Daily Archives: June 27, 2017

June 27, 2017

Thirty-six percent of Hispanic families in the U.S. with a common form of retinitis pigmentosa got the disease because they carry a mutation of the arrestin-1 gene, according to a new study from researchers at The University of Texas Health Science Center at Houston (UTHealth) School of Public Health.

Retinitis pigmentosa is a group of rare, genetic eye disorders in which the retina of the eye slowly degenerates. The disease causes night blindness and progressive loss of peripheral vision, sometimes leading to complete blindness. According to Stephen P. Daiger, Ph.D., senior author of the study, an estimated 300,000 people in the U.S. suffer from the disease, which gets passed down through families.

In the study published recently in Investigative Ophthalmology & Visual Science, UTHealth researchers found that in a U.S. cohort of 300 families with retinitis pigmentosa, 3 percent exhibited a mutation of the arrestin-1 gene. However, more than 36 percent of Hispanic families from the cohort exhibited the arestin-1 mutation and they all came from areas in the Southwestern U.S., such as Texas, Arizona and Southern California.

"When I started studying retinitis pigmentosa in 1985, we set out to find the 'one' gene that causes the disease. Thirty-three years later, we've found that more than 70 genes are linked to retinitis pigmentosa," said Daiger, a professor in the Human Genetics Center and holder of the Thomas Stull Matney, Ph.D. Professorship in Environmental and Genetic Sciences at UTHealth School of Public Health.

Some of the genes that cause retinitis pigmentosa are recessive, which means two mutations are required, and some are dominant, which means you only need one mutation. Arrestin-1 piqued Daiger's interest because that particular mutation is dominant while all previously found mutations in the gene are recessive. This unexpected finding shows that even a single mutation in the gene is sufficient to cause the disease.

Daiger and his team have identified the genetic cause of retinitis pigmentosa for 75 percent of families in their cohort. Possible treatments for some forms of retinitis pigmentosa are being tested but are still limited. However, the speed at which companies are developing gene therapies and small molecule therapies gives reason to hope, he said. Daiger and his collaborators have begun to connect some of the patients in the retinitis pigmentosa cohort to clinical trials that treat specific genes.

"I want our cohort families to know that even if there is not an immediate cure for their specific gene mutation, at this rate it won't be long until a therapy becomes available," said Daiger, who also holds the Mary Farish Johnston Distinguished Chair in Ophthalmology at McGovern Medical School at UTHealth.

Support for the study, titled "A novel dominant mutation in SAG, the arrestin-1 gene, is a common cause of retinitis pigmentosa in Hispanic families in the Southwestern United States," was provided by the William Stamps Farish Fund and the Hermann Eye Fund.

Explore further: Scientists discover gene tied to profound vision loss

More information: Lori S. Sullivan et al. A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States, Investigative Opthalmology & Visual Science (2017). DOI: 10.1167/iovs.16-21341

An exhaustive hereditary analysis of a large Louisiana family with vision issues has uncovered a new gene tied to an incurable eye disorder called retinitis pigmentosa, according to an examination led by scientists at The ...

Researchers have started a new gene therapy clinical trial to treat X-linked retinitis pigmentosa (XLRP), the most common cause of blindness in young people.

An international team of researchers has discovered that mutations in the human gene CWC27 result in a spectrum of clinical conditions that include retinal degeneration and problems with craniofacial and skeletal development. ...

Progressive development of night blindness and tunnel vision, sometimes from the early age of 2, are trademarks of retinitis pigmentosa. Being the most common inherited disorder of the retina, retinitis pigmentosa affects ...

Columbia University Medical Center (CUMC) and University of Iowa scientists have used a new gene-editing technology called CRISPR, to repair a genetic mutation responsible for retinitis pigmentosa (RP), an inherited condition ...

Researchers at UCL Institute of Ophthalmology and Moorfields Eye Hospital with funding from Fight for Sight, in collaboration with a team from Baylor College of Medicine in the USA, have discovered a new retinitis pigmentosa ...

Using a new skin cell model, researchers have overcome a barrier that previously prevented the study of living tissue from people at risk for early heart disease and stroke. This research could lead to a new understanding ...

