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Things have been progressing rapidly in the clinical testing field with advances in technologies, lower costs, and constant improvement in data analysis.  Microarrays have been the gold standard for cytogenetics applications with detection of larger changes (CNVs) and NGS has been reserved for smaller sequence changes (single/few base changes). With decreasing costs of an NGS assay, more have been looking at developing algorithms to obtain copy number from sequencing results.  BioDiscovery was one of the first to create an algorithm to detect copy number changes from NGS and we are continually improving on our methods and are now on our 4th generation of the algorithm.

There has been a lot of talk about obtaining copy number from NGS mostly in the research arena but more recently it has been at the forefront for clinical usage.  Many genetic testing professionals would like to streamline and replace the existing multi-testing structure with a single test that can be used to ascertain many different types of genomic events. In a paper published in 2016 the authors estimated that microarray analysis detects only ~12% of causative events in patients with genetic disorders (1).  Those patients without a causative finding are then referred to a second test which in most cases is sequencing. Performing two tests results in higher costs as well as longer time to diagnosis. 

“In order to have a CNV analysis process that could be implemented as a routine in clinical laboratories, we opted for a commercially available software, with a graphical interface offering integration of different algorithms and corrections necessary to call CNVs.“

Dr. Darine Villela and colleagues in Dr. Carla Rosenberg's lab at the University of Sao Paulo, Brazil sought to find an integrated solution to combine two tests into one – one that was cost effective and easy to adopt in a clinical setting.  They noted that there are several tools for CNV analysis from sequencing data, but the homemade tools are designed for a specific pipeline, are not user-friendly and require a high degree of bioinformatics expertise. They knew they needed a solution that would be easy to implement in a clinical lab and chose a commercial target enrichment kit and BioDiscovery’s Nexus Copy Number for analysis. 

“Nexus Copy Number™ has been specifically developed for microarray analysis in cytogenetics, is optimized for copy number estimation, and is an open platform allowing input of many types of data, including next generation sequencing.”

They used BioDiscovery’s BAM MSR algorithm (which uses both targeted and off-target reads) to estimate copy number from targeted panels and compared it to results from microarrays and found the resolution and sensitivity quite similar to those provided by microarrays.  Another reason they found BioDiscovery's software ideal is that the software is platform independent and the algorithm can extract CNV from other sequencing data including WES and WGS as well as microarrays.

The authors concluded that the approach presented for estimating CNV from targeted panels enables a cost-effective solution for simultaneous detection of CNVs and sequence variants. They expect that the two diagnostic methods (CMA and sequencing) will be replaced by a single platform that can derive CNV, AOH, and sequence variants from sequencing data in both the clinical and research settings.

Learn more about Nexus Copy Number and the BAM MSR algorithm for research applications. A newer and improved version of the BAM MSR (multiscale reference) algorithm is now included in our software for clinical labs, NxClinical, making it even easier to apply Dr. Villela's vision of a single test system to the clinical lab. 



Pfundt R, del Rosario M, Vissers L, Kwint MP, Janssen IM, de Leeuw N, Yntema HG, Nelen
MR, Lugtenberg D, Kamsteeg EJ et al. Detection of clinically relevant copynumber
variants by exome sequencing in a large cohort of genetic disorders.
Genetics in Medicine (2017) 9:667:675

D. Villela, S.S. da Costa, A.M. Vianna-Morgante, A.C.V. Krepischi, C. Rosenberg. Efficient detection of chromosome imbalances and exome single nucleotide variants using targeted sequencing in the clinical setting. European Journal of Medical Genetics (2017). doi: 10.1016/j.ejmg. 2017.08.020.