CNV-ClinViewer: Enhancing the Clinical Interpretation of Large Copy-number Variants Online

Overview

Journal Bioinformatics

Publisher Oxford University Press

Specialty Biology

Date 2023 Apr 27

PMID 37104749

Authors

Marie Macnee

Eduardo Perez-Palma

Tobias Brunger

Chiara Klockner

Konrad Platzer

Arthur Stefanski

Ludovica Montanucci

Allan Bayat

Maximilian Radtke

Ryan L Collins

Michael Talkowski

Daniel Blankenberg

Rikke S Moller

Johannes R Lemke

Michael Nothnagel

Patrick May

Dennis Lal

Affiliations

Soon will be listed here.

Abstract

Motivation: Pathogenic copy-number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts.

Results: Here, we introduce the CNV-ClinViewer, an open-source web application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment, the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators' patient care and for basic scientists' translational genomic research.

Availability And Implementation: The web application is freely available at https://cnv-ClinViewer.broadinstitute.org and the open-source code can be found at https://github.com/LalResearchGroup/CNV-clinviewer.

Citing Articles

Systematic assessment of structural variant annotation tools for genomic interpretation.

Liu X, Gu L, Hao C, Xu W, Leng F, Zhang P Life Sci Alliance. 2024; 8(3).

PMID: 39658089 PMC: 11632063. DOI: 10.26508/lsa.202402949.

Importance of copy number variants in childhood apraxia of speech and other speech sound disorders.

Ricky Chan E, Benchek P, Miller G, Brustoski K, Schaffer A, Truitt B Commun Biol. 2024; 7(1):1273.

PMID: 39369109 PMC: 11455877. DOI: 10.1038/s42003-024-06968-y.

Control-FREEC viewer: a tool for the visualization and exploration of copy number variation data.

Crippa V, Fina E, Ramazzotti D, Piazza R BMC Bioinformatics. 2024; 25(1):72.

PMID: 38355453 PMC: 10868011. DOI: 10.1186/s12859-024-05694-w.

Genetic landscape of Parkinson's disease and related diseases in Luxembourg.

Landoulsi Z, Pachchek S, Bobbili D, Pavelka L, May P, Kruger R Front Aging Neurosci. 2024; 15:1282174.

PMID: 38173558 PMC: 10761438. DOI: 10.3389/fnagi.2023.1282174.

A novel case of 16q22.3 duplication syndrome in a child with overgrowth: case report and literature review.

Moschella A, Capra A, Corica D, Pepe G, Di Tommaso S, Sallicandro E BMC Med Genomics. 2023; 16(1):315.

PMID: 38049856 PMC: 10696707. DOI: 10.1186/s12920-023-01716-3.

References

Gurbich T, Ilinsky V . ClassifyCNV: a tool for clinical annotation of copy-number variants. Sci Rep. 2020; 10(1):20375. PMC: 7683568. DOI: 10.1038/s41598-020-76425-3. View

Babione J, Ocampo W, Haubrich S, Yang C, Zuk T, Kaufman J . Human-centred design processes for clinical decision support: A pulmonary embolism case study. Int J Med Inform. 2020; 142:104196. DOI: 10.1016/j.ijmedinf.2020.104196. View

Rehm H, Berg J, Brooks L, Bustamante C, Evans J, Landrum M . ClinGen--the Clinical Genome Resource. N Engl J Med. 2015; 372(23):2235-42. PMC: 4474187. DOI: 10.1056/NEJMsr1406261. View

Lek M, Karczewski K, Minikel E, Samocha K, Banks E, Fennell T . Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016; 536(7616):285-91. PMC: 5018207. DOI: 10.1038/nature19057. View

Collins R, Brand H, Karczewski K, Zhao X, Alfoldi J, Francioli L . A structural variation reference for medical and population genetics. Nature. 2020; 581(7809):444-451. PMC: 7334194. DOI: 10.1038/s41586-020-2287-8. View

