Identifying structural variants in COVID-19

SAN DIEGO—Bionano Genomics has reported the first publication from the COVID-19 Host Genome Structural Variant Consortium. The study, which can be found on medRxiv, found that optical genome mapping (OGM) with Bionano’s Saphyr System identified structural variants (SVs) that affect genes in pathways that control immune response, inflammatory response, viral reproduction, and mucosal function. The authors believe these SVs could provide key insights into the pathogenesis of COVID-19, and its outcomes in patients who become severely ill.

The consortium was formed by Dr. Ravindra Kolhe from Augusta University, with the goal of identifying large SVs that factor into the clinical course and outcomes of patients who contract COVID-19. Unlike other analyses of the host genome — which are usually limited to genome-wide association studies or exome/genome sequencing, and aim to detect single basepair changes — the consortium focuses on finding larger variants in patients’ genomes because they are believed to have a greater potential to impact genes. 

Study contributions came from scientists at Augusta University, the University of California San Diego, Radboud University Medical Center, the Rockefeller University, University of Texas M.D. Anderson Cancer Center, Columbia University Medical Center, Virginia Commonwealth University, New York Genome Center, Harvard Medical School, and Bionano Genomics. The consortium selected the Saphyr System for OGM genome analysis due to its documented performance as the leading platform for detecting large SVs.

“As director of a high-volume testing lab at Augusta University for COVID-19 I’ve seen first-hand the pain and devastation this virus can cause in those who get severely ill. The majority of the ICUs across the country are filled with patients fighting for their lives, yet we did not know why some become so severely ill while the same virus causes only mild symptoms in most,” said Kolhe, who is senior author of the study.

“Our study shows clearly that many of the severely affected patients carry genetic variants that may cause or at least contribute to the severity of their disease by weakening the effectiveness of the immune response, increasing viral replication, or making it easier for the virus to spread between cells in the body,” he continued. “Importantly, the large genomic variants detected by optical genome mapping in this study are typically missed by the short-read sequencing or SNP-based methods used in other studies, which explains why previous studies haven’t made the same impact.”

The study reports the analysis of the genomes of 37 patients who were admitted to the ICU at Augusta University with severe COVID-19 disease. 30 patients required mechanical ventilation, with a mean intubation duration of 12 days. Of the 37 patients, 25 recovered and 12 died of the virus. The SVs revealed by Saphyr were confirmed with other technologies such as quantitative PCR.

One of the most compelling findings among the SVs identified was the duplication of the STK26 gene, a key element of the toll-like receptor signaling pathway that controls the cell’s response to viral infection. In the follow-on analysis of the expression of STK26 in patients with the duplication, the study found significant upregulation of STK26 in all of the severely ill patients who were tested, but did not find it in asymptomatic COVID-19 patients — implying the duplication to be a potential novel, prognostic biomarker for the severe immune response seen in severely ill patients.

“This study demonstrates that the wide variation in symptoms exhibited by patients is likely not random for most of them, but instead, at least partially, the result of SVs affecting critical pathways in patients’ defenses against infection and immune responses to the disease. The results also demonstrate that even when a disease has already been studied extensively with sequencing, OGM with Saphyr has the potential to reveal significant insights not seen without it,” noted Dr. Erik Holmlin, CEO of Bionano Genomics. “While we are devastated by the loss of lives caused by this global pandemic, we are grateful that our genome analysis platform can contribute to a better understanding of the disease and possibly help save lives.”

The authors will present these results at Bionano’s Next-Generation Cytogenomics Symposium on January 15, and interested parties can register for the presentation.