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In silico approaches for pathogenicity prediction of missense variants of uncertain significance (VUS) in ADPKD |
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| รหัสดีโอไอ | |
| Creator | Parnthanutcha Wetchanien, Duangkamon Bunditworapoom, Manop Pithukpakorn, Chanin Limwongse, Kriengsak Vareesangthip, Anunchai Assawamakin, Wanna Thongnoppakhun |
| Title | In silico approaches for pathogenicity prediction of missense variants of uncertain significance (VUS) in ADPKD |
| Publisher | Genetics Society of Thailand |
| Publication Year | 2559 |
| Journal Title | Genomics and Genetics |
| Journal Vol. | 9 |
| Journal No. | 1 |
| Page no. | 42 - 49 |
| Keyword | ADPKD, variant of uncertain significance(VUS), in silico, pathogenicity, missense |
| ISSN | 24655198 |
| Abstract | Autosomal dominant polycystic kidneydisease (ADPKD) is the most common dominantlyinherited kidney disease, being caused by mutations inPKD1 (85%) and PKD2 (15%). Approximately 25%of all PKD1 mutations are pathogenic missense,but additional 12.8% of those are reported asindeterminate or missense variants of uncertainsignificance (VUS), of which the deleterious natureare unclear in clinical practice. Functional studies toassess the impact of missense variants, particularlyfor PKD1, are difficult due to the large size andambiguous functions of the proteins, polycystins. Avariety of in silico tools were developed to evaluateinterspecies variations and biochemical impacts ofamino acid substitutions of missense VUS. Toevaluate the tool suitability for PKD1 and PKD2, weapplied additional 12 state-of-the-art web-based toolswith their claimed superior performances based ondifferent algorithms for the prediction in parallel withthe three benchmark programs (PolyPhen2, SIFT andMutationTaster). A total of 15 tools were assessed in agene-specific manner with PKD1 and PKD2 variantsof known pathogenicity from the PKDB mutationdatabase. We found that each of the genes hadsuitable predictions from different sets of tools.Combined uses of 3, 5, 8 and 12 tools with highperformance in descending order (in which thebenchmarks were excluded) gave consensuspredictions for the selected nine VUS in PKD1,except one VUS which might have a mildpathogenicity that only the use of 12 tools predicteddifferently. In this situation, using more numbers oftools might prevent the misinterpretation of milderVUS. Classification of the pathogenicity of the VUSin PKD1 and PKD2 became an essential part ofmolecular diagnosis of ADPKD and is useful for aclinical decision and would expand knowledge ofmutation spectrum in ADPKD. |