Fan C, Wang Z, Sun Y, Sun J, Liu X, Kang L . AutoCNV: a semiautomatic CNV interpretation system based on the 2019 ACMG/ClinGen Technical Standards for CNVs. BMC Genomics. 2021; 22(1):721. PMC: 8496072. DOI: 10.1186/s12864-021-08011-4. View

Kent W, Sugnet C, Furey T, Roskin K, Pringle T, Zahler A . The human genome browser at UCSC. Genome Res. 2002; 12(6):996-1006. PMC: 186604. DOI: 10.1101/gr.229102. View

Kohler S, Gargano M, Matentzoglu N, Carmody L, Lewis-Smith D, Vasilevsky N . The Human Phenotype Ontology in 2021. Nucleic Acids Res. 2020; 49(D1):D1207-D1217. PMC: 7778952. DOI: 10.1093/nar/gkaa1043. View

Tweedie S, Braschi B, Gray K, Jones T, Seal R, Yates B . Genenames.org: the HGNC and VGNC resources in 2021. Nucleic Acids Res. 2020; 49(D1):D939-D946. PMC: 7779007. DOI: 10.1093/nar/gkaa980. View

10.

Nusrat S, Harbig T, Gehlenborg N . Tasks, Techniques, and Tools for Genomic Data Visualization. Comput Graph Forum. 2019; 38(3):781-805. PMC: 6876635. DOI: 10.1111/cgf.13727. View

11.

Landrum M, Lee J, Benson M, Brown G, Chao C, Chitipiralla S . ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2017; 46(D1):D1062-D1067. PMC: 5753237. DOI: 10.1093/nar/gkx1153. View

12.

Bates D, Kuperman G, Wang S, Gandhi T, Kittler A, Volk L . Ten commandments for effective clinical decision support: making the practice of evidence-based medicine a reality. J Am Med Inform Assoc. 2003; 10(6):523-30. PMC: 264429. DOI: 10.1197/jamia.M1370. View

13.

Firth H, Richards S, Bevan A, Clayton S, Corpas M, Rajan D . DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009; 84(4):524-33. PMC: 2667985. DOI: 10.1016/j.ajhg.2009.03.010. View

14.

Saitsu H, Kato M, Shimono M, Senju A, Tanabe S, Kimura T . Association of genomic deletions in the STXBP1 gene with Ohtahara syndrome. Clin Genet. 2012; 81(4):399-402. DOI: 10.1111/j.1399-0004.2011.01733.x. View

15.

Huang N, Lee I, Marcotte E, Hurles M . Characterising and predicting haploinsufficiency in the human genome. PLoS Genet. 2010; 6(10):e1001154. PMC: 2954820. DOI: 10.1371/journal.pgen.1001154. View

16.

Graham T, Kushniruk A, Bullard M, Holroyd B, Meurer D, Rowe B . How usability of a web-based clinical decision support system has the potential to contribute to adverse medical events. AMIA Annu Symp Proc. 2008; :257-61. PMC: 2655970. View

17.

Ehret J, Engels H, Cremer K, Becker J, Zimmermann J, Wohlleber E . Microdeletions in 9q33.3-q34.11 in five patients with intellectual disability, microcephaly, and seizures of incomplete penetrance: is STXBP1 not the only causative gene?. Mol Cytogenet. 2015; 8:72. PMC: 4587785. DOI: 10.1186/s13039-015-0178-8. View

18.

Nambot S, Masurel A, El Chehadeh S, Mosca-Boidron A, Thauvin-Robinet C, Lefebvre M . 9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping. Eur J Hum Genet. 2015; 24(6):830-7. PMC: 4867444. DOI: 10.1038/ejhg.2015.202. View

19.

Rooney Riggs E, Andersen E, Cherry A, Kantarci S, Kearney H, Patel A . Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2019; 22(2):245-257. PMC: 7313390. DOI: 10.1038/s41436-019-0686-8. View

20.

Aguirre M, Rivas M, Priest J . Phenome-wide Burden of Copy-Number Variation in the UK Biobank. Am J Hum Genet. 2019; 105(2):373-383. PMC: 6699064. DOI: 10.1016/j.ajhg.2019.07.001. View