CNVxplorer: a web tool to assist clinical interpretation of CNVs in rare disease patients

Abstract

Copy Number Variants (CNVs) are an important cause of rare diseases. Array-based Comparative Genomic Hybridization tests yield a ∼12% diagnostic rate, with ∼8% of patients presenting CNVs of unknown significance. CNVs interpretation is particularly challenging on genomic regions outside of those overlapping with previously reported structural variants or disease-associated genes. Recent studies showed that a more comprehensive evaluation of CNV features, leveraging both coding and non-coding impacts, can significantly improve diagnostic rates. However, currently available CNV interpretation tools are mostly gene-centric or provide only non-interactive annotations difficult to assess in the clinical practice. Here, we present CNVxplorer, a web server suited for the functional assessment of CNVs in a clinical diagnostic setting. CNVxplorer mines a comprehensive set of clinical, genomic, and epigenomic features associated with CNVs. It provides sequence constraint metrics, impact on regulatory elements and topologically associating domains, as well as expression patterns. Analyses offered cover (a) agreement with patient phenotypes; (b) visualizations of associations among genes, regulatory elements and transcription factors; (c) enrichment on functional and pathway annotations and (d) co-occurrence of terms across PubMed publications related to the query CNVs. A flexible evaluation workflow allows dynamic re-interrogation in clinical sessions. CNVxplorer is publicly available at http://cnvxplorer.com.

Graphical Abstract

CNV annotation process and analyses offered by CNVxplorer together with its integration within the clinical workflow for genetic diagnosis of rare disease patients.

Figure 1.

CNVxplorer overview and integration within the clinical diagnosis workflow. The figure represents the annotation process and analyses offered by CNVxplorer together with its integration in the clinical workflow for genetic diagnosis of rare disease patients. CNVxplorer provides analyses tools for CNV interpretation the irrespective of the technology used to identify them. Thus, CNV calling together with prior bioinformatics filtering needs to be done upstream the use of the application. CNVxplorer offers a dynamic workflow for the investigation of a comprehensive set of genomic, epigenomic and clinical features together with diverse gene-set enrichment analyses and the automatic exploration of the biomedical literature. The application is interactive allowing clinical experts to re-evaluate the analysis process in an iterative way. Finally, it corresponds to the geneticist, researcher MD or clinical diagnosis staff to provide CNV clinical classificatios following technical standards and medical recommendations and after further checking the original annotation sources for in-depth details. Abbreviations: CNV: Copy Number Variants; aCGH: array comparative genomic hybridization; NGS: Next Generation Sequencing; WES:Whole Exome Sequencing; WGS: Whole Genome Sequencing; lncRNAs: long non-coding RNAs; miRNA: micro RNAs; TF: Transcription Factors; TADs: Topologically Associating Domains; ACMG: American College of Medical Genetics and Genomics; ClinGen: Clinical Genome Resource; Achro-puce: network of French cytogeneticists; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources; OMIM: Online Mendelian Inheritance in Man; HP term: Human Phenotype term; KO: Knock-out; MGI: Mouse Genome Informatics; GO: Gene Ontology; GTEx: Genotype-Tissue Expression project; HPA: Human Protein Atlas; TSEA: Tissue-specific gene enrichment analysis; NCBI: National Center for Biotechnology Information.