Advancing Genetic Research: The Role of VarSeq and VS-CNV in Breakthrough Discoveries

         March 31, 2024

In the rapidly evolving field of genomics, innovative technologies, and methodologies are constantly being developed to enhance our understanding and diagnosis of genetic disorders. Golden Helix’s VarSeq and VS-CNV software platforms stand at the forefront of this revolution, offering powerful tools for genetic data analysis and interpretation. This blog highlights recent research endeavors where these tools have been instrumental. From the comprehensive analysis of the Twist Exome with CNV backbone for improved detection of copy number variations (CNVs) in clinical settings to the re-evaluation of genotypes in patients with adenomatous polyposis of unknown etiology, and the in-depth characterization of YWHAG-related epilepsy, these studies exemplify the transformative potential of integrating advanced genetic analysis software in research. Through these investigations, Golden Helix customers are contributing to the broader scientific knowledge and paving the way for more accurate and personalized approaches to genetic testing and diagnosis.

P715: Analyzing performance of the Twist exome with CNV backbone at various probe densities leveraging Golden Helix VS-CNV


Clinical Whole Exome Sequencing (WES) offers a high diagnostic yield test by detecting pathogenic variants in all coding genes of the human genome. WES is poised to consolidate multiple genetic tests by accurately identifying Copy Number Variation (CNV) events, typically necessitating microarray analyses. However, standard commercial exome kits are limited to targeting exon coding regions, leaving significant gaps in coverage between genes which could hinder comprehensive CNV detection. To replace microarrays, advances in both assay design and computation methods are needed.


Addressing the need for comprehensive coverage, Twist Bioscience has developed an enhanced Twist Exome 2.0 Plus Comprehensive Exome Spike-in capture panel with added “backbone” probes. These probes target common SNPs polymorphic in multiple populations and are evenly distributed in the intergenic and intronic regions, with three varying densities at 25kb, 50kb, and 100kb intervals. This backone enables the genome-wide detection of CNVs and loss of heterozygosity (LOH), on top of single nucleotide variations (SNVs) and small insertions and deletions (InDels) that come with Twist Exome 2.0 product offering. Concurrently, Golden Helix has developed a multi-modal CNV caller designed specifically for target-capture NGS data to detect single-exon to whole-chromosome aneuploid CNV events. This study evaluates the combined efficacy of the backbone-probe enhanced exome capture panel and VS-CNV 2.6 in identifying known CNVs using the Coriell CNVPANEL01 reference set of 43 samples.


The integration of the enhanced capture panel with VS-CNV 2.6 achieved a 100% sensitivity rate for the detection of known CNV events at all three probe densities. The application of best-practice quality metrics and filters was shown to have a minimal impact on this high sensitivity. Furthermore, the inclusion of high-density backbone probes improves the resolution and precision of CNV event boundaries.


The findings underscore the potential of the augmented Twist Exome in tandem with the VS-CNV caller. This combination presents a promising alternative to conventional microarray assays, potentially obviating the need for additional testing in clinical CNV detection. The study’s results advocate for the implementation of this integrated approach as a more efficient and equally sensitive method for CNV analysis in a clinical setting.

Nathan Fortier, Tina Han, Alessandro Davassi, Alonzo Lee, Tanya Tannous, Gabe Rudy, Andreas Scherer,
P715: Analyzing performance of the Twist exome with CNV backbone at various probe densities leveraging Golden Helix VS-CNV, Genetics in Medicine Open, Volume 2, Supplement 1, 2024, 101619, ISSN 2949-7744,

Re-evaluating the genotypes of patients with adenomatous polyposis of unknown etiology: a nationwide study

In the Danish Polyposis Register, patients with over 100 cumulative colorectal adenomas of unknown genetic etiology, named in this study colorectal polyposis (CP), is registered and treated as familial adenomatous polyposis (FAP). In this study, we performed genetic analyses, including whole genome sequencing (WGS), of all Danish patients registered with CP and estimated the detection rate of pathogenic variants (PV). We identified 231 families in the Polyposis Register, 31 of which had CP. A polyposis-associated gene panel was performed and, if negative, patients were offered WGS and screening for mosaicism in blood and/or adenomas. Next-generation sequencing (NGS) was carried out for 27 of the families (four declined). PVs were detected in 11 families, and WGS revealed three additional structural variants in APC. Mosaicism of a PV in APC was detected in two families. As the variant detection rate of eligible families was 60%, 93% of families in the register now have a known genetic etiology.

Karstensen, J.G., Hansen, T.v.O., Burisch, J. et al. Re-evaluating the genotypes of patients with adenomatous polyposis of unknown etiology: a nationwide study. Eur J Hum Genet (2024).

Clinical and molecular characterization of patients with YWHAG-related epilepsy


YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy.


We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients.


The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype–phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001).


This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype–phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Cetica V, Pisano T, Lesca G, Marafi D, Licchetta L, Riccardi F, et al. Clinical and molecular characterization of patients with YWHAG-related epilepsy. Epilepsia. 2024;00:1–12.

The body of research presented herein underscores the significant strides being made in genetic diagnostics and patient care, facilitated by Golden Helix’s VarSeq and VS-CNV software. The enhanced detection of CNVs using the Twist Exome with CNV backbone, the elucidation of genetic underpinnings in colorectal polyposis, and the detailed characterization of YWHAG-related epilepsy, all represent crucial steps forward in our collective endeavor to understand and combat genetic diseases. These studies highlight the critical role of advanced computational tools in uncovering genetic variations that elude traditional testing methods, thereby offering hope for more effective treatments and interventions. As we continue to unravel the complexities of the human genome, the insights gained from these research initiatives promise to inform clinical practices and improve outcomes for patients with genetic disorders, showcasing the transformative impact of precision medicine.

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