Reading scientific articles that our customers have recently published is one of my favorite things here at Golden Helix. It is fascinating to learn about the research and to see the various ways our software gets put to the test.
Since we are rolling out our most extensive VarSeq update yet, I thought it would be a great time to look at some recently published research on pediatric cancer and also genetic disorders and how VarSeq can help. Researchers greatly benefit from the clinical grade variant annotation and filtering capabilities of VarSeq, as will be discussed below.

Mutation in the exocyst component EXOC2 cause severe defects in human brain development

A collaboration between Australian and Italian geneticists and Vanderbilt researchers discovered functional mutations that caused the delivery of specific proteins to the plasma membrane to be greatly reduced. This points to EXOC2 variants as the cause of the patients’ neurological disorders that include progressive microcephaly, epilepsy, developmental delay, and brain abnormalities. They found multiple variants in EXOC2; one was homozygous and led to nonsense-mediated decay of the transcript and the others were compound heterozygous missense variants that lead to reduced exocytosis. Variants annotation was completed by using VarSeq. VarSeq’s family and frequency-based filtering were also employed. Ongoing research is likely to identify more variants in this protein complex that will lead to a better understanding of the impacts on exocytosis and synaptogenesis.

Van Bergen, N., Ahmed, S., Collins, F., Cowley, M., Vetro, A., & Dale, R. et al. (2020). Mutations in the exocyst component EXOC2 cause severe defects in human brain development. Journal Of Experimental Medicine, 217(10). https://doi.org/10.1084/jem.20192040

Genetic Screening of Patients with Primary Immunodeficiency by Whole-Exome Sequencing

Primary immunodeficiencies are congenital disorders of the immune system. A research team from Turkey discovered three novel disease-causing variants and were able to genetically diagnose 5 out of 8 PID patients, using NGS analysis. VarSeq software was used for the annotation of the variants. Variants found in 1,000 Genome Project, ExAc, and GnomAD databases with MAF > 0.01 were excluded, and the other variants were filtered for rare nonsense, missense, and indel changes within the exons and splice-site regions. Their results, which were also validated by Sanger sequencing, show that whole-exome sequencing can facilitate cost-effective, rapid, and life-saving diagnoses. As there is no obvious candidate gene in many PIDs, NGS may be the best option for genetic diagnosis.

Erman, B., & Çipe, F. (2020). Genetic Screening of the Patients with Primary Immunodeficiency by Whole-Exome Sequencing. Pediatric Allergy, Immunology, And Pulmonology, 33(1), 19-24. https://doi.org/10.1089/ped.2019.1097

A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity

Calpainopathy is the most common type of AR limb-girdle muscular dystrophy (LMGD). A team from the University Hospital of Copenhagen reported the first single missense variant in CAPN3, resulting in a dominantly inherited calpainopathy. VarSeq was employed to carry out the variant annotation and filtering processes. Their findings suggest that dominantly inherited calpainopathy is not unique to the previously reported c.643_663del mutation of CAPN3 and that they should be considered for other single variations in the gene, especially small in-frame deletions/insertions and missense mutations.

Vissing, J, Dahlqvist, JR, Roudaut, C, et al. A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity. Human Mutation. 2020; 41: 1507– 1513. https://doi.org/10.1002/humu.24066

Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high frequency of cancer-prone syndromes

In Denmark, 235 children newly diagnosed with cancer were invited to participate in a nationwide population-based study to answer how frequently those with cancer had or were likely to have a cancer predisposition syndrome (CPS) Researchers in Denmark sequenced the patients’ genome, mapped family pedigrees, and made physical examinations to gain a full and comprehensive understanding. This study revealed that a tenth of all patients carried a causative genetic variant based on tools that evaluate the type of cancer, physical characteristics, and family history. Overall, roughly half of the patients were suspected of carrying an underlying genetic cause of their cancer and one-tenth had a verified underlying genetic variant predisposing to cancer development in childhood. This could suggest that the amount of childhood cancer cases attributed to genetic factors might be even higher. VarSeq was utilized in the annotation and filtration of variants of clinical interest. The results demonstrate that there is great value in screening pediatric cancer patients for CPS and indicate that more childhood cancers are linked to predisposing germline variants than originally suspected.

Byrjalsen A, Hansen TVO, Stoltze UK, Mehrjouy MM, Barnkob NM, Hjalgrim LL, et al. (2020) Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high frequency of cancer prone syndromes. PLoS Genet 16(12): e1009231. https://doi.org/10.1371/journal.pgen.1009231

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. Feel free to check out some of our other blogs that always contain important news and updates for the next-gen sequencing community.