Identification of novel USH2A mutations in patients with autosomal recessive retinitis pigmentosa via targeted next‑generation sequencing

Zhu, Xianjun; Xiao, Li; Tian, Wenjun; Yang, Yeming; Sun, Kuanxiang; Li, Shuzhen

doi:10.3892/mmr.2020.11087

Cited by 5 publications

(7 citation statements)

References 36 publications

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“…Studies of two newly identified USH2A variants in two Korean families have demonstrated more profound and progressive hearing loss than expected for USH2, requiring cochlear implantation . Furthermore, some USH2A associated genotypes show variable expressivity, with phenotypic variance seen both interfamilial and intrafamilial (Liu et al 1999;Bernal et al 2005;Austin-Tse et al 2018;Qu et al 2020;Zhu et al 2020).…”

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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Section: Usher Syndrome Type IImentioning

confidence: 99%

Review of Genotype-Phenotype Correlations in Usher Syndrome

et al. 2021

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“…The association between the va r iations in usher syndrome-causative genes and the resultant usher syndrome diseases or phenotypes in patients are highly variable; the genotype/phenotype associations are also divergent (1,3,4). Since eudy et al (5) first identified three mutations in the USH2A gene in patients with usher syndrome type iia with rP and hearing loss, additional USH2A mutations have been shown to be associated with usher syndrome type IIA (10)(11)(12)(32)(33)(34)(35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

“…Since Eudy et al ( 5 ) first identified three mutations in the USH2A gene in patients with Usher syndrome type IIA with RP and hearing loss, additional USH2A mutations have been shown to be associated with Usher syndrome type IIA ( 10 – 12 , 32 – 39 ). Patients with autosomal recessive RP (arRP; RP39; OMIM, 613809) without hearing loss were also identified to possess USH2A mutations, highlighting the complexity of genotype/phenotype associations in this disease ( 4 ). For example, Rivolta et al ( 40 ) identified USH2A mutations in patients with arRP without hearing loss.…”

Section: Discussionmentioning

confidence: 99%

“…Usher syndrome is a group of genetically and clinically heterogeneous autosomal recessive diseases with progressive retinitis pigmentosa (RP) and sensorineural hearing deficiencies, including Usher syndrome types I, II and III ( 1 – 4 ). Patients with Usher syndrome type II (USH2) present with mild hearing impairments but normal vestibular responses, and type II is the most common type amongst the three types ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

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Novel compound heterozygous nonsense variants, p.L150* and p.Y3565*, of the USH2A gene in a Chinese pedigree are associated with Usher syndrome type�IIA

Cheng

Zhou

et al. 2020

Mol Med Rep

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usher syndrome refers to a group of genetically and clinically heterogeneous autosomal recessive diseases with retinitis pigmentosa (RP) and hearing deficiencies. The association between usher syndrome-causative genes and resultant Usher syndrome phenotypes in patients are highly variable. In the present study, a chinese family with usher syndrome was recruited, and targeted next-generation sequencing, Sanger sequencing and segregation analysis were performed. The expression profiles and functional effects of the pathogenic variants of USH2A identified were analyzed. Novel nonsense compound heterozygous variants, c.T449G (p.L150*) and c.T10695A (p.Y3565*), were identified in the USH2A gene, which showed co-segregation with the disease phenotype causing usher syndrome type iia in the recruited chinese pedigree. The p.L150* variant was predicted to produce a truncated protein which lacked almost all the functional domains of USH2A, whereas the p.Y3565* variant is located in one of the fibronectin type 3 domains, resulting in the loss of several fibronectin type 3 domains at the C-terminus of USH2A by producing the truncated protein. It was shown that Ush2a mrna expression levels were higher in the retina compared with those in the eye tissues (lens, sclera and cornea), uterus, ovary, breast, testis, spleen, kidney, liver, intestine, brain, skeletal muscle and blood. Additionally, the protein structure was shown to be highly conserved by comparing Homo sapiens USH2A to eight other species. To the best of our knowledge, the present study is the first to identify two novel pathogenic variants, c.T449G (p.L150*) and c.T10695A (p.Y3565*), in the USH2A gene in a patient with usher syndrome type iia, thereby expanding the known spectrums of USH2A causative mutations. The present discovery may assist in understanding the molecular pathogenesis underlying the development of rP and usher syndrome type iia, and in the development of diagnostic, therapeutic and genetic counseling strategies in patients with Usher syndrome type IIA disease.

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“…In this scenario, identifying novel disease genes or variants is important to increase the diagnostic rate and to facilitate new approaches for clinical care of IRD patients. The advances in next-generation sequencing (NGS) technologies have ushered in a new era for genetic diagnosis and disease-gene discovery 7 . Recent studies have reported the clinical utility of Whole Genome Sequencing (WGS), especially for rare diseases 8 , 9 , and its large expectations on personalized medicine 10 , highlighting that the use of WGS as a first diagnostic strategy could constitute a unique and powerful analysis.…”

Section: Introductionmentioning

confidence: 99%

A comprehensive WGS-based pipeline for the identification of new candidate genes in inherited retinal dystrophies

et al. 2022

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To enhance the use of Whole Genome Sequencing (WGS) in clinical practice, it is still necessary to standardize data analysis pipelines. Herein, we aimed to define a WGS-based algorithm for the accurate interpretation of variants in inherited retinal dystrophies (IRD). This study comprised 429 phenotyped individuals divided into three cohorts. A comparison of 14 pathogenicity predictors, and the re-definition of its cutoffs, were performed using panel-sequencing curated data from 209 genetically diagnosed individuals with IRD (training cohort). The optimal tool combinations, previously validated in 50 additional IRD individuals, were also tested in patients with hereditary cancer (n = 109), and with neurological diseases (n = 47) to evaluate the translational value of this approach (validation cohort). Then, our workflow was applied for the WGS-data analysis of 14 individuals from genetically undiagnosed IRD families (discovery cohort). The statistical analysis showed that the optimal filtering combination included CADDv1.6, MAPP, Grantham, and SIFT tools. Our pipeline allowed the identification of one homozygous variant in the candidate gene CFAP20 (c.337 C > T; p.Arg113Trp), a conserved ciliary gene, which was abundantly expressed in human retina and was located in the photoreceptors layer. Although further studies are needed, we propose CFAP20 as a candidate gene for autosomal recessive retinitis pigmentosa. Moreover, we offer a translational strategy for accurate WGS-data prioritization, which is essential for the advancement of personalized medicine.

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Identification of novel USH2A mutations in patients with autosomal recessive retinitis pigmentosa via targeted next‑generation sequencing

Cited by 5 publications

References 36 publications

Review of Genotype-Phenotype Correlations in Usher Syndrome

Review of Genotype-Phenotype Correlations in Usher Syndrome

Novel compound heterozygous nonsense variants, p.L150* and p.Y3565*, of the USH2A gene in a Chinese pedigree are associated with Usher syndrome type�IIA

A comprehensive WGS-based pipeline for the identification of new candidate genes in inherited retinal dystrophies

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