Copy Number Variations (CNVs) refer to alterations in the DNA of a genome that result in cells having an abnormal number of copies of one or more sections of the DNA (10.3389/fgene.2013.00092).They contribute to normal phenotypic variations, but also predispose us to certain diseases, such as neurodevelopmental disorders, autoimmune diseases, and increased cancer susceptibility (10.1159/000184719). Aneuploidies, which are abnormalities resulting from breakage and incorrect rejoining of chromosome segments could be considered as special cases of CNVs.

CNV analysis is recognised as a challenging area within clinical genomics. Discerning CNVs from biological or technical noise, particularly with short-read sequencing, which is still the most popular sequencing technology, is not obvious. Particularly CNVs nested within repetitive genomic regions or those of considerable size pose problems (10.1093/bioinformatics/bts535). Bioinformatic analysis requires specialised computational tools and algorithms (10.1038/s41431-020-0675-z). Also interpretation of CNVs poses problems: the biological effect of variety in the extension or limits of CNV boundaries is not clear, particularly when considering effects depending on multiple genes and intraregional co-evolution of gene function.

To help standardise the classification part of the analyses, a joint consensus recommendation was published in 2020 by the American College of Medical Genetics and Genomics and the Clinical Genome Resource (10.1038/s41436-019-0686-8). It improves the quality of CNV interpretation in clinical settings by addressing critical aspects of CNV evaluation. The article includes assessment methodologies, extensive variant classification criteria, and effective communication of findings to clinicians and patients. Following these recommendations, Euformatics developed a CNV workbench, which is now available in the Genomics Hub.

The CNV workbench has been designed to greatly reduce the effort involved in CNV classification by comprehensively calculating the ACMG/ClinGen classification score and allowing to visualise the result in compact (Figure 1) as well as fully documented mode. The recommendation system automatically evaluates CNV from several angles, such as size, genomic content, literature evidence, and inheritance patterns. In practice, larger CNVs stand out as they are more likely to have a phenotypic impact. The gene content of the CNVs is also considered, as those that encompass known disease-associated genes are of particular interest. A detailed evaluation of genomic content using published research and public databases is done automatically alongside the evaluation of inheritance patterns and family history.

Figure 1. Genomics Hub’s CNV workbench.

Figure 1. Genomics Hub’s CNV workbench.

Overall, the Genomics Hub has been designed with modules to create an end-to-end solution that can start from the sequencer raw data output and end with a tailored clinical report. Automated comprehensive quality control is included to allow the monitoring of both the bioinformatic pipeline and the wet lab steps. The CNV workbench helps users to effortlessly evaluate CNVs and identify intricate connections between CNVs and associated clinical syndromes. Be confident, and keep pace as the genomic world evolves with the Genomics Hub.

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