BRCA1/BRCA2 Testing Varies Widely Worldwide Interview with:

Amanda Toland, PhD, Cancer biology and genetics researcher of The Ohio State University Comprehensive Cancer Center -- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 

Dr. Toland

Amanda Toland, PhD,
Cancer biology and genetics researcher of
The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute What is the background for this study? What are the main findings?

Response: The Breast Information Core (or BIC) is a database that catalogs BRCA1 and BRCA2 sequenced variants.  The BIC is hosted by the National Human Genome Research Institute at NIH and has a steering committee that oversees the BIC and has members from Europe, the middle East, Australia and the US.  In BIC SC discussions, we learned that there are differences in how BRCA1/2 clinical is testing between countries.

To characterize this variation, we performed an international survey of 86 genetic testing labs from around the world.

Our main findings are that there were many variations between testing laboratories.  These include: technologies differed for finding “large” genetic sequence variants, what parts of the genes were assessed, how genetic variants were classified as disease associated or not being associated with diseases, if genetic sequencing information was shared in public databases and testing volume.

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Genetic Pathways Determine Susceptibility to Dengue Shock Syndrome Interview with:

CDC/ Frederick Murphy

This transmission electron microscopic (TEM) image depicts a number of round, Dengue virus particles that were revealed in this tissue specimen. CDC image

Luisa Pereira PhD
Institute for Research and Innovation in Health
University of Porto What is the background for this study? What are the main findings?

Response: By using admixture mapping along the genome in Thai cohorts, we were able to identify new candidate genes conferring protection/susceptibility to dengue fever. A very interesting result was that the set of genes differed with the dengue phenotype: genes coding proteins that may link to the virus, conditioning its entrance in the host cells and mobility therein were associated with the less severe phenotype; genes related with blood vessels permeability were associated with the dengue shock syndrome.  Continue reading

How Much Genetic Information From Prenatal Testing Do Pregnant Women Want?

“Pregnancy 1” by operalynn is licensed under CC BY Interview with:
Professor Jane Halliday, PhD
Group Leader, Public Health Genetics
Murdoch Childrens Research Institute
The Royal Children’s Hospital
Parkville, Victoria  AUS What is the background for this study?

Response: The aim of the study was to examine the choice that pregnant women make about the amount of genetic information they want from their pregnancy. Women who underwent prenatal testing via chorionic villus sampling (CVS) or amniocentesis were recruited from across seven sites in Victoria.

Provision of this choice is not routinely offered but we thought it was important to look at this issue carefully, in a real-time setting, because, over the last five years, advances in technology have transformed how genetic abnormalities can be detected during a pregnancy.  Rather than examining genetic material (chromosomes) down the microscope, it is now possible to use a technique called ‘microarray’ which can do the analysis with 100 times greater depth than can be achieved using a microscope. The plus side is that the microarray technique can detect a far greater number of potentially important genetic differences; but a down side is that it can also detect many changes for which the impact on the health of the baby is unknown or uncertain.

Examples of genetic differences that carry certainty are major chromosome abnormalities such as the trisomies e.g. Down Syndrome, and deletions associated with severe intellectual disability in 100% of cases, e.g. 1p.36 deletion. Uncertain findings are the various small deletions and duplications that are known to only have an adverse outcome in 10-20% of people with them.

All participants were provided with a decision aid which described in detail the choice available in regards to the genetic information. The options were ‘targeted’, where only the information that would affect health of the baby was provided, or ‘extended’, where all information, even the uncertain aspects, was provided. Participants were asked to read the decision aid, complete a ten minute survey along with indicating their choice of genetic information.

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Genetic Risk Score Predictive of Aggressive Prostate Cancer Interview with:
“DNA” by Caroline Davis2010 is licensed under CC BY 2.0Tyler Seibert, MD, PhD

Radiation Oncology
Center for Multimodal Imaging & Genetics
UC San Diego What is the background for this study?

Response: Prostate cancer is an extremely common condition in men. Many die from it each year, and many others live with debilitating pain caused by prostate cancer. Screening for prostate cancer with prostate-specific antigen (PSA) testing can be effective, but there are concerns with the test.

  • First, screening everyone gives a large proportion of false-positive results, and those men end up undergoing unnecessary procedures such as prostate biopsy. S
  • econd, a significant portion of men who develop prostate cancer will develop a slow-growing form of the disease that is likely not life-threatening and may not require treatment.

    These concerns have led to a drop in prostate cancer screening. But avoiding screening leaves a large number of men vulnerable to diagnosis of an aggressive prostate cancer at a later stage, when it is more difficult—or impossible—to be cured. Doctors are left to guess which of their patients are at risk of aggressive disease and at which age they need to start screening those patients.