A research team has successfully used magnets implanted behind a person's eyes to treat nystagmus, a condition characterised by involuntary eye movements.

The first results from a functional genetic catalogue of the laboratory mouse has been shared with the biomedical research community, revealing new insights into a range of rare diseases and the possibility of accelerating ...

Whole genome sequencing involves the analysis of all three billion pairs of letters in an individual's DNA and has been hailed as a technology that will usher in a new era of predicting and preventing disease. However, the ...

Researchers have found that genes for coronary heart disease (CAD) also influence reproduction, so in order to reproduce successfully, the genes for heart disease will also be inherited.

When Ricky Ramon was 7, he went for a routine checkup. The pediatrician, who lingered over his heartbeat, sent him for a chest X-ray, which revealed a benign tumor in the top-left chamber of his heart. For Ramon, it was the ...

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Gene mutation linked to retinitis pigmentosa in Southwestern US Hispanic families - Medical Xpress

In a new paper recently published in the Journal of Clinical Oncology: Precision Oncology, researchers at Baylor College of Medicine and Texas Childrens Hospital report that genomic sequencing information may be more valuable for families of pediatric cancer patients than has previously been recognized.

The paper reports results from the Baylor Advancing Sequencing in Childhood Cancer Care (BASIC3) study led by Baylors Dr. Sharon Plon, professor of pediatrics-oncology and molecular and human genetics; Dr. Will Parsons, associate professor of pediatrics-oncology and molecular and human genetics; and Dr. Amy McGuire, director of the Center for Medical Ethics and Health Policy. The BASIC3 study evaluates the impact of incorporating a type of genomic sequencing called whole exome sequencing into the clinical care of children newly diagnosed with cancer being treated at Texas Childrens Cancer Center. This technology can reveal information about the genetics of the childs tumor as well as identify genes that the patient or parents may have that are associated with cancer, other diseases and conditions that would require immediate clinical action. Most parents also opted to find out if they or their child carry a gene for a disease that they could pass on to future generations. Through this study, investigators sought to understand what parents of newly diagnosed pediatric cancer patients think about receiving this type of information.

The BASIC3 research team interviewed more than 60 parents before and after they received their childs exome sequencing results. Parents described a wide range of ways in which they found the information valuable for their child, themselves and other family members. As expected, parents hoped that the information would improve their childs care through cancer treatment tailored to their childs specific cancer or through appropriate monitoring in the future. However, they also perceived benefit of whole exome sequencing even when it would not change the childs clinical care.

Concerns about how children and parents will react to genomic sequencing information as well as respect for the future rights of children to decide whether they want that information have led to a general consensus against disclosing sequencing information that does not have clear clinical utility, said McGuire, one of the principal investigators of the BASIC3 study. However, our study showed that parents of children with a serious illness found this information valuable for a wide variety of reasons, which raises questions about whether this consensus is appropriate for this population.

Parents in the BASIC3 study wanted to know where their childs cancer had come from and hoped that genomic sequencing would help them understand why this had happened to their family. They described relief from both guilt and worry upon finding that their childs disease was not caused by a known cancer-related gene. Parents who discovered their child had a genetic risk of cancer expressed that having that knowledge could help the child make their own reproductive decisions. In addition, some parents noted that the exome sequencing results prompted them to have the childs siblings and other family members receive genetic testing to assess their risk. If no genetic risk of cancer or other diseases was discovered, parents felt reassured of the health of their other children, including any potential children in the future.

On the whole, parents were remarkably positive about genomic sequencing, even if the results did not change their childs medical treatment, said Dr. Janet Malek, first author of the paper and associate professor of medicine and medical ethics at the Center for Medical Ethics and Health Policy. They found the information valuable for themselves and other family members in a broad range of ways. These results suggest that we need to think carefully about how we understand the risks and benefits of using this technology, when we should recommend its use and how we talk about it with patients and families.

The results from this interview study improve the understanding of parents perspectives of whole exome sequencing. Researchers and clinicians can use parents broad range of utility to re-evaluate how risks and benefits should be described and to inform decisions about using whole exome sequencing in clinical care. The Baylor team is planning to continue researching this topic with a new and larger longitudinal survey based-study across multiple sites in Texas that will compare the various benefits and concerns of receiving exome sequencing results. Currently, Malek and colleagues are analyzing what the roles of guilt, regret and parental responsibility have in how parents in the BASIC3 study perceive the value of their childs whole exome sequencing results.

