The splicing effect of variants at branchpoint elements in cancer genes.

Autor:	Canson DM; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia., Dumenil T; Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Parsons MT; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., O'Mara TA; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Davidson AL; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia., Okano S; Statistics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Signal B; Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia., Mercer TR; Genomics and Epigenetics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; Australian Institute of Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia., Glubb DM; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Spurdle AB; Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: Amanda.Spurdle@qimrberghofer.edu.au.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2022 Feb; Vol. 24 (2), pp. 398-409. Date of Electronic Publication: 2021 Nov 30.
DOI:	10.1016/j.gim.2021.09.020
Abstrakt:	Purpose: Branchpoint elements are required for intron removal, and variants at these elements can result in aberrant splicing. We aimed to assess the value of branchpoint annotations generated from recent large-scale studies to select branchpoint-abrogating variants, using hereditary cancer genes as model. Methods: We identified branchpoint elements in 119 genes associated with hereditary cancer from 3 genome-wide experimentally-inferred and 2 predicted branchpoint data sets. We then identified variants that occur within branchpoint elements from public databases. We compared conservation, unique variant observations, and population frequencies at different nucleotides within branchpoint motifs. Finally, selected minigene assays were performed to assess the splicing effect of variants at branchpoint elements within mismatch repair genes. Results: There was poor overlap between predicted and experimentally-inferred branchpoints. Our analysis of cancer genes suggested that variants at -2 nucleotide, -1 nucleotide, and branchpoint positions in experimentally-inferred canonical motifs are more likely to be clinically relevant. Minigene assay data showed the -2 nucleotide to be more important to branchpoint motif integrity but also showed fluidity in branchpoint usage. Conclusion: Data from cancer gene analysis suggest that there are few high-risk alleles that severely impact function via branchpoint abrogation. Results of this study inform a general scheme to prioritize branchpoint motif variants for further study. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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