Our study sought to develop a tool to provide men and their doctors with objective, personalized information about each man’s risk of prostate cancer. Based on the man’s genetics, we wanted to predict the risk of aggressive prostate cancer and at what age in his life that risk becomes elevated.

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Genetic Expression of Intelligence Influenced By Environment, Especially in Childhood

“Reading is fun!” by Isaac Wedin is licensed under CC BY Interview with:
Bruno Sauce, PhD and
Louis D. Matzel, PhD
Department of Psychology, Program in Behavioral and Systems Neuroscience
Rutgers University
New Jersey, USA What is the background for this study?

Response: Scientists have known for decades that intelligence has a high heritability, which means that much of the individual differences in IQ we see in people are due to genetic differences. Heritability is a value that ranges from 0.0 (meaning no genetic component) to 1.0 (meaning that the trait is completely heritable). For example, the heritability of breast cancer is estimated at 0.27; the heritability of body mass index is 0.59; and the heritability of major depression is 0.40. In comparison, the heritability of IQ is estimated to be as high as 0.8 – quite a high value!

More recently, however, there have been studies showing that intelligence has a high malleability: the studies cover cognitive gains consequent to adoption/immigration, changes in IQ’s heritability across life span and socioeconomic status, gains in IQ over time from societal and scientific progress, the slowdown of age-related cognitive decline, the gains in intelligence from early education, differences in average IQ between countries due to wealth and development, and gains in intelligence that seem to happen from working memory training.

Intelligence being both highly heritable and highly malleable is seemingly paradoxical, and this paradox has been the source of continuous controversy among scientists.

Why does it matter? Because IQ predicts many important outcomes in life, such as academic grades, income, social mobility, happiness, marital stability and satisfaction, general health, longevity, reduced risk of accidents, and reduced risk of drug addiction (among many other outcomes). A clear understanding of the genetic and environmental causes of variation in intelligence is critical for future research, and its potential implications (and applications) for society are immense.

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Brain Imaging Associated With Heritable Cognitive Ability and Psychopathology Interview with:
“The Fourth Sex: Adolescent Extremes” by Victor Soto is licensed under CC BY 2.0Dag Alnaes, PhD
Norwegian Centre for Mental Disorders Research
KG Jebsen Centre for Psychosis Research
Division of Mental Health and Addiction, Oslo University Hospital
Oslo, Norway What is the background for this study? What are the main findings?

Response: The transition from childhood to adulthood is characterized by swift and dramatic changes, both in our environment and in our brains. This period of life also coincides with the onset of many mental disorders.

To gain a better understanding of why, the clinical neurosciences must attempt to disentangle the complex and dynamic interactions between genes and the environment and how they shape our brains. The ultimate goal is to be able to predict which individuals are at risk before clinical symptoms appear. Advanced brain imaging has been proposed to represent one promising approach for such early detection, but there is currently no robust imaging marker that allows us to identify individuals at risk with any clinically relevant degree of certainty.

Our study shows that self-reported early signs of mental illness are associated with specific patterns of brain fiber pathways in young people, even if they may not fulfill criteria for a formal diagnosis or are currently in need of treatment.  Continue reading

Lampreys Can Regenerate Severed Spinal Cord – Maybe Humans Can Too Interview with:
Ona Bloom PhD
“Duluth Boat Show - Sea Lamprey Booth” by USFWSmidwest is licensed under CC BY 2.0Associate Professor, Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases,
The Feinstein Institute for Medical Research
Associate Professor, Department of Molecular Medicine,
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell What is the background for this study? What are the main findings?

Response: Scientists have known for years that an ancient species of fish called the lamprey has a remarkable ability to rebuild their spinal cord after it’s been severed. After the lamprey spinal cord is cut, they recover from paralysis to fully swimming again in about twelve weeks, without taking any medicines or other treatments. We are studying the lamprey because we want to know the recipe of molecular ingredients that supports successful recovery after spinal cord injury.

The genome of this animal was reported about 5 years ago, in a publication led by my colleagues Dr. Jeramiah Smith at the University of Kentucky and Dr. Weiming Li at Michigan State University.  It turns out that many aspects of the lamprey genome are similar to ours, particularly in the central nervous system. Therefore, we think it is a reasonable expectation that what we learn from lamprey could give us some relevant clues about what might be different about the responses in mammals and other animals that are not good at regenerating their spinal cord.

