Identification of 13 novel <i>USH2A</i> mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing

Qu, Linghui; Jin, Xin; Long, Yanling; Ren, Jiayun; Chuang-huang, Weng; Xu, Haiwei; Liu, Yong; Meng, Xiangjun; Li, Shiying; Yin, Zhinan

doi:10.1042/bsr20193536

Cited by 6 publications

(8 citation statements)

References 26 publications

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“…In two Japanese RP patients, compound heterozygous mutations c.10859T>C/ p .Ile3620Thr; c.14766G>A/ p .Trp4922* and c.10859T>C/ p .Ile3620Thr; c.11328T>G/ p .Tyr3776* were detected, respectively ( Inaba et al, 2020 ). In a Chinese family RP-F6, mutations c.10859T >C/ p .Ile3620Thr and c.12880delA/ p .I4294Lfs*21 were detected in patients II -3, which were inherited from parents, respectively ( Qu et al, 2020 ). In a Chinese study of RP and USH caused by USH2A mutation, compound heterozygous mutation c.10859T>C/ p .Ile3620Thr; c.8559–2 A G/- was detected in one USH patient.…”

Section: Resultsmentioning

confidence: 99%

Genetic Characteristics and Variation Spectrum of USH2A-Related Retinitis Pigmentosa and Usher Syndrome

Jiang

Han

et al. 2022

Front. Genet.

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Purposes: We aimed to characterize the USH2A genotypic spectrum in a Chinese cohort and provide a detailed genetic profile for Chinese patients with USH2A-IRD.Methods: We designed a retrospective study wherein a total of 1,334 patients diagnosed with IRD were included as a study cohort, namely 1,278 RP and 56 USH patients, as well as other types of IEDs patients and healthy family members as a control cohort. The genotype-phenotype correlation of all participants with USH2A variant was evaluated.Results: Etiological mutations in USH2A, the most common cause of RP and USH, were found in 16.34% (n = 218) genetically solved IRD patients, with prevalences of 14.87% (190/1,278) and 50% (28/56). After bioinformatics and QC processing, 768 distinct USH2A variants were detected in all participants, including 136 disease-causing mutations present in 665 alleles, distributed in 5.81% of all participants. Of these 136 mutations, 43 were novel, nine were founder mutations, and two hot spot mutations with allele count ≥10. Furthermore, 38.5% (84/218) of genetically solved USH2A-IRD patients were caused by at least one of both c.2802T>G and c.8559–2 A>G mutations, and 36.9% and 69.6% of the alleles in the RP and USH groups were truncating, respectively.Conclusion: USH2A-related East Asian-specific founder and hot spot mutations were the major causes for Chinese RP and USH patients. Our study systematically delineated the genotype spectrum of USH2A-IRD, enabled accurate genetic diagnosis, and provided East Asian and other ethnicities with baseline data of a Chinese origin, which would better serve genetic counseling and therapeutic targets selection.

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Section: Resultsmentioning

confidence: 99%

Genetic Characteristics and Variation Spectrum of USH2A-Related Retinitis Pigmentosa and Usher Syndrome

Jiang

Han

et al. 2022

Front. Genet.

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“…Over 130 variants in USH2A have been associated with this subtype, with the most common mutation c.2299delG accounting for up to 45% of cases (Aller et al 2006;Dreyer et al 2008;Kuang et al 2020). Other USH2A pathogenic variants include nonsense, frameshift, missense, deletions, duplications, splicesite mutations, and compound heterozygotes; some of these mutations have been associated with nonsyndromic RP (Rivolta et al 2000;Dai et al 2008;Nakanishi et al 2009;Austin-Tse et al 2018;He et al 2020;Kuang et al 2020;Qu et al 2020;Zhu et al 2020). In French Canadian populations within Quebec, the deletion c.4338_4339delCT (p.C1447QfsX29) is responsible for over 50% of USH2 cases (Ebermann et al 2009).…”

