2020 has started strong for Golden Helix customers who are engaged in research projects! We are delighted to see so many publications in January citing our products. As always, we are proud to be a part of these scientific discoveries as well as many others, too numerous to mention! With depth impossible to capture in a few words, I encourage you to click on the title links to access each article and read these publications in their entirety. See how VarSeq and SVS software can help you with your quest to advance science and medicine!

A Targeted Next Generation Sequencing Panel for Non-syndromic Early Onset Severe Obesity and Identification of Novel Likely -Pathogenic Variants in the MC4R and LEP Genes

According to the World Health Organization, childhood obesity is one of the most serious health challenges in this century, affecting every country in the world. The etiology of this rapidly increasing problem is proving to be more complex than it appears on the surface. Along with well-known lifestyle and dietary factors, genetic factors are also proving to play a significant role and are reported to contribute from 40% to 70% variation in body mass between individuals. A research team from India used VarSeq to analyze previously identified variants and GenomeBrowse to visualize the .bam files while focusing their investigation into the genetic contributions to one form of hereditary obesity labeled as non-syndromic early-onset severe obesity (NEOSO). Out of 46 patients tested, four were found to have variants categorized as pathogenic/likely pathogenic in the MC4R or LEP gene. The team hopes their discovery will support the wide use of whole exome sequencing for children with early-onset obesity despite them not having any syndromic features. The ongoing identification of newer variants will aid in the prognosis and treatment of NEOSO and hopefully lead to the development of novel therapeutic options.

Nikhil Phadke & Colleagues, GenePathDX / Published in The Indian Journal of Pediatrics

BDNF Val⁶⁶Met Positive Players Demonstrate Diffusion Tensor Imaging Consistent with Impaired Myelination Associated With High Levels of Soccer Heading: Indication of a Potential Gene-Environment Interaction Mechanism

In a first of its kind study, investigators from the Albert Einstein College of Medicine, The Feinstein Institute for Medical Research, and Sutter Health Research Center combined efforts to explore the role of brain-derived neurotrophic factor (BDNF) within the previously discovered association of soccer heading (directing the soccer ball using the head) with white matter microstructure. As part of the Einstein Soccer Study, which is a multi-faceted longitudinal study of heading and its consequences in adult amateur soccer players, the research team utilized Diffusion Tensor Imaging (DTI) and genetic analysis in their methods. SVS software was used to analyze the data that had been genotyped to include BDNF Val⁶⁶ Met, which is a single nucleotide polymorphism (SNP) in the BDNF gene known to be associated with impaired cognition in mild traumatic brain injury patients. They hypothesized that the presence of the polymorphism would demonstrate a more adverse DTI outcome in players that lacked the Met polymorphism. The results of this study support continued investigations into the role the BDNF Met allele plays in the adverse effects of soccer heading. The team hopes that someday their findings may serve as the basis of assessment of player risk for what is widely considered the world’s most popular sport.

Yun Freudenberg-Hua & Colleagues, Feinstein Institute for Medical Research / Published in Frontiers in Neurology

Genetic Variants in Toll-Like Receptor 4 are Associated with Lack of Steroid-Responsiveness in Pediatric ITP Patients

A US-based research group used SVS software to perform whole exome sequencing in pediatric patients suffering from immune thrombocytopenia (ITP) to better understand why some patients don’t respond to common upfront treatments. ITP is a rare bleeding disorder that occurs as a result of unusually low levels of platelets. Despite advancements made in understanding the pathophysiology of the disease, effective treatment remains challenging and patients are mostly managed using a trial-and-error approach, with corticosteroids being the most frequently prescribed initial treatment. While some respond to steroid treatment, others may suffer unnecessary side effects that could be avoided if there was a method of effectively predicting the response to the treatment. During their investigation, the team was successful with the help of SVS software in identifying two candidate single nucleotide variants (SNPs) in the Toll-like Receptor 4 (TLR4) gene that may alter the ability of steroids to control inflammation. The team is hopeful their discovery will spur the use of genetic sequencing to develop a personalized medicine approach to the treatment of ITP.

Jonathan Flanagan & Colleagues, Baylor College of Medicine / Published in the American Journal of Hematology

Modification Effect of Sex and Obesity on the Correlation of LEP Polymorphisms with Leptin Levels in Taiwanese Obese Women

Researchers in Taiwan investigated the environmental and genetic effects of single nucleotide polymorphisms (SNPs) in the LEP gene on leptin levels, obesity and obesity-related metabolic traits in Taiwanese people. The study consisted of 599 human subjects, 18 years or older, placed into four categories: obese females, obese males, nonobese females, and nonobese males. Using the linear regression model in SVS for their interaction analysis, the team was able to investigate the sex- and obesity-specific effects of leptin level variation. The data showed that LEP polymorphisms are independently associated with leptin levels in the obese female study group. They were further able to suggest that the genetic determinants for leptin levels differ between obese and nonobese individuals as well as between sexes. When compared to previous study findings, the data from this study demonstrated obesity status and sex may express a modifying effect on LEP transcription in this population of participants.

Semon Wu & Colleagues, Chinese Cultural University / Published in Molecular Genetics & Genomic Medicine

Early Infantile Epileptic-dyskinetic Encephalopathy Due to Biallelic PIGP Mutations

Italian researchers were presented an opportunity to study the causes of early-onset epileptic-dyskinetic encephalopathy in a large consanguineous family where four members were affected. This condition, although rare, presents with epilepsy, developmental delay, and abnormal movements, which are common to many neurodevelopmental disorders. Finding the root cause is challenging. Identifying four patients from one family exhibiting symptoms allowed the team to focus their investigation on the genetic root of the condition.  The team utilized VarSeq in their whole exome sequencing (WES) analysis and performed trio-WES where possible. The data showed that a homozygous variant in the phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) gene was present in all four patients. PIGP is a member of the large glycosylphosphatidylinositol (GPI) anchor biosynthesis gene family which has been previously identified as playing a role in CNS development. The variant is unique in that to date, it is the only mutation found in the GPI gene family that is X-linked recessive. Further investigation using flow cytometry also showed reduced expression of CD 16 in the granulocytic membrane in the affected group. Through their investigation, the results support testing CD 16 as a marker for inherited GPI deficiency disorders potentially caused by this mutation in the PIGP gene.  

Davide Mei & Colleagues, Meyer Children’s Hospital / Published in Neurology Genetics

Population and Evolutionary Genetics of the PAH Locus to Uncover Overdominance and Adaptive Mechanisms in Phenylketonuria: Results from a Multiethnic Study

Researchers from throughout France combined efforts to uncover the pathogenic variants responsible for Phenylketonuria (PKU). PKU is an inherited autosomal recessive disorder and the most common inborn error of amino acid metabolism identified in Europe. It is related to the toxic accumulation of phenylalanine in the blood and brain, and if left untreated, can lead to severe physical, neurological and cognitive dysfunction. Using a multiethnic nationwide group of patients who had previously been diagnosed with PKU, the team set out to assess the effects of population divergence and balancing selection on the locus responsible for phenylalanine metabolism. Utilizing SVS software in their exome-wide association analysis, the team was able to suggest a contributing role of population divergency and balancing selection to demonstrate heterozygote advantage and overdominance mechanisms on the phenylalanine hydroxylase (PAH) gene. The team hopes their study will also offer a new paradigm regarding the combination of evolutionary and adaptive events in various populations to explain the overdominance of some genetic variants on the PAH gene.

Abderrahim Oussalah & Colleagues, University of Lorraine and University Hospital of Nancy / Published in The Lancet