January 2021 Publications

         January 28, 2021

New discoveries using NGS data analysis are never-ending and are pushing precision medicine to the forefront. In this month’s customer publication blog, I am focusing on our VarSeq software as investigators harness its power to perform a variety of investigational study designs. From cancer to inherited rare disease research, VarSeq is the rising star in research and diagnostic tools. At Golden Helix, we are very proud to be part of such important scientific discoveries and we appreciate our customers and their dedication to the advancement of NGS diagnostic techniques. As we begin a new year, we wish you all great success, and please remember we are always here to support your efforts. Read on to see how VarSeq can assist in your continued success!

Whole-exome Sequencing of non-BRACA1/BRACA2 Mutation Carrier Cases at High-risk for Hereditary Breast/Ovarian Cancer

An international collaboration amongst researchers from Brazil, Portugal, Canada, and the US resulted in the largest Brazilian whole exome sequencing (WES) study of families at high risk for hereditary breast and ovarian cancers (HBOC) performed to date. The germline variants in BRCA1/BRCA2 are known to be the cause of approximately 25% of the familial breast and ovarian cancers. But, for many families, the genetic cause associated with HBOCs remains unknown. Building on recent WES studies that have proven to be an effective diagnostic approach for individuals lacking the usual pathogenic molecular alterations, the team enlisted 52 unrelated Brazilian women at high risk for HBOC who had previously tested negative for pathogenic germline variants in BRCA1/BRCA2/TP53. With the help of data analyzed using VarSeq software, the group’s findings suggested several other cancer-associated genes such as RAD54L, FAN1, DROSHA, POLQ, and SLC34A2 may also have a role in HBOC. Additionally, this study presented evidence that other moderate-risk genes may be associated with the development of HBOC. The group hopes their findings will help the efforts of molecular cataloging of breast/ovarian tumors lacking the typical BRCA1/BRCA2 mutations and will result in better diagnostic tools available to these patients.

Felicio, P. S., Grasel, R. S., Campacci, N., Paula, A. E., Galvão, H. C., Torrezan, G. T., Sabato, C. S., Fernandes, G. C., Souza, C. P., Michelli, R. D., Andrade, C. E., Barros, B. D., Matsushita, M. M., Revil, T., Ragoussis, J., Couch, F. J., Hart, S. N., Reis, R. M., Melendez, M. E., … Palmero, E. I. (2020). Whole‐exome sequencing of non‐ BRCA1/BRCA2 mutation carrier cases at high‐risk for hereditary breast/ovarian cancer. Human Mutation. https://doi.org/10.1002/humu.24158

Bi-Allelic Pathogenic Variations in MERTK Including Deletions are Associated with an Early Onset Progressive Form of Retinitis Pigmentosa

Researchers from Denmark performed a targeted sequence panel analysis to better understand the genetic mechanisms responsible for early-onset progressive retinitis pigmentosa (RP). RP is a rare disorder that is inherited and often leads to blindness. It usually starts in childhood but exactly when it starts and how quickly it gets worse varies from person to person.  Using VarSeq’s powerful CNV calling tool, the team analyzed 677 individuals with inherited retinal diseases (IRDs) and identified 24 CNV’s. In addition to increasing the understanding of the genetic and clinical characteristics of individuals with MERTK-related retinal dystrophies, their study also underlines the importance of using robust bioinformatic pipelines to analyze data from NGS targeted panels for CNV’s when retinal dystrophies are suspected. The team hopes their discoveries will aid in the evolution of gene therapies for IRDs.