Other contributors to this work include Dr. Melody Slashinski, Jill Robinson, Amanda Gutierrez, and Dr. Laurence McCullough. Drs. Plon, McGuire and Parsons are also members of the NCI-designated Dan L Duncan Comprehensive Cancer Center at Baylor. The BASIC3 study is a Clinical Sequencing Exploratory Research (CSER) program project supported by Grant No. 1U01HG006485 from the National Human Genome Research Institute, National Cancer Institute.

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Genomic sequencing may benefit parents of cancer patients - Baylor College of Medicine News (press release)

June 27, 2017 by David Slipher In this mouse cortex, a mutation in the CHD8 gene caused increased brain size, or megalencephaly, a condition also present in people with autism spectrum disorder. The colored sections correspond to different layers of the developing cortex. Credit: Alex Nord/UC Davis

While the definitive causes remain unclear, several genetic and environmental factors increase the likelihood of autism spectrum disorder, or ASD, a group of conditions covering a "spectrum" of symptoms, skills and levels of disability.

Taking advantage of advances in genetic technologies, researchers led by Alex Nord, assistant professor of neurobiology, physiology and behavior with the Center for Neuroscience at the University of California, Davis, are gaining a better understanding of the role played by a specific gene involved in autism. The collaborative work appears June 26 in the journal Nature Neuroscience.

"For years, the targets of drug discovery and treatment have been based on an unknown black box of what's happening in the brain," said Nord. "Now, using genetic approaches to study the impact of specific mutations found in cases, we're trying to build a cohesive model that links genetic control of brain development with behavior and brain function."

The Nord laboratory studies how the genome encodes brain development and function, with a particular interest in understanding the genetic basis of neurological disorders.

Mouse brain models

There is no known specific genetic cause for most cases of autism, but many different genes have been linked to the disorder. In rare, specific cases of people with ASD, one copy of a gene called CHD8 is mutated and loses function. The CHD8 gene encodes a protein responsible for packaging DNA in cells throughout the body. Packaging of DNA controls how genes are turned on and off in cells during development.

Because mice and humans share on average 85 percent of similarly coded genes, mice can be used as a model to study how genetic mutations impact brain development. Changes in mouse DNA mimic changes in human DNA and vice-versa. In addition, mice exhibit behaviors that can be used as models for exploring human behavior.

Nord's laboratory at UC Davis and his collaborators have been working to characterize changes in brain development and behavior of mice carrying a mutated copy of CHD8.

"Behavioral tests with mice give us information about sociability, anxiety and cognition. From there, we can examine changes at the anatomical and cellular level to find links across dimensions," said Nord. "This is critical to understanding the biology of disorders like autism."

By inducing mutation of the CHD8 gene in mice and studying their brain development, Nord and his team have established that the mice experience cognitive impairment and have increased brain volume. Both conditions are also present in individuals with a mutated CHD8 gene.

New implications for early and lifelong brain development

Analysis of data from mouse brains reveals that CHD8 gene expression peaks during the early stages of brain development. Mutations in CHD8 lead to excessive production of dividing cells in the brain, as well as megalencephaly, an enlarged brain condition common in individuals with ASD. These findings suggest the developmental causes of increased brain size.

More surprisingly, Nord also discovered that the pathological changes in gene expression in the brains of mice with a mutated CHD8 continued through the lifetime of the mice. Genes involved in critical biological processes like synapse function were impacted by the CHD8 mutation. This suggests that CHD8 plays a role in brain function throughout life and may affect more than early brain development in autistic individuals.

While Nord's research centers on severe ASD conditions, the lessons learned may eventually help explain many cases along the autism spectrum.

Collaborating to improve understanding

Nord's work bridges disciplines and has incorporated diverse collaborators. The genetic mouse model was developed at Lawrence Berkeley National Laboratory using CRISPR editing technology, and co-authors Jacqueline Crawley and Jill Silverman of the UC Davis MIND Institute evaluated mouse behavior to characterize social interactions and cognitive impairments.