Section: Usher Syndrome Type IImentioning

confidence: 99%

Review of Genotype-Phenotype Correlations in Usher Syndrome

et al. 2021

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Usher syndrome (USH) encompasses a group of clinically and genetically heterogenous disorders defined by the triad of sensorineural hearing loss (SNHL), vestibular dysfunction, and vision loss. USH is the most common cause of deaf blindness. USH is divided clinically into three subtypes—USH1, USH2, and USH3—based on symptom severity, progression, and age of onset. The underlying genetics of these USH forms are, however, significantly more complex, with over a dozen genes linked to the three primary clinical subtypes and other atypical USH phenotypes. Several of these genes are associated with other deaf-blindness syndromes that share significant clinical overlap with USH, pointing to the limits of a clinically based classification system. The genotype-phenotype relationships among USH forms also may vary significantly based on the location and type of mutation in the gene of interest. Understanding these genotype-phenotype relationships and associated natural disease histories is necessary for the successful development and application of gene-based therapies and precision medicine approaches to USH. Currently, the state of knowledge varies widely depending on the gene of interest. Recent studies utilizing next-generation sequencing technology have expanded the list of known pathogenic mutations in USH genes, identified new genes associated with USH-like phenotypes, and proposed algorithms to predict the phenotypic effects of specific categories of allelic variants. Further work is required to validate USH gene causality, and better define USH genotype-phenotype relationships and disease natural histories—particularly for rare mutations—to lay the groundwork for the future of USH treatment.

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“…A founder effect has been identified for a USH2A variant p.Cys1447fs that accounts for 55.6 % of the USH2 cases among Quebec French-Canadians [41]. However, great majority of reported USH2A variants are rare private mutations segregating in single families from different ethnic populations worldwide [42][43][44][45]. Involvement of USH2A private variants in causing profound hearing loss or deafness and IRDs in Pakistani families has been described in previous studies [16,[46][47][48] Here, we report a novel missense private variant (c.4029T > G, p.Asn1343Lys) in the USH2A gene in a Pakistani family with KC phenotype.…”

Section: Discussionmentioning

confidence: 99%

USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families

et al. 2021

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Background Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy, affecting approximately 1 in 4000 individuals worldwide. The most common form of syndromic RP is Usher syndrome (USH) accounting for approximately 20–30 % of RP cases. Mutations in the USH2A gene cause a significant proportion of recessive non-syndromic RP and USH type II (USH2). This study aimed to determine the causative role of the USH2A gene in autosomal recessive inherited ocular diseases and to establish genotype-phenotype correlation associated with USH2A variants. Methods We performed direct Sanger sequencing and co-segregation analysis of the USH2A gene to identify disease causing variants in a non-syndromic RP family, two USH2 families and two Keratoconus (KC) families. Results Disease causing variants in the USH2A gene were identified in two families displayed KC and USH2 phenotypes. A novel variant c.4029T > G, p.Asn1343Lys in the USH2A gene was detected in a Pakistani family with KC phenotype. In addition, a missense variant (c.7334 C > T, p. Ser2445Phe) in the USH2A gene was found segregating in another Pakistani family with USH2 phenotype. Homozygosity of identified missense USH2A variants was found associated with autosomal recessive inherited KC and USH2 phenotypes in investigated families. These variants were not detected in ethnically matched healthy controls. Moreover, the USH2A variants were predicted to be deleterious or potentially disease causing by PolyPhen-2, PROVEAN and SIFT. Conclusions This study provided first evidence for association of a novel USH2A variant with KC phenotype in a Pakistani family as well as established the phenotype-genotype correlation of a USH2A variant (c.7334 C > T, p. Ser2445Phe) with USH2 phenotype in another Pakistani family. The phenotype-genotype correlations established in present study may improve clinical diagnosis of affected individuals for better management and counseling.

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Identification of 13 novel USH2A mutations in Chinese retinitis pigmentosa and Usher syndrome patients by targeted next-generation sequencing

Cited by 6 publications

References 26 publications

Genetic Characteristics and Variation Spectrum of USH2A-Related Retinitis Pigmentosa and Usher Syndrome

Genetic Characteristics and Variation Spectrum of USH2A-Related Retinitis Pigmentosa and Usher Syndrome

Review of Genotype-Phenotype Correlations in Usher Syndrome

USH2A gene variants cause Keratoconus and Usher syndrome phenotypes in Pakistani families

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