Golden Helix Customer Publications – April 2021

         April 29, 2021

Researchers and clinicians alike benefit from the powerful capabilities of Golden Helix’s software. Our tools are continuously validated, and we like to showcase a few articles each month that demonstrate the multitude of use cases and advancements in science. For our April installment, I would like to highlight the clinical space, with users spanning the globe, all with a common purpose: enabling precision medicine. 

Venous thromboembolism is caused by prothrombin p.Arg541Trp mutation in Japanese individuals

Researchers from various organizations at the National Center for Global Health and Medicine in Tokyo found that Venous thromboembolism (VTE) is heritable at a rate of somewhere between 35-60%. It is clinically significant to identify the variants and mutations that predispose carriers to VTE. This oftentimes fatal condition has been detected chiefly in families showing an autosomal dominant form of inheritance. Researchers focused on whole-exome sequencing to find variants of interest. Single-nucleotide variations (SNVs) and insertions and deletions were annotated using Golden Helix’s VarSeq variant analysis software. They retrieved rare and putatively pathogenic variants, including SNVs. Exome sequencing identified a nonsynonymous mutation in the gene encoding prothrombin, p.Arg541Trp or p.R541W in the proband and his affected mother. Although this mutation has not been registered in ClinVar to date, it was recently reported in the Chinese population as a rare functional mutation associated with an increased risk for VTE7. The study demonstrated the p.R541W variant in VTE patients of Japanese descent and the subsequent knowledge that it is reproducibly detected amongst East Asian populations. It should trigger medical follow-up for individuals carrying this variant. Finally, the study also emphasizes the importance of this whole-exome sequencing in clarifying patient’s genetic factors. 

Yamamoto, J., Yamamoto, M., Takano, K. et al. Venous thromboembolism is caused by prothrombin p.Arg541Trp mutation in Japanese individuals. Hum Genome Var 8, 13 (2021). https://doi.org/10.1038/s41439-021-00145-x

Integrative sequencing discovers an ATF1-motif enriched molecular signature that differentiates hyalinizing clear cell carcinoma from mucoepidemoid carcinoma

Researchers from several departments at the University of Michigan Medical School collaborated on this study to define the molecular profile of a rare salivary gland cancer called hyalinizing clear cell carcinoma (HCCC). They also sought to identify a molecular gene signature that would allow the differentiation between HCCC and a similar disease, mucoepidemoid carcinoma (MEC). There is an occurrence of CREB family gene fusions that show a clear molecular distinction, researchers say. Still, otherwise, there is not much information regarding the tumor and events surrounding the disruptions. Researchers provided the first fully integrated sequencing of hyalinizing clear cell carcinoma. The authors used golden Helix’s VarSeq software to annotate the variants in the analysis. Researchers discovered an ATF1-motif enriched gene signature that may have clinical utility for molecular differentiation of HCCC cases from a cohort of MECs. They also identified two potentially druggable targets in their samples and, in the future, hope to discover more potentially actionable alterations that may benefit the clinical care of recurrent HCCC patients.

M.E. Heft Neal, E. Gensterblum-Miller, A.D. Bhangale, A. Kulkarni, J. Zhai, J. Smith, C. Brummel, S.K. Foltin, D. Thomas, H. Jiang, J.B. McHugh, J.C. Brenner, Integrative sequencing discovers an ATF1-motif enriched molecular signature that differentiates hyalinizing clear cell carcinoma from mucoepidemoid carcinoma, Oral Oncology, Volume 117,2021,105270, ISSN 1368-8375,https://doi.org/10.1016/j.oraloncology.2021.105270.

Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer

Researchers in Australia, France, and the U.S. collaborated on this study that looked at prostate cancer and the treatment decisions surrounding diagnoses. By identifying which men at the time of prostate cancer diagnosis have, or will progress to, an aggressive form of the disease will help clinicians make better treatment recommendations. Golden Helix’s software allowed researchers to annotate and filter the rare genetic variants identified in the germline DNA of 837 cases diagnosed with prostate cancer. The study applied a new recommended definition of aggressive prostate cancer and provides further evidence that rare germline pathogenic variants in ATM, BRCA1, and BRCA2 are associated with increased risk of this bold, clinically relevant subset of prostate cancer. Clinicians can incorporate this evidence into risk prediction models to more precisely identify men with the highest risk of aggressive prostate cancer and prevent unnecessary treatment for patients with a more indolent form. 

Nguyen-Dumont, T.; Dowty, J.G.; MacInnis, R.J.; Steen, J.A.; Riaz, M.; Dugué, P.-A.; Renault, A.-L.; Hammet, F.; Mahmoodi, M.; Theys, D.; et al. Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer. Cancers 2021, 13, 1495. https://doi.org/ 10.3390/cancers13071495

Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss

A major collaborative study between organizations in the United Kingdom, Belgium, and Denmark utilized long-read sequencing to understand variants in the CEP78 gene. Inactivating variants and a missense variant in the gene have been identified in an autosomal recessive cone-rod dystrophy with hearing loss (CRDHL). This rare inherited retinal disease also contains complex structural variants (SV). Researchers identified these SV via shallow whole-genome sequencing and analysis on whole-exome sequencing data. Targeted or whole-genome nanopore long-read sequencing (LRS) was used to delineate breakpoint junctions at the nucleotide level. VarSeq was used to annotate and filter variants of clinical relevance. Overall, this study supports that the CEP78 locus is prone to distinct SVs and that SV analysis should be considered in a genetic workup of CRDHL. Finally, it demonstrated the power of sWGS and both targeted and whole-genome LRS in identifying and characterizing complex SVs in patients with ocular diseases.

Ascari, G., Rendtorff, N., De Bruyne, M., De Zaeytijd, J., Van Lint, M., Bauwens, M., Van Heetvelde, M., Arno, G., Jacob, J., Creytens, D., Van Dorpe, J., Van Laethem, T., Rosseel, T., De Pooter, T., De Rijk, P., De Coster, W., Menten, B., Rey, A., Strazisar, M., Bertelsen, M., Tranebjaerg, L. and De Baere, E., 2021. Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss. Frontiers in Cell and Developmental Biology, 9.

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

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