A gene was the c.11864G>A mutation (p.Trp3955*), which accounted for half of the mutant alleles (9/18). In an earlier study of another sample of Russian patients with Usher syndrome, the p.Trp3955* mutation was found in 30% (6/28) of mutant gene alleles, which was not statistically different from the results of this study (ꭓ 2 = 2.182, p = 0.14) [ 29 ].…”

Section: Resultscontrasting

confidence: 85%

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

Shatokhina

Галеева

Степанова

et al. 2022

IJMS

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Hearing loss is one of the most genetically heterogeneous disorders known. Over 120 genes are reportedly associated with non-syndromic hearing loss (NSHL). To date, in Russia, there have been relatively few studies that apply massive parallel sequencing (MPS) methods to elucidate the genetic factors underlying non-GJB2-related hearing loss cases. The current study is intended to provide an understanding of the mutation spectrum in non-GJB2-related hearing loss in a cohort of Russian sensorineural NSHL patients and establish the best diagnostic algorithm. Genetic testing using an MPS panel, which included 33 NSHL and syndromic hearing loss (SHL) genes that might be misdiagnosed as NSHL genes, was completed on 226 sequentially accrued and unrelated patients. As a result, the molecular basis of deafness was found in 21% of the non-GJB2 NSHL cases. The total contribution pathogenic, and likely pathogenic, variants in the genes studied among all hereditary NSHL Russian patients was 12%. STRC pathogenic and likely pathogenic, variants accounted for 30% of diagnoses in GJB2-negative patients, providing the most common diagnosis. The majority of causative mutations in STRC involved large copy number variants (CNVs) (80%). Among the point mutations, the most common were c.11864G>A (p.Trp3955*) in the USH2A gene, c.2171_2174delTTTG (p.Val724Glyfs*6) in the STRC gene, and c.107A>C (p.His36Pro) and c.1001G>T (p.Gly334Val) in the SLC26A4 gene. Pathogenic variants in genes involved in SHL accounted for almost half of the cases with an established molecular genetic diagnosis, which were 10% of the total cohort of patients with non-GJB2-related hearing loss.

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Section: Resultscontrasting

confidence: 85%

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

Shatokhina

Галеева

Степанова

et al. 2022

IJMS

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“…The high frequency of p.Trp3955Ter mutation and its relatively homogenic haplotypic structure in non-related patients can be explained as a founder effect, presumably as a result of migrations from neighbouring populations. Interestingly, very recent study showed 50% of p.Trp3955Ter mutation in Russian cohort of USH2A patients, however their haplotype was not yet determined [38]. At least four different p.Trp3955Ter-linked haplotypes were observed in homozygous individuals, contributing the one common ancestral p.Trp3955Ter mutational event.…”

Section: Discussionmentioning

confidence: 95%

Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation

Zupan

Fakin

Battelino

et al. 2019

Genes

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Purpose: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G>A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. Methods: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. The High-Resolution Melting (HRM) method was developed for fast and reliable detection of the c.11864G>A mutation. Results: The c.11864G>A mutation represents the vast majority of pathogenic alleles in Slovenian USH2A-Usher syndrome population (84%). The median age of onset of nyctalopia was 16 years and all patients younger than 40 years had hyperautofluorescent rings on fundus autofluorescence imaging. The Kaplan Meier survival analysis showed a decline of central vision after the age of 40, with 50% patients reaching visual acuity (VA) ≤ 0.05 at the average age of 66 years visual field diameter less than 20° at the average age of 59 years. There was a relatively large phenotypic variability in the retinal and audiological phenotype. Analysis of the p.Trp3955Ter-homozygous patients revealed four different haplotypes, with the frequency of the most common haplotype ~65%. Disease severity did not correlate with the haplotype. Conclusions: According to the natural history of homozygous p.Trp3955Ter patients any therapy aimed to slow disease progression in these patients would be best started before the age of 40. Phenotypic variability suggests the presence of cis and/or trans factors outside the USH2A gene that are able to affect disease severity. High frequency of p.Trp3955Ter mutation in Slovenian USH2A gene pool appears to be initiated from different unrelated founders because of migrations from neighboring populations. The mutation on haplotype 2 seems to be the major founder allele.

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“…Genetic screening and the accurate diagnosis of Usher syndrome in different populations is necessary (Ben-Rebeh et al, 2016;Sun et al, 2018;Santana et al, 2019). Efficient molecular diagnosis of Usher syndrome in a patient's early childhood is of utmost importance, allowing better genetic counseling and therapeutic management (Ben-Rebeh et al, 2016;Ivanova et al, 2018;Maddalena et al, 2018;Jouret et al, 2019). With accurate gene diagnosis for Usher syndrome, the repair of specific mutations using a CRISPR/Cas9 editing system may be possible.…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the CDH23 Gene Causing Usher Syndrome Type ID in a Chinese Patient

et al. 2020

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Usher syndrome includes a group of genetically and clinically heterogeneous autosomal recessive diseases, such as retinitis pigmentosa (RP) and sensorineural hearing loss. Usher syndrome type I (USHI) is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to RP. The relationships between the Usher syndrome causing genes and the resultant phenotypes of Usher syndrome have not yet been fully elucidated. In the present study, we recruited a Chinese family with Usher syndrome and conducted paneled next-generation sequencing, Sanger sequencing, segregation analysis, and expression profile analysis. The functional effects of the identified cadherin-related 23 (CDH23) pathogenic variants were analyzed. The M101 pedigree consisted of a proband and seven family members, and the proband was a 39-year-old Chinese male who claimed that he first began to experience night blindness 11 years ago. We revealed novel, missense compound heterozygous variants c. 2572G > A (p.V858I) and c. 2891G > A (p.R964Q) in the CDH23 gene, which co-segregated with the disease phenotype causing Usher syndrome type ID (USH1D) in this Chinese pedigree. CDH23 mRNA was highly expressed in the retina, and this protein was highly conserved as revealed by the comparison of Homo sapiens CDH23 with those from nine other species. This is the first study to identify the novel, missense compound heterozygous variants c. 2572G > A (p.V858I) and c.2891G > A (p.R964Q) of CDH23, which might cause USH1D in the studied Chinese family, thereby extending CDH23 mutation spectra. Identifying CDH23 pathogenic variants should help in the detailed phenotypic characterization of USH1D.

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Genetic screening of Russian Usher syndrome patients toward selection for gene therapy

Cited by 13 publications

References 21 publications

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation

Targeted Next-Generation Sequencing Identified Novel Compound Heterozygous Variants in the CDH23 Gene Causing Usher Syndrome Type ID in a Chinese Patient

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