Jespersgaard, C., Bertelsen, M., Arif, F., Gellert-Kristensen, H., Fang, M., & Jensen, H. et al. (2020). Bi-Allelic Pathogenic Variations in MERTK Including Deletions Are Associated with an Early Onset Progressive Form of Retinitis Pigmentosa. Genes, 11(12), 1517. https://doi.org/10.3390/genes11121517

A Novel Splice-Site Mutation in the ELN Gene Suggests an Alternative Mechanism for Vascular Elastinopathies

Mutations in elastin (ELN gene) result in a broad range of elastinopathies including defects such as supravalvular aortic stenosis (SVAS) which affect the heart and autosomal dominant cutis laxa (ADCL) which is characterized by a mix of defects including skin tissue with loss of elasticity as well as SVAS. Both conditions, although caused by mutations in the same gene, are mutually exclusive and suggest there are distinct underlying molecular mechanisms at play. A research team in Columbia examined a case where a child from a family with a history of vascular elastinopathies also presented with SVAS but did not exhibit ADCL. Using VarSeq to filter the variants in the ELN gene, the team discovered a novel splice-site mutation which may help to explain why a handful of missense mutations can cause SVAS. They hope their discovery will support a deeper understanding of the effect the position of a variant can have in this case of SVAS without the usual dual diagnosis of ADCL.

Velandia-Piedrahita, C. A., Morel, A., Fonseca-Mendoza, D. J., Huertas-Quiñones, V. M., Castillo, D., Bonilla, J. D., Hernandez-Toro, C. J., Miranda-Fernández, M. C., Restrepo, C. M., & Cabrera, R. (2020). A novel splice-site mutation in the ELN gene suggests an alternative mechanism for vascular Elastinopathies. The Application of Clinical Genetics, 13, 233-240. https://doi.org/10.2147/tacg.s282240

Genetic Analysis of Sinonasal Undifferentiated Carcinoma Discovers Recurrent SWI/SNF Alterations and a Novel PGAP3-SRPK1 Fusion Gene

Sinonasal Undifferentiated Carcinoma (SNUC) is a rare cancer of the nasal cavity and/or the paranasal sinuses. These tumors are aggressive which results in most patients presenting at an advanced stage and generally have poor outcomes. There have been no novel or targeted agents introduced for SNUC treatment since its initial identification as a condition. This is partially due to the limited investigations into the underlying genetic factors defining SNUC pathogenesis. Researchers at the University of Michigan recently employed VarSeq software in the exome sequencing portion of their study aimed at unlocking some of the genetic unknowns associated with SNUC’s. Their efforts have led to several remarkable discoveries in this preliminary study that may be of interest as prognostic biomarkers for larger studies and could potentially present new targetable therapeutic options.

Neal, M., Birkeland, A., Bhangale, A., Zhai, J., Kulkarni, A., & Foltin, S. et al. (2020). Genetic Analysis of Sinonasal Undifferentiated Carcinoma Discovers Recurrent SWI/SNF Alterations and a novel PGAP3-SRPK1 Fusion Gene. https://doi.org/10.21203/rs.3.rs-115402/v1

The Mutational Repertoire of Uterine Sarcomas and Carcinosarcomas in a Brazilian Cohort: A Preliminary Study

Investigators from Brazil and the US recently conducted a study that was aimed at contributing to the catalog of genetic mutations involved in the carcinogenic processes of uterine sarcomas (USs) and carcinosarcomas (UCSs). Because they are rare, there have been few studies conducted to date focusing on the mutational characterizations of these tumors.  The team used VarSeq to perform gene-targeted NGS of 409 cancer-related genes in several tumor samples to select reputed somatic variants to broaden the understanding of genetic components and currently available data. They are hopeful their findings will contribute to the discovery of new biomarkers for precision medicine-based approaches to treatments of these neoplasms. Although preliminary, this study builds a solid foundation for moving forward with further studies using larger cohorts and they believe that including functional analysis methods will advance the treatment options for these difficult to treat tumors. Feel free to also check out some of our other blogs that always contain important news and updates for the next-gen sequencing community.

da Costa, L., dos Anjos, L., Kagohara, L., Torrezan, G., De Paula, C., & Baracat, E. et al. (2021). The mutational repertoire of uterine sarcomas and carcinosarcomas in a Brazilian cohort: A preliminary study. Clinics, 76. https://doi.org/10.6061/clinics/2021/e2324

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