In this study, we found that the expression of many genes in the spinal cord and brain of lampreys change during their recovery from spinal cord injury. Some of the genes that get activated are similar to what happens when our peripheral nervous system is injured, which is better at regenerating than the central nervous system. We also identified that a pathway called the Wnt pathway plays an important role in the regeneration and recovery process. This is a large, complex network of genes that are important in many biological processes, from embryological development in fruit flies to cancer in humans. Continue reading

Genetics Underlies Differences in Parkinson’s Disease Progression Interview with:

Rachel Saunders-Pullman, MD, MPH Associate Professor of Neurology Icahn School of Medicine at Mount Sinai Chief, Movement Disorders, Mount Sinai Beth Israel Co-Director Clinical/Translational Research and Research Mentoring Movement Disorders, Department of Neurology, Mount Sinai Beth Israel New York, NY 10003

Dr. Saunders-Pullman

Rachel Saunders-Pullman, MD, MPH
Associate Professor of Neurology
Icahn School of Medicine at Mount Sinai
Chief, Movement Disorders, Mount Sinai Beth Israel
Co-Director Clinical/Translational Research and Research Mentoring
Movement Disorders, Department of Neurology,
Mount Sinai Beth Israel
New York, NY 10003 What is the background for this study? What are the main findings? 

Response: There is a diversity in causes of Parkinson’s Disease (PD), and this may lead to heterogeneity in drug response. While LRRK2 PD due to G2019S mutations may fully mimic idiopathic PD (IPD), cross-sectional study suggests that the course may be slightly milder than IPD. Further, the pathology is heterogeneous with a minority not demonstrating Lewy bodies, and this may also correspond to less severe non-motor features.

To better understand the course of PD associated with the G2019S LRRK2 mutation (the most common LRRK2 mutation), we evaluated motor and cognitive progression in individuals enrolled in the LRRK2 Ashkenazi Jewish Consortium. Subjects were recruited from a Center in Tel Aviv, Israel, Sourasky Medical Center, and from two centers in New York, Columbia University and Mount Sinai Beth Israel. 144 participants were LRRK2 mutation carriers and 401 were not. We utilized all study visits, and constructed linear mixed-effects models to estimate the association between harboring the LRRK2 mutation and rate of change of both motor features- as assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS), and cognition, as measured by the Montreal Cognitive Assessment Scale (MoCA). Models adjusted for sex, site, age, disease duration and (for the motor models) cognitive score.

We found a small but significant difference in rate of progression, with LRRK2 PD progressing at 0.69 points/year, and IPD at 1.06 points/year. While the cognitive decline was also less in the LRRK2 PD (-0.10 vs. -0.19 in the IPD, this difference was not statistically different (p=0.08).

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Genetic Link Between Corneal Thickness and Risk of Glaucoma Interview with:

Eldon E. Geisert, PhD Professor of Ophthalmology Emory School of Medicine

Dr. Geisert

Eldon E. Geisert, PhD
Professor of Ophthalmology
Emory School of Medicine What is the background for this study? What are the main findings?

Response: In the late 1990s a group of doctors began a study of glaucoma patients to determine if there were phenotypes that are predictive for developing glaucoma.

In this Ocular Hypertension Treatment Study (OHTS) one of the highly correlated ocular traits was central corneal thickness (CCT). The early clinical studies found that people with thinner corneas were at a higher risk of developing glaucoma. In two large studies, examining thousands of people a number of genes were identified that were risk factors for glaucoma or that controlled CCT in humans. In both cases the identified genes accounted for less than 10% of the genetic risk for glaucoma and less than for 10% of the genetic control for CCT. There was little data linking the genetic control of CCT to the glaucoma risk.

Our group has taken an indirect approach to the question, using well-defined mouse genetic system to identify genes modulating CCT and then interrogating human glaucoma data to determine if these genes are associated with glaucoma risk.   Continue reading

LUXTURNA Proves Effectiveness of Single Gene Therapy To Cure Rare Cause of Blindness Interview with:

Dr. Stephen M. Rose, PhD Chief Research Officer Foundation Fighting Blindness

Foundation Fighting Blindness

Dr. Stephen Rose PhD
Chief Research Officer
Foundation Fighting Blindness (FFB)

Dr. Rose comments on the announcement of the FDA approval of voretigene neparvovec (LUXTURNA™) gene therapy for inherited blindness due to mutations in the RPE65 gene.

What is the background for this announcement? What were the main findings from the study?

Response: While it has been 30 years since the RPE65 gene was identified as causing Leber’s Congenital Amaurosis, this shows that it is possible to have an effective gene therapy for an inherited disease. As the first gene therapy for the eye or for an inherited disease, LUXTURNA is a historic milestone in the search for cures for all inherited retinal diseases (IRDs). As a one-time gene therapy, LUXTURNA will not only be life-changing for patients with vision loss due to mutations in the RPE65 gene, it also provides critical momentum for gene therapies – for the eye and other diseases – now in the clinic.  Continue reading