Nord also partnered with co-author Konstantinos Zarbalis of the Institute for Pediatric Regenerative Medicine at UC Davis to examine changes in cell proliferation in the brains of mice with the CHD8 mutation, and with Jason Lerch from the Mouse Imaging Centre at the Hospital for Sick Children in Toronto, Canada, to conduct magnetic resonance imaging on mouse brains.

"It's the act of collaboration that I find really satisfying," Nord said. "The science gets a lot more interesting and powerful when we combine different approaches. Together we were able to show that mutation to CHD8 causes changes to brain development, which in turn alters brain anatomy, function and behavior."

In the future, Nord hopes to identify how CHD8 packages DNA in neural cells and to determine the specific impacts to early brain development and synaptic function. Nord hopes that deep exploration of CHD8 mutations will ultimately yield greater knowledge of the general factors contributing to ASD and intellectual disability.

Explore further: Study shows connection between key autism risk genes in the human brain

More information: Andrea L Gompers et al. Germline Chd8 haploinsufficiency alters brain development in mouse, Nature Neuroscience (2017). DOI: 10.1038/nn.4592

Journal reference: Nature Neuroscience

Provided by: UC Davis

A new study reveals an important connection between dozens of genes that may contribute to autism, a major step toward understanding how brain development goes awry in some individuals with the disorder.

In a collaboration involving 13 institutions around the world, researchers have broken new ground in understanding what causes autism. The results are being published in Cell magazine July 3, 2014: "Disruptive CHD8 Mutations ...

Autistic-like behaviors and decreased cognitive ability may be associated with disruption of the function of the Adenomatous Polyposis Coli (APC) gene. When Tufts researchers deleted the gene from select neurons in the developing ...

Scientists studying the role of a protein complex in the normal development of the mouse brain unexpectedly created a mouse model that replicates clinical symptoms of patients with complex neurological disorders such as hyperactivity, ...

In the nucleus of eukaryotic cells, DNA is packaged with histone proteins into complexes known as chromatin, which are further compacted into chromosomes during cell division. Abnormalities in the structure of chromosomes ...

A new Northwestern Medicine study found evidence suggesting how neural dysfunction in a certain region of the brain can lead to obsessive and repetitive behaviors much like obsessive-compulsive disorder (OCD).

While the definitive causes remain unclear, several genetic and environmental factors increase the likelihood of autism spectrum disorder, or ASD, a group of conditions covering a "spectrum" of symptoms, skills and levels ...

Many cognitive processes, such as decision-making, take place within seconds or minutes. Neuroscientists have longed to capture neuron activity during such tasks, but that dream has remained elusiveuntil now.

Many genes linked to late-onset Alzheimer's disease (AD) are expressed in myeloid cells and regulated by a single protein, according to research conducted at the Icahn School of Medicine at Mount Sinai and published June ...

Neuroscientists from the University of Chicago have developed a computer model that can simulate the response of nerves in the hand to any pattern of touch stimulation on the skin. The tool reconstructs the response of more ...

Viruses have evolved to be highly effective vehicles for delivering genes into cells. Seeking to take advantage of these traits, scientists can reprogram viruses to function as vectors, capable of carrying their genetic cargo ...

Since scientists began studying the brain, they have asked whether the biology they observed can really be tied to external behaviors. Researchers are building a substantial understanding of the biophysical, molecular, and ...

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Mice provide insight into genetics of autism spectrum disorders - Medical Xpress

Two new studies suggest that one in five seemingly healthy people hasDNA mutations that puts him or herat increased risk for genetic disease.

BlackJack3D/iStockPhoto

By Ryan CrossJun. 26, 2017 , 6:15 PM

Some doctors dream of diagnosing diseasesor at least predicting disease riskwith a simple DNA scan. But others have said the practice, which could soon be the foundation of preventative medicine, isnt worth the economic or emotional cost. Now, a new pair of studies puts numbers to the debate, and one is the first ever randomized clinical trial evaluating whole genome sequencing in healthy people. Together, they suggest that sequencing the genomes of otherwise healthy adults can for about one in five people turn up risk markers for rare diseases or genetic mutations associated with cancers.

