Customer Publications – March 2021

         March 25, 2021

Breakthroughs and discoveries in personalized medicine occur every day and here at Golden Helix, we are proud to play a role in so many cutting-edge investigations. It is always my pleasure to provide a brief description of what is only a small sample of our customer success stories over the course of four weeks and this month is no exception. From our SNP & Variation Suite (SVS) platform to our industry-leading VSClinical software package, our products are always hard at work to help these discoveries take flight. Read on to see how others are using these powerful tools to break new ground, support existing theories and create efficiency in the clinical diagnostic space!

Whole-Exome Sequencing in Patients Affected by Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Reveals New Variants Potentially Contributing to the Phenotype

Idiosyncratic adverse drug reactions are unexpected reactions to drugs that are not dose-related or immune-mediated responses. They are often defined as genetically determined abnormal responses. With the recent advances in genetic testing, these potentially devastating reactions may be somewhat preventable. Researchers from the University of Rosario in Columbia harnessed the power of next-generation sequencing (NGS) to explore the root causes of two rare adverse drug reactions (ADRs). Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have the potential to be considered a polygenic pathology due to the variants affecting the functions of numerous other genes. The team took a whole-exome approach to focus on 313 candidate genes potentially involved in etiology, drug metabolism, and gene regulation. Using VarSeq software for variant filtering, they were able to provide evidence that depending upon the specific drug being taken, different variants and alleles in combinations of frequently occurring and rare variants may contribute to the pathogenesis of SJS-TEN. The team is hopeful their findings will provide a starting point for future studies involving SJS-TEN’s complex genetic causes that will identify new biomarkers to help alleviate the risk of this rare, but serious ADR.

Fonseca, D., Morel, A., Llinas-Caballero, K., Bolivar-Salazar, D., & Laissue, P. (2021). Whole-Exome Sequencing in Patients Affected by Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Reveals New Variants Potentially Contributing to the Phenotype. Pharmacogenomics And Personalized Medicine, Volume 14, 287-299.

Serum IgG Profiling of Toddlers Reveals a Subgroup with Elevated Seropositive Antibodies to Viruses Correlating with Increased Vaccine and Autoantigen Responses

Investigators from the US incorporated a genome-wide association (GWAS) component to their study of serum IgG profiling aimed at identifying children with increased risk of clinical disease. The ability to produce antibodies is obviously very important to protecting individuals against infections and it plays a critical role in enabling vaccines to direct the antibody response. Despite the importance, little has been reported to date about the variations that may exist in responses mounted by toddlers and children in general. In the first phase of the study, the team performed a comparative analysis of IgM and IgG antibody production in a cohort of 1- and 2-year-old toddlers towards 110 distinct antigens. Further focusing on the 17% of the cohort that exhibited elevated IgG responses to specific RNA and DNA viruses, several live attenuated viruses, and a few autoantigens, they performed the GWAS portion of the study using SVS software to better understand the role genetic risk alleles play in the immune response. By adding the genetic analysis, the team was able to identify polymorphisms in several genes in a subset of the cohort that were associated with noticeable elevations of cytokine levels and a clinical history of eczema and asthma. The results of their study may be helpful to identify individuals that are at risk for immune system abnormalities at a very young stage of life by incorporating genetic analysis methods.

Pichilingue-Reto, P., Raj, P., Li, QZ. et al. Serum IgG Profiling of Toddlers Reveals a Subgroup with Elevated Seropositive Antibodies to Viruses Correlating with Increased Vaccine and Autoantigen Responses. J Clin Immunol (2021).

Novel CARMIL2 Loss-of-function Variants are Associated with Pediatric Inflammatory Bowel Disease

An international team of scientists collaborated to learn more about the genetic causes of early onset Inflammatory Bowel Disease (IBD). Pediatric IBD is characterized as a group of conditions which can cause chronic inflammation in the digestive tract. Affected children may present with symptoms such as weight loss, bloody diarrhea, and abdominal pain. These conditions may also relate to poor growth and anemia as well. In a recent study, biallelic Loss-of Function (LoF) variants of the CARMIL2gene have been implicated as the monogenic cause of very early onset IBD. Using a WES approach to learn more about CARMIL2’s role in four pediatric patients, they used VarSeq software to import, filter, and perform inheritance modeling on the variants from each trio in the cohort group from Canada. The results of their study have shown that the phenotypic spectrum of CARMIL2 deficiency is broader than previously known and the team’s data support the addition of CARMIL2 in the diagnostic evaluation of patients with suspected monogenic IBD. They are suggesting that genetic diagnosis may be vital in monogenic IBD and will help guide treatment, prevent surgery or other unnecessary treatments, and aid with genetic counseling efforts. 

Bosa, L., Batura, V., Colavito, D. et al. Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease. Sci Rep 11, 5945 (2021).

Personalised Virtual Gene Panels Reduce Interpretation Workload and Maintain Diagnostic Rates of Proband-only Clinical Exome Sequencing for Rare Disorders

With more and more clinics utilizing genomic strategies as part of their diagnostic tool kit, it has become increasingly important that diagnostic laboratories improve the efficiency of their variant interpretations. Clinical exome and genome sequencing strategies have proven to display advantages over other diagnostic techniques as they provide the capability to identify previously undetected pathogenic variants. This is a broader approach than relying on custom gene panels or single-gene analysis since they can include genes not previously surveyed. However, the speed of variant interpretation presents a significant challenge when a lab is adopting NGS as a clinical diagnostic offering. A team from the University of Manchester in the UK recently used VarSeq’s VSClinical functionality to demonstrate how the semi-automated generation of personalized gene panels can increase the accuracy and efficiency when performing the task of variant analysis as well as providing a cost-effective solution for offering genetic variant interpretation in clinical settings. In this study, the team assessed a clinician-led and phenotype-based approach for virtual gene panel generation to analyze targeted clinical exome sequencing data in patients with a presumed rare monogenic disease. The data generated in their investigation provides evidence that utilizing personalized virtual gene panels is a sustainable approach for targeted clinical exome sequencing in patients with rare diseases. Additionally, they demonstrated that using semi-automated prioritization of previously reported variants could increase the efficiency of the analysis workload. The team is optimistic their approach will pave the way for a deeper adoption of genomic analysis strategies for personalized medicine in clinical settings.

David Gokhale, Ronnie Wright, Harriet Jackson, University of Manchester / Pre-print for the Journal of Medical Genetics

I hope you enjoyed this collection of featured publications. To find the complete list of publications citing Golden Helix products, please visit our Published Articles page on our website.

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