Customer Publications Throughout February 2020

Our customers are making great contributions to human research and precision medicine every month! In February, VarSeq’s Clinical Suite dominated the published works citing Golden Helix. It is an honor for us to be at the forefront of so many important genetic investigations and we appreciate the efforts of those who work for the greater good. Read further to see how Golden Helix products can be applied to many methodologies and could be used to power your next groundbreaking discovery!

Exome Sequencing Revealed DNA Variants in NCOR1, IGF2BP1, SGLT2 and NEK11 as Potential Novel Causes of Ketotic Hypoglycemia in Children

An international group of researchers contributed to an investigation into the deeper causes of idiopathic ketotic hypoglycemia (IKH) in children. IKH is known to be the most frequent type of non-diabetes-related hypoglycemia in children and to date, it is not well understood. Patients diagnosed with IKH are typically recovering from or experiencing a decrease in oral intake due to illness with vomiting or prolonged fasting. Symptoms may include various stages of neuroglycopenia and ketosis. The diagnosis is usually made using the process of elimination by excluding the routine hormonal and metabolic causes of hypoglycemia initially. Using VarSeq in their whole exome sequencing methods for downstream filtering and trio exome analyses, the team identified four novel DNA variants as potential causes of IKH. The find suggests that IKH may be a heterogeneous disorder which can be split into at least four novel diseases. The researcher team is hopeful their discovery will prove to be a big step towards identifying a possible or definite genetic cause of the unexplained disorder, leading to a personalized medicine approach to diagnosis and treatment.

Klaus Brusgaard, Martin Larsen & Colleagues, Odense University Hospital / Published in Nature Scientific Reports

Associations of Apolipoprotein E ε4 Genotype and Ball Heading with Verbal Memory in Amateur Soccer Players

In a recent investigation from the Einstein Soccer Study, the research team explored a potential genetic risk factor contributing to reduced neuropsychological performance (NP) associated with repeated heading of soccer balls. (If you missed last month’s Customer Publication blog which highlighted a similar investigation from the Einstein Soccer Study, click here!) The team targeted a specific gene (Apolipoprotein E or ApoE) known to harbor a haplotype allele (APOE ε4) to determine if players carrying the polymorphism were at greater risk of exhibiting worse NP than those without. APOE ε4 was identified as a major risk factor for Alzheimer’s disease roughly 20 years ago and has also been implicated in reduced NP in boxers and US football players, but little is known about the role it may play in sub concussive soccer heading. Using SVS software to analyze the genotyped data from 352 amateur soccer players who participated in the study, the team was able to find evidence that the presence of APOE ε4 and a history of 12-month heading exposure are significantly associated with decreased verbal memory performance. The team hopes the data from this study will eventually support the development of official recommendations for safe levels of soccer heading, aimed at protecting players from harm.

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

Novel KLHL26 Variant Associated with a Familial Case of Ebstein’s Anomaly and Left Ventricular Noncompaction

According to the CDC, congenital heart defects (CHDs) are the most common type of birth defect. One in four babies born with a heart defect are found to have a critical CHD, requiring surgery or other procedures in the first year of life. Researchers from Wisconsin set out to discover the genetic secrets of a very rare CHD called Ebstein’s anomaly (EA), which is diagnosed in less than 1% of all CHD cases. In many cases, a condition called left ventricular noncompaction (LVNC) is also present with the EA diagnosis. The research team studied a multigenerational family with 10 of 17 members affected by EA/LVNC to determine if there were underlying genetic contributors in common. By incorporating VarSeq software into their exome filtering methods, the team was able to identify a novel variant in the KLHL26 gene not previously associated with Mendelian disease. This discovery will be added to the growing evidence that mutated KLHL proteins can disrupt cardiac muscle development and may ultimately result in the presentation of the familial EA/LVNC phenotype.

Gabrielle Geddes & Colleagues, Medical College of Wisconsin / Published in Molecular Genetics & Genomic Medicine

Six Years’ Experience with LipidSeq: Clinical and Research Learnings from a Hybrid, Targeted Sequencing Panel for Dyslipidemias

For the past six years, a Canadian research group has been using a targeted hybrid sequencing panel specifically designed to better understand the genomic loci associated with dyslipidemia. Dyslipidemia refers to an abnormal amount of lipids in the blood which can be caused by either genetic factors or diet and lifestyle. The condition is quite common and is an important risk factor for coronary artery disease and stroke. The panel, called LipidSeq, allows the team to take a deeper look into the monogenic and polygenic forms of dyslipidemia. Our industry-leading VarSeq with CNV analysis tool (VS-CNV®)  has enabled the team to analyze for CNV’s with a single NGS test, replacing multiple assays in the testing process. Besides providing an abundance of published data, the LipidSeq panel has helped the team contribute greatly to the familial hypercholesterolemia variants in the ClinVar database. Their findings have also been individually impactful for patients. As a result of LipidSeq’s successful design, it has been used by the institution as a template to develop a panel for neurodegenerative conditions as well.  

John Robinson & Colleagues, Robarts Research Institute / Published in BMC Medical Genomics

Modeling Rectal Cancer to Advance Neoadjuvant Precision Therapy

The progress towards effectively treating rectal cancer has been slowed mainly due to the lack of disease-specific preclinical models that accurately represent the unique molecular profile and biology of the disease. Attempting to advance precision therapy for rectal cancer patients, a research team from the US developed a method of creating patient-derived xenograft (PDX) and in vitro patient-derived tumor organoid (PDTO) platforms. Using tumor samples obtained from rectal cancer patients prior to treatment, the team implanted the cells into immunodeficient laboratory mice to create the xenograft model. VarSeq software was employed during the tertiary analysis of the tumor DNA sequencing portion of the study, which found that second passaged xenografts showed 100% correlation with the corresponding human tumor. The results of this study show that the PDX and PDTO platforms hold promise to advance personalized care for those suffering from rectal cancer by providing a translational research resource for biomarker discovery as well as the potential to play an important role in experimental therapy development.

Medical University of South Carolina / Published in the International Journal of Cancer

Novel Phenotype of Syndromic Premature Ovarian Insufficiency Associated with TP63 Molecular Defect

In Denmark, a research team from Odense University Hospital investigated the role a novel paternally inherited nonsense variant play in syndromic premature ovarian insufficiency (POI). Limb-mammary syndrome (LMS) is a POI which evidence supports is associated with heterozygous variants in the TP63 gene. The team studied a family where two sisters were exhibiting ovarian, uterine and mammary symptoms compatible with LMS, except that neither had the limb anomalies which are very frequently associated with the condition. Using VarSeq software to annotate and filter variants in their tetra-based whole-exome sequencing approach, the team was able to determine that both sisters and their father carried the same novel nonsense variant in the TP63 gene implicated in LMS despite the lack of limb anomalies. This phenotype represents a novel POI syndromic phenotype associated with TP63 variants. The results of this study also support the growing evidence that the TP63 gene is an important component in oocyte function and the development of the ovaries.

Kristina P. Sorensen, Odense University Hospital / Published in Clinical Genetics

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