As I prepared to write the Customer Publication blog this month, I was excited by the number of recently published papers that stood as examples of how both VarSeq and SVS software are employed to advance diagnostics and treatments in human medicine. We often think of SVS as the go-to platform for Agrigenomics, however both of our platforms have broad applications and influence in the field of clinical research and medical advancement. Please read further to learn more about how Golden Helix supports our customers in their quest to unlock the secrets of the human body and enable precision medicine!
Although the consumption of sugar-sweetened beverages (SSB) has previously been highly associated with obesity, there is little understanding of the metabolic mechanisms that underlie the correlation. A team of researchers recently incorporated the use of a technique called metabolomics to help unlock the metabolic secrets hidden within the association between SSB consumption and obesity. Metabolomics is the study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms. The team performed their metabolomics analysis along with genome-wide genotyping in a study group consisting of Hispanic subjects from the ongoing Boston Puerto Rican Health Study. The team used SVS for their principal component analysis of 83 SNPs in 10 genes which were then used to examine the gene-diet interaction with SSB intake on obesity. Combining metabolomics and genomics allowed the team to identify two metabolic pathways linking SSB intake to obesity as well as discovering a strong interaction between genetic variants in the identified pathways and SSB intake. The team is hopeful their findings have identified a potential mechanism by which SSB intake increases the risk of obesity, thus adding a piece to the puzzle of understanding the root cause of the association.
Chao-Qiang Lai & Colleagues, USDA Agricultural Research Service / Published in The Journal of Obesity
Working on behalf of the Pediatric Cardiac Genomics Consortium, a group of researchers in the US set out to enhance the data from an earlier investigation by expanding their analysis from SNP data to include a genome wide association study (GWAS) focusing primarily on the maternal genotype and the relationship it has to conotruncal birth defects (CTD). With the help of SVS software, the team provided suggestive evidence that three candidate genes are most likely to influence congenital birth defect risk via effects on early embryonic development. In what is thought to be the first gene based GWAS of maternal genotypes and CHD, the team is hopeful they have shed some light on not just heart defects, but on a range of adverse reproductive outcomes. They are hoping additional studies of the relationship between the maternal genome and birth defects will result in broader implications for reproductive counseling and planning.
Laura Mitchell, A.J. Agopian & Colleagues, UTHealth School of Public Health / Published in PLoS ONE
Investigators from Brazil and Texas joined forces to deep dive into the burden of somatic mutations of hepatoblastomas. Hepatoblastomas (HB) are a rare tumor originating in the liver and is the most common cancerous liver tumor usually identified in early childhood. The team used VarSeq to annotate their data and filter variants in the exome sequencing portion of the study, along with GenomeBrowse to visually validate those variants classified as Pathogenic/Likely pathogenic as somatic alterations. As a result of their very detailed investigation, they were able to identify a recurrent somatic missense mutation (in exon 3 of CX3CL1) which may play a role in HB development or progression. To read more about their investigation of this rare form of pediatric cancer, click on the title to access the study in its entirety.
Ana Krepischi & Carla Rosenberg, University of Sao Paulo, Dirce Carraro, A.C. Camarago Cancer Center & Colleagues / Published in Frontiers in Oncology
A multi-national research team combined their effort to study the effect of matrix metallopeptidase 20 (MMP20) mutations on dentinogenesis (the formation of dentin, a substance that forms the majority of teeth). Although the role of MMP20 mutations is known to contribute to amelogenesis imperfecta (a disorder that causes abnormal formation of the enamel of teeth), their effect on the formation of dentin is unclear. Despite consisting of the same inorganic component as enamel, dentin is formed through a developmental process distinct from that of enamel. Using VarSeq to annotate variants in their whole exome sequencing study, the team compared individual VCF files against a variety of data sources, including gene annotation, function prediction and frequency information to determine if there is a relationship between MMP20 mutations and dentinogenesis. Their data seems to support that loss of function of MMP20 causes not only enamel malformations but also defects in the development of dentin as well, which is evidence not previously reported in humans.
Jan Hu, Hong Zhang, University of Michigan & Colleagues / Published in Molecular Genetics & Genomic Medicine
In this case study from Canada, a team of investigators presented a novel approach to treating a patient in need of a miracle. Shortly after delivery, an infant girl became tachypneic (exhibiting rapid breathing) which progressed rapidly to respiratory distress requiring intubation. Upon further testing, she was diagnosed with a primary congenital lactic acidosis and cardiomyopathy. When the first line of treatment to help the newborn failed, the course of treatment was shifted to the administration of dichloroacetate (DCA), which proved to stabilize her. Since most cases of lactic acidosis are caused by one or more inherited mutations and armed with the knowledge that mutations in the MTFMT (mitochondrial methionyl-tRNA formyltransferase) gene have been linked to previous cases exhibiting reduced cellular energy production similar to hers, they took a deeper dive into this young patient’s genetic background. With VarSeq employed for the tertiary analysis, the team identified a homozygous, stop-gain mutation in a conserved, deleterious nucleotide in the MTFMT gene. Further administrations of DCA, dosage adjusted over time as she grows, has demonstrated the ability to normalize her lactate levels as well as improve her cardiomyopathy. At the time of writing, the patient had received two years of follow-up care and is reported to be in overall good general health on a maintenance dosage of DCA. The team is hopeful their case study demonstrating the novel use of DCA in a patient with MTFMT deficiency will provide a potential therapeutic option that warrants further study.
Marina Kerr, Alberta Children’s Hospital, University of Calgary & Colleagues / Published in Molecular Genetics and Metabolism Reports
Researchers in Japan recently published a paper confirming the link between two genetic risk factors and Vogt-Koyanagi-Harada (VKH) disease in a Japanese population. Replicating a recent genome-wide association study (GWAS) where the novel risk factors (IL23R-C1orf141 and ADO-ANF365-EGR2) were identified in a Han Chinese population, the team used SVS software to perform their own GWAS in Japanese patients diagnosed with VKH disease. VHK is an autoimmune disease that affects pigmented tissues, such as the eyes, inner ear, skin and the meninges of the central nervous system. The most notable symptom is a rapid loss of vision and it occurs more frequently in people with dark skin pigmentation, as well as in those of Asian, Native American and Hispanic descent. The team is hopeful their data will result in future genetic studies with larger samples of Asian and other ethnic populations to confirm and validate the link this data supported.
Akira Meguro, Yokahama City University & Colleagues / Published in PLoS ONE
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.