QueryOR: a comprehensive web platform for genetic variant analysis and prioritization

Bertoldi, Loris; Forcato, Claudio; Vitulo, Nicola; Birolo, Giovanni; Pascale, Fabio De; Feltrin, Erika; Schiavon, Riccardo; Anglani, Franca; Negrisolo, Susanna; Zanetti, Alessandra; D’Avanzo, Francesca; Tomanin, Rosella; Faulkner, Georgine; Vezzi, Alessandro; Valle, Giorgio

doi:10.1186/s12859-017-1654-4

Cited by 22 publications

(19 citation statements)

References 49 publications

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“…The bioinformatic analysis was performed on the Ion Torrent Server and the Torrent SuiteTM (https://ts-pgm.epigenetic.ru/ion-docs/Torrent-Variant-Caller-Plugin.html) for variant calling and to align the reads to the human genome reference 19 (hg19, https://grch37.ensembl.org/). Data were then analyzed by QueryOR web platform (https://queryor.cribi.unipd.it/cgi-bin/queryor/mainpage.pl) (Bertoldi et al., ) and genetic variants (missense, nonsense, indels) filtered for a global minor allele frequency ≤0.001, shared by the affected individuals but not present in five healthy controls. Multiple protein alignment was performed using the ClustalW software (https://www.ebi.ac.uk/Tools/msa/clustalo/).…”

Section: Methodsmentioning

confidence: 99%

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Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

Barone

Gamberucci

et al. 2017

Human Mutation

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Here, we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy. These CASQ1 mutations affect conserved amino acids in position 44 (p.(Asp44Asn)), 103 (p.(Gly103Asp)), and 385 (p.(Ile385Thr)). Functional studies, based on turbidity and dynamic light scattering measurements at increasing Ca concentrations, showed a reduced Ca -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations and a slight increase in Ca -dependent aggregation for the p.Ile385Thr. Accordingly, limited trypsin proteolysis assay showed that p.Asp44Asn and p.Gly103Asp were more susceptible to trypsin cleavage in the presence of Ca in comparison with WT and p.Ile385Thr. Analysis of single muscle fibers of a patient carrying the p.Gly103Asp mutation showed a significant reduction in response to caffeine stimulation, compared with normal control fibers. Expression of CASQ1 mutations in eukaryotic cells revealed a reduced ability of all these CASQ1 mutants to store Ca and a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca entry. These results widen the spectrum of skeletal muscle diseases associated with CASQ1 and indicate that these mutations affect properties critical for correct Ca handling in skeletal muscle fibers.

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Section: Methodsmentioning

confidence: 99%

“…The CASQ1 mutations have been submitted to the locus-specific database (www.lovd.nl/CASQ1). (Bertoldi et al, 2017) and genetic variants (missense, nonsense, indels) filtered for a global minor allele frequency ≤0.001, shared by the affected individuals but not present in five healthy controls.…”

Section: Genetic Analysismentioning

confidence: 99%

Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

Barone

Gamberucci

et al. 2017

Human Mutation

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“…Data were analyzed as suggested by the manufacturer, with read alignment using TMAP and variant calling with TSVC, which are both included in the Ion Proton Suite (v 5.0). QueryOR (http://queryor.cribi.unipd.it, accessed on 27 November 2019) [85] was used to analyze and prioritize short-nucleotide variants (SNV). This web-based query platform enables quick, easy, in-depth variant prioritization by aggregating several functional annotations of both genes and variants.…”

Section: Whole-exome Sequencing (Wes)mentioning

confidence: 99%

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

Gianesello

Ceol

Bertoldi

et al. 2020

IJMS

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Dent disease (DD), an X-linked renal tubulopathy, is mainly caused by loss-of-function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC-5 antiporter that in proximal tubules (PT) participates in the receptor-mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC-5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC-5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty-three novel CLCN5 mutations were identified. ClC-5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC-5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.

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“…In order to overcome these difficulties, another generation of (freely available) tools have been developed that incorporate a rare disease patient's phenotype into the interpretation of their sequencing data. These include eXtasy [34], BiERapp [35], Phen-Gen [36], Exomiser [37], Phevor [38], PhenoVar [39], PhenIX [40], OVA [41], Phenolyzer [42], wANNOVAR [43], OMIM Explorer [44], QueryOR [45], GenIO [46], DeepPVP [47], MutationDistiller [48], Phrank [49], Xrare [50], PhenoPro [51], and Phenoxome [52]. Such phenotype-driven prioritization tools leverage existing genotype to phenotype information from various databases in order to prioritize candidate variants in those genes that are likely to be more relevant to the patient's phenotype.…”

Section: Introductionmentioning

confidence: 99%

An Improved Phenotype-Driven Tool for Rare Mendelian Variant Prioritization: Benchmarking Exomiser on Real Patient Whole-Exome Data

Cipriani

Pontikos

Arno

et al. 2020

Genes

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Next-generation sequencing has revolutionized rare disease diagnostics, but many patients remain without a molecular diagnosis, particularly because many candidate variants usually survive despite strict filtering. Exomiser was launched in 2014 as a Java tool that performs an integrative analysis of patients’ sequencing data and their phenotypes encoded with Human Phenotype Ontology (HPO) terms. It prioritizes variants by leveraging information on variant frequency, predicted pathogenicity, and gene-phenotype associations derived from human diseases, model organisms, and protein–protein interactions. Early published releases of Exomiser were able to prioritize disease-causative variants as top candidates in up to 97% of simulated whole-exomes. The size of the tested real patient datasets published so far are very limited. Here, we present the latest Exomiser version 12.0.1 with many new features. We assessed the performance using a set of 134 whole-exomes from patients with a range of rare retinal diseases and known molecular diagnosis. Using default settings, Exomiser ranked the correct diagnosed variants as the top candidate in 74% of the dataset and top 5 in 94%; not using the patients’ HPO profiles (i.e., variant-only analysis) decreased the performance to 3% and 27%, respectively. In conclusion, Exomiser is an effective support tool for rare Mendelian phenotype-driven variant prioritization.

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QueryOR: a comprehensive web platform for genetic variant analysis and prioritization

Cited by 22 publications

References 49 publications

Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies

An Improved Phenotype-Driven Tool for Rare Mendelian Variant Prioritization: Benchmarking Exomiser on Real Patient Whole-Exome Data

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