What that means for those people and any health care system considering genome screening remains uncertain, but some watching for these studies welcomed the results nonetheless. It's terrific that we are studying implementation of this new technology rather than ringing our hands and fretting about it without evidence, says Barbara Biesecker, a social and behavioral researcher at the National Human Genome Research Institute in Bethesda, Maryland.

The first genome screening study looked at 100 healthy adults who initially reported their family history to their own primary care physician. Then half were randomly assigned to undergo an additional full genomic workup, which cost about $5000 each and examined some 5 million subtle DNA sequence changes, known as single-nucleotide variants, across 4600 genessuch genome screening goes far beyond that currently recommended by the American College of Medical Genetics and Genomics (ACMG), which suggests informing people of results forjust 59 genes known or strongly expected to cause disease.

Of the 50 participants whose genomes were sequenced, 11 had alterations in at least one letter of DNA suspected to causeusually rarediseases, researchers report today in The Annals of Internal Medicine. But only two exhibited clear symptoms. One was a patient with extreme sensitivity to the sun. Their DNA revealed a skin condition called variegate porphyria. Now that patient knows they will be much less likely to get bad sunburns or rashes if they avoid the sun and certain medications, says Jason Vassy, a primary care clinician-investigator at Veteran Affairs Boston Healthcare System and lead author of the study.

The team also found that every sequenced patient carried at least one recessive mutation linked to a diseasea single copy of a mutant gene that could cause an illness if two copies are present. That knowledge can be used to make reproductive decisionsa partner may get tested to see if they have a matching mutationand prompt family members to test themselves for carrier status. And in what Vassy calls a slightly more controversial result, the team examined participants chances of developing eight polygenic diseases, conditions that are rarely attributed to a single genetic mutation. Here, they compiled the collective effects of multiple genesup to 70 for type II diabetes and 60 for coronary heart diseaseto predict a patients relative risk of developing the disease.

Just 16% of study volunteers who only reported their family history were referred to genetic counselors or got follow-up laboratory tests. In the genome sequencing group, the number was 34%.

Some researchers have expressed concern that such whole genome screening will skyrocket medical costs or cause undue psychological harm. Aside from the initial cost of sequencing (which was covered by the study), patients who underwent the genomic screen paid an average of $350 additional in healthcare costs over the next 6 months, Vassy and colleagues reported. But contrary to fears of emotional trauma, neither the sequencing group nor the control group showed any changes in anxiety or depression 6 months after the study.

Vassy stresses that their study was small and needs follow-up, but it still impressed Christa Martin, a geneticist at Geisinger Health System, in Danville, Pennsylvania, who worked on the ACMGs recommendations for genome sequencing. I almost feel like the authors undersold themselves, she says. Many of their patients are making health behavioral changes, so they are using the information in a positive way.

The study was extremely well designed and very appropriately run, adds Barbara Koenig, a medical anthropologist who directs the University of CaliforniaSan Francisco Bioethics Program. But she still questions the assumption by many physicians, ethicists, and patient advocates that more information is always beneficial. It is just hard to know how all this information is going to be brought together in our pretty dysfunctional healthcare system.

Another paper published last week on the preprint server bioRxiv, which has not yet undergone peer review, yields similar results. Using whole-exome sequencing, which looks only at the protein-coding regions of the genome, Michael Snyder, director of the Stanford Center for Genomics and Personalized Medicine in Palo Alto, California, and colleagues found that 12 out of 70 healthy adults, or 17%, unknowingly had one or more DNA mutations that increased the risk for genetic diseases for which there are treatment or preventative options.

Both studies suggest that physicians should look at genes beyond the ACMGs 59 top priorities, Snyder says. He argues that whole-genome sequencing should be automatically incorporated into primary care. You may have some super-worriers, but I would argue that the information is still useful for a physician to have. Vassy, however, says that there isnt yet enough evidence to ask insurance companies to reimburse whole genome sequencing of healthy patients.

We like a quick fix and the gene is an important cultural icon right now, so we probably give it more power than it really has, Koenig says. But these are still really early days for these technologies to be useful in the clinic.

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One in five 'healthy' adults may carry disease-related genetic mutations - Science Magazine